No file available
To read the file of this research,
you can request a copy directly from the authors.
Inhalable Lactoferrin–Chondroitin Nanocomposites for Combined Delivery of Doxorubicin and Ellagic Acid to Lung Carcinoma
Preprints and early-stage research may not have been peer reviewed yet.
Abstract
Aim:
The use of inhalable nanomedicines can overcome the Enhanced permeation and retention effect (EPR)-associated drawbacks in lung cancer therapy via systemic nanomedicines.
Methods:
We developed a lactoferrin-chondroitin sulfate nanocomplex for the co-delivery of doxorubicin and ellagic acid nanocrystals to lung cancer cells. Then, the nanocomplex was converted into inhalable nanocomposites via spray drying.
Results:
The resulting 192.3 nm nanocomplex exhibited a sequential faster release of ellagic acid, followed by doxorubicin. Furthermore, the nanocomplex demonstrated superior cytotoxicity and internalization into A549 lung cancer cells mediated via Tf and CD44 receptors. The inhalable nanocomposites exhibited deep lung deposition (89.58% fine particle fraction (FPF)) with powerful antitumor efficacy in lung cancer bearing mice.
Conclusion:
Overall, inhalable lactoferrin-chondroitin sulfate nanocomposites would be a promising carrier for targeted drug delivery to lung cancer.
... The findings of AbdElwakil and his colleagues support the use of nanocarriers for this purpose after in vivo investigation; their findings demonstrate that tumor growth biomarkers respond to a system of microencapsulated nano complexes bearing less amount of medicines compared to the ordinary injectable forms. 48 Moreover, gold nanoparticles have been inspected in inhalation drug delivery for treating lung cancer. Results were encouraging as accumulated levels of the medicines were measured in the target tissues.Another advantage of the use of gold nanoparticles is the ability to attach variable moieties to increase the specificity and potency of the medication. ...
Nanotechnology innovations have a positive impact on multidisciplinary health sectors, in particular, drug delivery. Variable nanocarriers were utilized in order to decrease systemic toxicity and enhance the delivery of drug particles to the targeted tissues. Systemic delivery of medicines through the pulmonary route of administration is still within limited boundaries. Delivering medicines loaded into nanoparticles through the pulmonary route for treating chronic and acute diseases such as diabetes, cancers, and even hormone therapy would be a novelty. Nanocarriers include lipid nanoparticles, liposomes, nano-emulsions, solid lipid nanoparticles, non-structured lipid carriers, and Multifarious inhaled Lipid-Based Nanocarriers. Promising results were obtained after delivering cytotoxic, hypoglycemic and anabolic agents. Although revolution in drug delivery and enhancements of drug efficacy are predicted, limitations and health hazards have to be taken into consideration. Physical stability, high loading capacity, good adhesion to the pulmonary wall are among the formulation supremacy. Also from a patient perspective, inhaled drugs carried by nanoparticles have minor side effects, faster response, more convenience to carry, and wide dosage intervals. Disadvantages range from expelling the minute particles which could result in delivering sub-effective doses to more serious health problems such as increased thrombosis activity.
... The concept is to simultaneously target a multiplicity of malignant pathways as a novel strategy. Many recent preclinical and clinical experiments have shown that combined treatment of multiple compounds utilizing nano-formulations improves OVC therapy outcomes [19][20][21][22]. ...
According to the world cancer research fund international (WCRFI), ovarian cancer is considered the 8th-most prevalent form of cancer in women, with approximately 313,000 new cases recorded in 2020. The high emergence of chemoresistance, recurrence, and harmful side effects imposed by currently existing treatments, viz., chemotherapy, radiation therapy, and surgical debulking, generates a void for effective therapeutic options. The traditional paradigm of a single target approach, based on Ehrlich's magic bullets, for a disease with multiple complexities has been challenged by the new concept of magic shotguns, which simultaneously alleviates multiple causes and pathways responsible for the disease. The relevance of various natural and synthetic polymeric nanoparticles for the delivery of anti-cancer agent(s) with the capacity to target multiple active receptors can provide an effective therapy coupled with a lower incidence of recurrence. Such systems offer high synergy, low dose dependent side effects, overcome multidrug resistance, and benefit the metastatic stage of ovarian cancer treatment. As a practical matter, it would be advantageous to create a "magic shotgun" that can deliver promiscuous chemotherapeutic agents, encased in polymeric nanoparticles, to multiple targets with significantly improved biopharmaceutical attributes over existing conventional therapy. In this article, we discuss in detail the nanotechnology-based approach to treating ovarian cancer, including the genetic pathways involved and the future prospects of the magic shotgun approach.
... Another study demonstrated that the stability and antioxidant activity of EGCG could be enhanced by binding with BSAi-carrageenan nanocomplex [64] . Similarly, the complex of Lactoferrin-chondroitin has been used for the combined delivery of doxorubicin and ellagic acid for enhanced anti-tumour activity and ultimately improve in vitro/in vivo transport of drugs [65] . ...
Protein has been used as the carrier for protecting and targeting polyphenols and increasing their shelf-life. Interactions of a protein molecule with polyphenols are important, which change functions and physiochemical properties of the complex and provide protection to polyphenols. Interactions between proteins and polyphenols are largely non-covalent. Factors that affect such interactions include pH, temperature, and the structure of both proteins and polyphenols. Moreover, excellent stability of polyphenols can be achieved by using nanoencapsulation techniques such as emulsion, nanohydrogel, and nanocomplex formation. The use of protein combined with other compounds such as lipids and carbohydrates was found to be the most suitable carrier for polyphenols encapsulation. This review aims to describe the interaction between proteins and polyphenols, focusing on applying nanoencapsulation for increasing stability and targeted delivery of phenolic compounds.
... Combining the pronounced benefits of both Lf and ChS in one nanosystem may possibly generate a promising complex for targeting lung tumor cells. 11 There has been an increasing interest in research on Quer; a natural flavonoid found in plants for its satisfying biological properties. 12-13 Quer has a potent anticancer, antiinflammatory, antibacterial and antioxidant properties owing to its capability of producing reactive oxygen species (ROS). ...
In view of the promising applications of nanoparticles in drug delivery, this study highlights the fabrication of new bioactive green protein–polysaccharide nanocomplexes with significant antibacterial and antitumor efficacies. We preformulated the water-insoluble drugs Quercetin (Quer) and Resveratrol (Res) as water-soluble nanocrystals to facilitate their entrapment in the electrostatic lactoferrin–chondroitin (Lf-ChS) nanocomplex. Quer and Res were physically entrapped in the Lf-ChS nanomatrix with high encapsulation efficiencies (EE %) of 85.2 and 90.1% w/w for Quer and Res, respectively. The in vitro synergetic antibacterial effects of the studied compounds against all bacterial strains were confirmed. Res-Quer Lf-ChS NPs revealed an enhanced cytotoxic effect against A549 lung cancer cells. A new model of polymicrobial lung infection was designed, where treatment with Res-Quer Lf-ChS NPs (233.5 ± 6.59 nm) resulted in a marked decline of 3.2 log units in bacterial counts. In the lung tumor model, the potent antitumor efficacy of the developed Res-Quer Lf-ChS NPs was demonstrated by a noticeable decline in both lung weight and the biomarkers compared to the positive control group that did not receive any treatment. In conclusion, the green Res-Quer Lf-ChS NPs possess antibacterial and antitumor attributes for potential lung infection and tumor therapy.
Apocynin (APO) is a plant derived antioxidant exerting specific NADPH oxidase inhibitory action substantiating its neuroprotective effects in various CNS disorders, including epilepsy. Due to rapid elimination and poor bioavailability, treatment with APO is challenging. Correspondingly, novel APO-loaded lipid nanocapsules (APO-LNC) were formulated and coated with lactoferrin (LF-APO-LNC) to improve br ain targetability and prolong residence time. Lavender oil (LAV) was incorporated into LNC as a bioactive ingredient to act synergistically with APO in alleviating pentylenetetrazol (PTZ)-induced seizures. The optimized LF-APO-LAV/LNC showed a particle size 59.7 ± 4.5 nm with narrow distribution and 6.07 ± 1.6mV zeta potential) with high entrapment efficiency 92 ± 2.4% and sustained release (35% in 72 h). Following subcutaneous administration, LF-APO-LAV/LNC brought about ⁓twofold increase in plasma AUC and MRT compared to APO. A Log BB value of 0.2 ± 0.14 at 90 min reflects increased brain accumulation. In a PTZ-induced seizures rat model, LF-APO-LAV/LNC showed a Modified Racine score of 0.67 ± 0.47 with a significant increase in seizures latency and decrease in duration. Moreover, oxidant/antioxidant capacity and inflammatory markers levels in brain tissue were significantly improved. Histopathological and immunohistochemical assessment of brain tissue sections further supported these findings. The results suggest APO/LAV combination in LF-coated LNC as a promising approach to counteract seizures.
Graphical Abstract
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties.
Graphical abstract
This picture was generated with BioRender
Although there are many treatment advances in oncology, cancer remains the cause of morbidity and mortality worldwide. The most common cancer types diagnosed in men are lung and prostate cancer. The use of anticancer drugs is known as the best strategy for the treatment of these cancer types. However, various limitations exist, including multidrug resistance, poor tumor tissue drug accumulation, and nonspecific cytotoxicity or off-target effects. On the other hand, combination chemotherapy is the most promising one, with numerous advantages among the approaches employed to solve the drawbacks. On the other hand, polymer-based nanomedicines are drug delivery systems that can further enhance the therapeutic outcomes of combination chemotherapy. This book chapter reports the preclinical results of polymer-based nanomedicines co-encapsulated with anticancer agents for efficient lung and prostate cancer therapy. This chapter discusses the challenges and advantages of nanomedicine; especially the delivery routes (e.g., by using nanoparticles, dendrimers, micelle, drug conjugate, nanocapsules, nanoliposomes, exosome, noisome, nanogel, etc.) are elaborated. Furthermore, a brief scenario of clinical trials and future perspectives using these approaches are discussed in this chapter.
Cervical cancer is one of the foremost common cancers in women. Lactoferrin (LF) has many biological functions, such as antitumor. This study aimed to explore the regulatory effect of bovine lactoferrin (bLF) on the proliferation and apoptosis of cervical cancer HeLa cells and to clarify the potential mechanism of action of bLF against HeLa cells. This study used CCK‐8, Trypan blue staining, and colony formation assays to verify the effect of bLF on HeLa cell proliferation. Hoechst 33258 fluorescence staining, AO/EB staining, and western blotting were used to determine the effects of bLF on apoptosis and autophagy in HeLa cells. We discovered that bLF significantly reduced the proliferation of HeLa cells in a dose‐ and time‐dependent manner compared to the control group. Furthermore, bLF primarily induced apoptosis in HeLa cells by increasing the expression of the proapoptotic proteins p53, Bax, and Cleaved‐caspase‐3 and downregulating the expression of the antiapoptotic protein Bcl‐2. In addition, the present study also showed that bLF treatment significantly activated autophagy‐related proteins LC3B‐II and Beclin I and down regulated the autophagosome transporter protein p62, indicating that bLF treatment can induce autophagy in HeLa cells. After pretreatment with the autophagy inhibitor, 3‐MA, which markedly found that autophagy inhibition by 3‐MA reversed bLF‐induced apoptosis, indicating that bLF can induce apoptosis by activating intracellular autophagy in HeLa cells. In the present study, our results support the theory of bLF significantly inhibited the proliferation of Hela cells by promoting apoptosis and reinforcing autophagy. The study will play an important role in therapying cervical cancer.
Background
Lung cancer is the second most lethal type of cancer, with a poor survival rate of 5 years. It is one of those malignant tumors that has grown most rapidly in the context of mortality and morbidity.
Aim
This review article aims to provide insight into current nanotechnological approaches taken into consideration that provide advantages over conventional chemotherapy.
Result and Discussion
After comparing conventional chemotherapy and nanotechnology-based therapies for lung cancer, the results showed that recent advances in nanomaterials proved to be more effective in lung cancer diagnosis, mitigation and treatment. Here, Surface-engineered smart nanocarrier-based inhalations, Bio-nanocarriers for lung cancer, gas plasma nanoparticles, and magnetic nanoparticles are discussed.
Conclusion
After summarizing these nanomaterials, investigators concluded that the in-vivo and invitro effectiveness of recently developed nanoparticles was found to be better than that of conventional nanoparticles.
Lung cancer is the leading cause of cancer-related death. In addition to new innovative approaches, practical strategies that improve the efficacy of already available drugs are urgently needed. In this study, an inhalable dry powder formulation is used to repurpose flubendazole, a poorly soluble anthelmintic drug with potential against a variety of cancer lineages. Flubendazole nanocrystals were obtained through nanoprecipitation, and dry powder was produced by spray drying. Through fractional factorial design, the spray drying parameters were optimized and the impact of formulation on aerolization properties was clarified. The loading limitations were clarified through response surface methodology, and a 15% flubendazole loading was feasible through the addition of 20% L-leucine, leading to a flubendazole particle size of 388.6 nm, median mass aerodynamic diameter of 2.9 μm, 50.3% FPF, emitted dose of 83.2% and triple the initial solubility. Although the cytotoxicity of this formulation in A549 cells was limited, the formulation showed a synergistic effect when associated with paclitaxel, leading to a surprising 1000-fold reduction in the IC50. Compared to 3 cycles of paclitaxel alone, a 3-cycle model combined treatment increased the threshold of cytotoxicity by 25% for the same dose. Our study suggests, for the first time, that orally inhaled flubendazole nanocrystals show high potential as adjuvants to increase cytotoxic agents' potency and reduce adverse effects.
Nowadays, fisetin (FIS) is extensively studied as potent anticancer surrogate with a multitarget actions against various types of cancers including breast cancer. However, its poor aqueous solubility handicapped its clinical utility. The current work endeavored, for the first time, to develop FIS phytosomes (FIS-PHY) for improving its physicochemical properties and subsequently its anticancer activity. Optimization of FIS- phytosomes involved different preparation techniques (Thin film hydration and ethanol injection) and different FIS: phospholipid molar ratios (1:1, 1:2, and 1:3). Complex formation was confirmed by complexation efficiency, infrared spectroscopy (IR), solubility studies and transmission electron microscope. The optimized FIS-PHY of 1:1 molar ratio (PHY1) exhibited a nanometric particle size of 233.01 ± 9.46 nm with homogenous distribution (PDI =0.27), negative zeta potential of - 29.41 mV, 100% complexation efficiency and controlled drug release over 24 h. In-vitro cytotoxicity study showed 2.5-fold decrease in IC50 of PHY1 compared with free FIS. Also, pharmacodynamic studies confirmed the promoted cytotoxicity of PHY1 against breast cancer through modulating TGF-β1/MMP-9 molecular pathways of tumorigenesis. Overall, overcoming FIS drawbacks were successfully achieved through development of innovative biocompatible phytosomal system.
Lactoferrin (LF) is a protein found in several bodily fluids, such as milk. This protein has a diverse range of functions and is evolutionarily conserved. Lactoferrin is a multifunction protein with distinct biological abilities affecting mammals' immune structures. Reports indicated that the daily uptake of LF from dairy products is unsatisfactory in detecting further health-promoting abilities. Research has shown that it protects against infection, mitigates cellular senescence, and improves nutritional quality. Additionally, LF is being studied as a potential treatment for various diseases and conditions, including gastrointestinal issues and infections. Studies have also demonstrated its effectiveness against various viruses and bacteria. In this article, we'll look closer at the structure of LF and its various biological activities, including its antimicrobial, anti-viral, anti-cancer, anti-osteoporotic, detoxifying, and immunomodulatory properties. More specifically, the protective effect of LF against oxidative DNA damage was also clarified through its ability to abolish DNA damaging issues without interfacing with host genetic material. Fortification with LF protects mitochondria dysfunction syndromes via sustaining redox status and biogenesis and suppressing apoptosis and autophagy singling. Additionally, we'll examine the potential benefits of lactoferrin and provide an overview of recent clinical trials conducted to examine its use in laboratory and living models.
Pulmonary delivery is an alternative route of administration with numerous advantages over conventional routes of administration. It provides low enzymatic exposure, fewer systemic side effects, no first-pass metabolism, and concentrated drug amounts at the site of the disease, making it an ideal route for the treatment of pulmonary diseases. Owing to the thin alveolar-capillary barrier, and large surface area that facilitates rapid absorption to the bloodstream in the lung, systemic delivery can be achieved as well. Administration of multiple drugs at one time became urgent to control chronic pulmonary diseases such as asthma and COPD, thus, development of drug combinations was proposed. Administration of medications with variable dosages from different inhalers leads to overburdening the patient and may cause low therapeutic intervention. Therefore, products that contain combined drugs to be delivered via a single inhaler have been developed to improve patient compliance, reduce different dose regimens, achieve higher disease control, and boost therapeutic effectiveness in some cases. This comprehensive review aimed to highlight the growth of drug combinations by inhalation over time, obstacles and challenges, and the possible progress to broaden the current options or to cover new indications in the future. Moreover, various pharmaceutical technologies in terms of formulation and device in correlation with inhaled combinations were discussed in this review. Hence, inhaled combination therapy is driven by the need to maintain and improve the quality of life for patients with chronic respiratory diseases; promoting drug combinations by inhalation to a higher level is a necessity.
Background:
Cardiovascular disease (CVD) is a significant worldwide factor contributing to human fatality and morbidity. With the increase of incidence rates, it is of concern that there is a lack of current therapeutic alternatives because of multiple side effects. Ellagic acid (EA), the natural polyphenol (C14H6O8), is abundant in pomegranates, berries, and nuts. EA and its intestinal microflora metabolite, urolithins, have recently attracted much attention as a potential novel "medicine" because of their wide pharmacological properties.
Purpose:
This study aimed to critically analyze available literature to summarize the beneficial effects of EA and urolithins, and highlights their druggability and therapeutic potential in various CVDs.
Methods:
We systematically studied research and review articles between 1984 and 2022 available on various databases to obtain the data on EA and urolithins with no language restriction. Their cardiovascular protective activities, underlying mechanism, and druggability were highlighted and discussed comprehensively.
Results:
We found that EA and urolithins may exert preventive and curative effects on CVD with negligible side effects and possibly regulate lipid metabolism imbalance, pro-inflammatory factor production, vascular smooth muscle cell proliferation, cardiomyocyte apoptosis, endothelial cell dysfunction, and Ca2+ intake and release. Potentially, this may lead to the prevention and amelioration of atherosclerosis, hypertension, myocardial infarction, cardiac fibrosis, cardiomyopathy, cardiac arrhythmias, and cardiotoxicities in vivo. Several molecules and signaling pathways are associated with their therapeutic actions, including phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, NF-κB, nuclear factor erythroid-2 related factor 2, sirtuin1, miRNA, and extracellular signal-regulated kinase 1/2.
Conclusion:
In vitro and in vivo studies shows that EA and urolithins could be used as valid candidates for early prevention and effective therapeutic strategies for various CVDs.
Despite current progress in the development of targeted therapies for cancer treatment, there is a lack in convenient therapeutics for colorectal cancer (CRC). Lactoferrin nanoparticles (Lf NPs) are a promising drug delivery system in cancer therapy. However, numerous obstacles impede their oral delivery, including instability against stomach enzymes and premature uptake during passage through the small intestine. Microencapsulation of Lf NPs offer a great solution for these obstacles. It can protect Lf NPs and their drug payloads from degradation in the upper gastrointestinal tract (GIT), reduce burst drug release, and improve the release profile of the encapsulated NPs triggered by stimuli in the colon. Here, we developed nanoparticle-in-microparticle delivery systems (NIMDs) for the oral delivery of docetaxel (DTX) and atorvastatin (ATR). The NPs were obtained by dual conjugation of DTX and ATR into the Lf backbone, which was further microencapsulated into calcium-crosslinked microparticles using polysaccharide-protein hybrid copolymers. The NIMDs showed no detectable drug release in the upper GIT compared to NPs. Furthermore, sustained release of the NPs from the NIMDs in rat cecal content was observed. Moreover, the in vivo study demonstrated the superiority of the NIMDs over NPs in CRC treatment by suppressing p-AKT, p-ERK1/2, and NF-κB. This study provides the proof of concept for using NIMDs to enhance the effect of protein NPs in CRC treatment.
Chronic respiratory disorders (CRDs) have been identified by the WHO as one of the major causes of worldwide death and disability burden, impacting people from all socioeconomic backgrounds. Despite advances in diagnostic and therapeutic approaches, effective treatment of CRDs remains a challenge as most drugs face difficulty reaching the lower respiratory tract at ideal concentrations with minimal adverse effects. Therefore, there is an urgent need to improve the quality of respiratory disease therapies in an efficient and cost-effective manner. For many years, nontoxic and biocompatible polymers of natural origin have been used as a carrier system to improve the pharmacokinetics and therapeutics of the drug molecules. Animal-derived polymers such as hyaluronic acid, albumin, collagen, gelatin, and chondroitin are widely used among other natural polymers because biocompatibility issues are often avoided. Among animal-derived polymers, gelatin has been extensively researched as a drug delivery carrier for many classes of drugs because of its ease of availability, excellent stability, biocompatibility, biodegradability, simple fabrication, and ability to modify drug release behavior and potential to restrain drug degradation. Gelatin as a polymer in drug delivery has been reported in various carrier-based systems, including nanoparticles, microspheres, microparticles, and micelles, with advantages for pulmonary delivery, including an enormous circulation to lung epithelial cells and higher accessibility of bioactive particles to infected cells. Hyaluronic acid and chondroitin sulphate are potentially multifunctional polymers, which are also found in the lungs and widely used for the treatment of lung disorders because of their intrinsic therapeutic potential, physicochemical, and biological features like biocompatibility, biodegradability, nonimmunogenicity, and improved drug targeting and prolonged release. A variety of carrier-based systems incorporating hyaluronic acid as a polymer (liposomes, micro/nanoparticles) has also been reported for the treatment of various lung disorders in an efficient manner. Using these polymers in lung drug delivery methods could help with biocompatibility issues.
Lactoferrin (LF) is a multifunctional iron-binding glycoprotein that exhibits a variety of properties, such as immunomodulatory, anti-inflammatory, antimicrobial, and anticancer, that can be used to treat numerous diseases. Lung diseases continue to be the leading cause of death and disability worldwide. Many of the therapies currently used to treat these diseases have limited efficacy or are associated with side effects. Therefore, there is a constant pursuit for new drugs and therapies, and LF is frequently considered a therapeutic agent and/or adjunct to drug-based therapies for the treatment of lung diseases. This article focuses on a review of the existing and most up-to-date literature on the contribution of the beneficial effects of LF on the treatment of lung diseases, including asthma, viral infections, cystic fibrosis, or lung cancer, among others. Although in vitro and in vivo studies indicate significant potency of LF in the treatment of the listed diseases, only in the case of respiratory tract infections do human studies seem to confirm them by demonstrating the effectiveness of LF in reducing episodes of illness and shortening the recovery period. For lung cancer, COVID-19 and sepsis, the reports are conflicting, and for other diseases, there is a paucity of human studies conclusively confirming the beneficial effects of LF.
Nanocomposites have become a promising approach for drug delivery in the pharmaceutical field due to several benefits and current research development. Polymer nanocomposites (PNCs) are blends of nanomaterials and polymers with at least one-dimensional structure and one component in the sub-100 nm range. By incorporating nanoparticles into the polymer matrix, it is feasible to create a new class of given characteristics. Nano-clay (a type of nanocomposite) is mainly used for the controlled release of therapeutics in various disease conditions. Nanocomposites are promising drug delivery systems due to several advantages, including surface and rheological characteristics. Considering physical and chemical properties, nanocomposites are divided into two different components. Polymer-fabricated nanocomposites are potentially used in multi-particulate systems, which results in a controlled drug release profile with improved mechanical integrity. Nanotechnology-based drug delivery nanocomposites offer an improved half-life, greater biocompatibility, minimum immunogenicity, site-specific targeting, and avoid membrane barriers. Specifically, one-dimensional (1D) nanocomposites show promising responses in theranostics due to improved surface area-to-volume ratios that offer specific targeting, improved encapsulation efficiency, and susceptibility to biomolecules.
A primary illness that accounts for a significant portion of fatalities worldwide is cancer. Among the main malignancies, lung cancer is recognised as the most chronic kind of cancer around the globe. Radiation treatment, surgery, and chemotherapy are some medical procedures used in the traditional care of lung cancer. However, these methods lack selectivity and damage nearby healthy cells. Several polysaccharide-based nanomaterials have been created to transport chemotherapeutics to reduce harmful and adverse side effects and improve response during anti-tumour reactions. To address these drawbacks, a class of naturally occurring polymers called polysaccharides have special physical, chemical, and biological characteristics. They can interact with the immune system to induce a better immunological response. Furthermore, because of the flexibility of their structures, it is possible to create multifunctional nanocomposites with excellent stability and bioavailability for the delivery of medicines to tumour tissues. This study seeks to present new views on the use of polysaccharide-based chemotherapeutics and to highlight current developments in polysaccharide-based nanomedicines for lung cancer.
Chondroitin sulfate (CS), a natural anionic mucopolysaccharide, belonging to the glycosaminoglycan family, acts as the primary element of the extracellular matrix (ECM) of diverse organisms. It comprises repeating units of disaccharides possessing β-1,3-linked N-acetyl galactosamine (GalNAc), and β-1,4-linked D-glucuronic acid (GlcA), and exhibits antitumor, anti-inflammatory, anti-coagulant, anti-oxidant, and anti-thrombogenic activities. It is a naturally acquired bio-macromolecule with beneficial properties, such as biocompatibility, biodegradability, and immensely low toxicity, making it the center of attention in developing biomaterials for various biomedical applications. The authors have discussed the structure, unique properties, and extraction source of CS in the initial section of this review. Further, the current investigations on applications of CS-based composites in various biomedical fields, focusing on delivering active pharmaceutical compounds, tissue engineering, and wound healing, are discussed critically. In addition, the manuscript throws light on preclinical and clinical studies associated with CS composites. A short section on Chondroitinase ABC has also been canvassed. Finally, this review emphasizes the current challenges and prospects of CS in various biomedical fields.
Nanomedicine, the theranostic interventions of nanotechnology provides an effective option over the conventional medicine. Through nanoengineering, tailor-made properties in terms of size, shape and chemical composition can be achieved which enables its enhanced interaction with the biological targets of interest and thereby ensures the effectual bioavailability of the bioactive component along with its sustained release. Even though the therapeutic value of the herbal medicines has been identified since long ago, the low absorption and bioavailability of these compounds greatly limited its applications. The development of nano-drug delivery systems offer opportunities to magnify the solubility, membrane permeation, absorptive endocytosis and sustained release which results in lower plasma fluctuations, and minimal side effects and hence have the promises for upscaling the functioning of various phytomedicines. Here, the nano formulation of the active ingredients can ensure its improved bio- distribution, precision targeting onto the pathological tissues and thereby protecting the healthy tissues through maintaining the lower dose. Nanomedicine has found its applications both in diagnostics and treatment of regenerative medicine, wherein nanorobots have been efficient in cell repair and targeted delivery, thereby supporting the growth of normal healthy cells. The treatment of mitochondrial dysfunctions, identified as the major underlying cause behind various diseases including cardiovascular diseases, neurological disorders, cancer and diabetes has posed a greater challenge owing to the inaccessibility of the drug into the compartmentalized organelle. The varied properties of nanoparticles viz biodegradation, fluorescence, near-infrared absorption and magnetization can aid in the development of various nanohybrid platforms for mitochondrial targeting of the therapeutics. The ability of the nanomedicine to integrate into various combinatorial therapies and immunotherapy can be exploited in the cancer and regenerative medicine. The current chapter thus focus on the cutting-edge intrusions in nanomedicines and its benefits over the conventional medicines.
Albeit its established efficacy as an anti-hyperlipidemic agent, pitavastatin (PIT) has been shown to have other various therapeutic effects. One of these effects is the anti-cancer activity against hepatocellular carcinoma (HCC). This effect has been evaluated in this study for the first time via its oral delivery loaded in bilosomes both in vitro in hepatocellular carcinoma (HCC) cell line; HepG2 and in vivo in an Ehrlich ascites carcinoma (EAC) model. Moreover, the impact of surface modification of bilosomes with lactoferrin (LF) as an active targeting ligand for HCC was investigated. Bilosomes were prepared by thin-film hydration and different molar phospholipid to bile salt ratios were used to optimize the bilosomal formulation. The molar phospholipid to bile salt ratio was adjusted to 4:1 at pH 7.4. LF-coated bilosomes possessed a particle size, PDI, entrapment efficiency, and zeta potential of 112.28 nm ± 6.35, 0.229 ± 0.06, 90.56% ± 3.22, and −7.86 mV ± 1.13, respectively. LF-coated bilosomes also increased permeation of PIT when tested on Caco-2 cells by 3.1-folds (compared to uncoated ones or free PIT solution). It also improved the cytotoxicity of HepG2 spheroids 44-folds more than PIT-free solution. RT-PCR analysis showed that LF-coated PIT-loaded bilosomes caused an improvement (2-fold increase) in the apoptotic potential of PIT mediated by caspase-3. In conclusion, the optimized LF-coated PIT-loaded bilosomes were cytotoxic to HCC with improved hepatocytes permeation and cellular uptake. Thus, the proposed formula could be a promising treatment for HCC.
Metastases are the consequence of a complicated process in which malignant cells detach from the initial cancerous cells and disseminate to other locations. Few therapy options are available that aim to prevent or counteract metastatic disorders. Identifying novel molecular targets and medications, developing techniques to distribute preexisting chemicals, and combining resources to supervise individualized treatment are all part of this process. Because of its improved sensitivity, accuracy, and multiplexed measurement capacity, nanotechnology has been investigated for the recognition of extracellular cancer biomarkers, cancer cells, and in bioimaging. Nanotechnology is a vast and rapidly expanding field with enormous potential in cancer treatment. Nanoparticles can treat resistant cancers with minimal harm to healthy tissues and organs by targeting cancer stem cells. Nanoparticles can also trigger immune cells, which can help to destroy malignancies. The potential of herbal-based nano formulation as a specialized and high-efficacy therapeutic method, opening the path for future research into the screening and use of herbal nanoparticles for cancer treatment. The possible impacts of nanoparticles in the therapy of metastatic cancer, specifically on cell stability, proliferation suppression, eventual interaction with adhesion molecules, and antiangiogenic activity, are discussed in this paper.
Lactoferrin (LF) is a naturally present iron-binding globulin with the structural properties of an N-lobe strongly positively charged terminus and a cage-like structure of nano self-assembly encapsulation. These unique structural properties give it potential for development in the fields of electrostatic spinning, targeted delivery systems, and the gut-brain axis. This review will provide an overview of LF's unique structure, encapsulation, and targeted transport capabilities, as well as its applications in immunity and gut microbiota regulation. First, the microstructure of LF is summarized and compared with its homologous ferritin, revealing both structural and functional similarities and differences between them. Second, the electrostatic interactions of LF and its application in electrostatic spinning are summarized. Its positive charge properties can be applied to functional environmental protection packaging materials and to improving drug stability and antiviral effects, while electrostatic spinning can promote bone regeneration and anti-inflammatory effects. Then the nano self-assembly behavior of LF is exploited as a cage-like protein to encapsulate bioactive substances to construct functional targeted delivery systems for applications such as contrast agents, antibacterial dressings, anti-cancer therapy, and gene delivery. In addition, some covalent and noncovalent interactions of LF in the Maillard reaction and protein interactions and other topics are briefly discussed. Finally, LF may affect immunological function via controlling the gut microbiota. In conclusion, this paper reviews the research advances of LF in electrostatic spinning, nano self-assembly, and immune and gut microbiota regulation, aiming to provide a reference for its application in the food and pharmaceutical fields.
Chemotherapy drugs have been used for a long time in the treatment of cancer, but serious side effects are caused by the inability of the drug to be solely delivered to the tumor when treating cancer with chemotherapy. Natural products have attracted more and more attention due to the antitumor effect in multiple ways, abundant resources and less side effects. Therefore, the combination of natural active ingredients and chemotherapy drugs may be an effective antitumor strategy, which can inhibit the growth of tumor and multidrug resistance, reduce side effects of chemotherapy drugs. Nano-drug co-delivery system (NDCDS) can play an important role in the combination of natural active ingredients and chemotherapy drugs. This review provides a comprehensive summary of the research status and application prospect of nano-delivery strategies for the combination of natural active ingredients and chemotherapy drugs, aiming to provide a basis for the development of anti-tumor drugs.
The development of bioactive components as a delivery system with the use of advanced nanoscience is opening new therapeutic avenues for the management of various diseases. Among recent novel applications, plant phytopharmaceuticals and nutraceuticals are the fastest growing areas of nanotechnology-based research for effective public healthcare. Bioactive compounds, either encapsulated or in entrapped form within novel drug delivery systems are reported as a booster treatment for the various chronic infections and life-threatening diseases, including cancer, cardiovascular disorders, hypertension, diabetes, asthma, malaria, microbial infections, immune disorders, and gastrointestinal disorders. Recently, considerable progress surged in understanding the factors associated with these diseases. A variety of nanoscience-based formulations such as polymeric matrix nanoparticles, aerosol inhalers/nebulizers nanoemulsion, and vesicular carrier systems including liposome, phytosome, transfersome, herbosome, ethosome, niosome, have proven valuable in the delivery of bioactive materials. Moreover, the scientific community had reported that the herbs and herbal bioactive compounds have notable recompense compared to the conventional method of delivering phytopharmaceuticals and plant extracts, with enhanced solubility, bioavailability, stability, tissue distribution, abridged toxicity, improved pharmacological efficacy, and protection from physicochemical degradation. The current chapter focuses on the carrier-based delivery of bioactive as a booster with advanced using nanoscience, such as nanoemulsion and vesicular drug delivery systems. In addition, the chapter also elaborates patented technologies along with potential bioactive products available in the market.
For the treatment and prevention of ocular diseases, eye drops or ointments are generally prescribed to patients. However, these conventional drug formulations suffer from low patient compliance and deliver a suboptimal low drug concentration at the target site. Therefore, new drug–device combinations are being explored to improve drug delivery to the eye.
Various drug–device combinations have been developed in the last few decades, while only a few have made it to the market. In this chapter, we provide a comprehensive overview of drug–device combinations that have reached the final preclinical and clinical stages. We focus on devices that are marketed for ocular diseases such as glaucoma, dry eye disease, infections, and inflammations. Furthermore, drug delivery devices for ocular surgeries are discussed.
Combination of therapeutics delivered by nanoparticles is promising for effective translation of nanomedicine, providing cancer patients with unique advantages such as providing an attractive method to better combat drug resistance, poor effectiveness, and systemic exposure caused by high doses. Many nanotherapeutics have been approved for cancer patients, but effects of these agents on survival have been modest and, at the same time, the clinical achievement created with immunotherapy have revolutionized the treating strategy of multiple advanced-stage malignancies. Nonetheless, future research is needed to discuss protection and biocompatibility, and the attention should be on toxicity particularly.
Chondroitin Sulfate (CS) is an anionic hetero polysaccharide possessing anti-inflammatory, antioxidant, antitumor, anticoagulant and antithrombogenic activities. It is biodegradable and has a high biocompatibility. Further, it inherits the ability of active and subcellular targeting due to its affinity for CD 44 receptors and glycosylation enzymes, which are overexpressed on the surface of tumor cells and intracellular organelles respectively. CS is known to degrade in the presence of physiological stimuli, the hyaluronidase (HAase) enzyme and reactive oxygen species (ROS) assisting in site specific drug release. Due to these properties, it serves as promising biomaterial for drug delivery and tissue engineering. In this review, the fundamental theory of CS, CS-based nanocarriers for the delivery of biopharmaceuticals and stimuli sensitive delivery systems such as HAase and ROS responsive nanocarriers for tumor targeted delivery are discussed critically. In addition, the manuscript describes the application of CS-based tissue constructs in tissue engineering and wound healing.
Pulmonary inhalation administration is an ideal approach to locally treat lung disease and to achieve systemic administration for other diseases. However, the complex nature of the structural characteristics of the lungs often results in the difficulty in the development of lung inhalation preparations. Nanocrystals technology provides a potential formulation strategy for the pulmonary delivery of poorly soluble drugs, owing to the decreased particle size of drug, which is a potential approach to overcome the physiological barrier existing in the lungs and significantly increased bioavailability of drugs. The pulmonary inhalation administration has attracted considerable attentions in recent years. This review discusses the barriers for pulmonary drug delivery and the recent advance of the nanocrystals in pulmonary inhalation delivery. The presence of nanocrystals opens up new prospects for the development of novel pulmonary delivery system. The particle size control, physical instability, potential cytotoxicity, and clearance mechanism of inhaled nanocrystals based formulations are the major considerations in formulation development.
Hybrid protein-inorganic nanoparticles (NPs) have captured the attention for both drug delivery and imaging of tumors owing to utilization of the perks of both inorganic and protein nanocarriers. Herein, numerous chemical and physical techniques of hybridization were utilized for combining iron oxides, gold, silica, calcium phosphate, and gadolinium NPs along with carbon nanotubes and quantum dots. Improvement of colloidal stability, enhancement water dispersibility, and biocompatibility with reduced toxicity were noticed as results of this hybridization. Protein corona is an outstanding topic that influences drug targeting, efficacy, systemic circulation period, and its fate. Understanding various aspects of this phenomena would be implicated in enhancing or hindering expected results of drug delivery.
Lactoferrin (LF) is a whey protein with various and valuable biological activities. For this reason, LF has been used as a supplement in formula milk and functional products. However, it must be considered that the properties of LF can be affected by technological treatments and gastrointestinal conditions. In this article, we have revised the literature published on the research done during the last decades on the development of various technologies, such as encapsulation or composite materials, to protect LF and avoid its degradation. Multiple compounds can be used to conduct this protective function, such as proteins, including those from milk, or polysaccharides, like alginate or chitosan. Furthermore, LF can be used as a component in complexes, nanoparticles, hydrogels and emulsions, to encapsulate, protect and deliver other bioactive compounds, such as essential oils or probiotics. Additionally, LF can be part of systems to deliver drugs or to apply certain therapies to target cells expressing LF receptors. These systems also allow improving the detection of gliomas and have also been used for treating some pathologies, such as different types of tumours. Finally, the application of LF in edible and active films can be effective against some contaminants and limit the increase of the natural microbiota present in meat, for example, becoming one of the most interesting research topics in food technology.
Polysaccharides can be elite carriers for therapeutic molecules due to their versatility and low probability to trigger toxicity and immunogenic responses. Local and systemic therapies can be achieved through particle pulmonary delivery, a promising non-invasive alternative. Successful pulmonary delivery requires particles with appropriate flowability to reach alveoli and avoid premature clearance mechanisms. Polysaccharides can form micro-, nano-in-micro-, and large porous particles, aerogels, and hydrogels. Herein, the characteristics of polysaccharides used in drug formulations for pulmonary delivery are reviewed, providing insights into structure-function relationships. Charged polysaccharides can confer mucoadhesion, whereas the ability for specific sugar recognition may confer targeting capacity for alveolar macrophages. The method of particle preparation must be chosen considering the properties of the components and the delivery device to be utilized. The fate of polysaccharide-based carriers is dependent on enzyme-triggered hydrolytic and oxidative mechanisms, allowing their complete degradation and elimination through urine or reutilization of released monosaccharides.
Lung cancer is the second most common and lethal cancer in the world. Chemotherapy is the preferred treatment modality for lung cancer and prolongs patient survival by effective controlling of tumor growth. However, owing to the nonspecific delivery of anticancer drugs, systemic chemotherapy has limited clinical efficacy and significant systemic adverse effects. Inhalation routes, on the other hand, allow for direct delivery of drugs to the lungs in high local concentrations, enhancing their anti-tumor activity with minimum side effects. Preliminary research studies have shown that inhaled chemotherapy may be tolerated with manageable adverse effects such as bronchospasm and cough. Enhancing the anticancer drugs deposition in tumor cells and limiting their distribution to other healthy cells will therefore increase their clinical efficacy and decrease their local and systemic toxicities. Because of the controlled release and localization of tumors, nanoparticle formulations are a viable option for the delivery of chemotherapeutics to lung cancers via inhalation. The respiratory tract physiology and lung clearance mechanisms are the key barriers to the effective deposition and preservation of inhaled nanoparticle formulations in the lungs. Designing and creating smart nanoformulations to optimize lung deposition, minimize pulmonary clearance, and improve cancerous tissue targeting have been the subject of recent research studies. This review focuses on recent examples of work in this area, along with the opportunities and challenges for the pulmonary delivery of smart nanoformulations to treat lung cancers.
Histone deacetylase inhibitors (HDACi) are cancer therapeutics that operate at the epigenetic level and which have recently gained wide attention. However, the applications of HDACi are generally hindered by their poor physicochemical characteristics and unfavorable pharmacokinetic profile. Inspired by the approved nanomedicine-based drugs in the market, nanocarriers could provide a resort to circumvent the limitations imposed by HDACi. Enhanced tumor targeting, improved cellular uptake and reduced toxicity are major advantages offered by HDACi-loaded nanoparticles. More importantly, site-specific drug delivery can be achieved via engineered stimuli-responsive nanosystems. In this review we elucidate the anticancer mechanisms of HDACi and their structure–activity relationships, with a special focus on their nanomedicine-based delivery, different drug loading concepts and their implications.
Nature offers a wide range of sources of inspiration for the synthesis of more effective drug delivery platforms. Bioinspired technology has been increasingly proposed for lung drug delivery applications. The strategy of combining the intrinsic and more general advantages of the biomimetic structures with specificities that improve the therapeutic outcomes of particular clinical situations is frequent. These include the surface engineering of the carriers by means of altering the material structure such as chemical modifications, the addition of specific ligands so that predefined targets are reached, and the tuning of the carrier properties to respond to specific stimuli. Furthermore, virus- and cell-derived biomimetic delivery systems combine the intrinsic hallmarks of biological membranes with the delivery capabilities of synthetic carriers. By mimicking these biological entities, we can efficiently interact with the human body and refine the ability to negotiate with the biological barriers that impair the therapeutic efficacy of lung drug delivery. This chapter addresses the features and properties of biomimetic delivery systems, the applications of bioinspired carriers and cell-based delivery aimed at lung drug delivery of active biological and pharmaceutical ingredients, focusing with particular interest on multifunctional carriers and vectors that endowed with improved circulation, enhanced targeting, and responsiveness to the biological environment.
To date, multifunctional nanohybrids have been proposed for catalysis, sensing, energy storage, imaging, and stimuli active therapies. Further, nanosized smart materials exhibit significant impact in targeted drug delivery applications. So far, various nanohybrids like porous silica, porous carbon, polymeric nanohybrids, liposomal particles, carbon nanotubes, iron nanoparticles, gold nanostructures have been considered as bioinspired smart nanohybrids for drug delivery applications due to high surface area, good biocompatibility, high cargo-loading capacity, long circulation time, specific biodistribution, easy surface modifications, etc. However, complicated synthesis process, poor control on premature cargo release, low product yield, poor stability, uncontrolled growth, and particle size are remaining challenges so far. Here in this chapter, a detailed review on the evolution of bioinspired nanohybrids for drug delivery applications has been discussed. Particularly, basic requirements of bioinspired nanohybrids for stimuli responsive drug delivery are highlighted here. In addition, various types of functional nanomaterials and their synthesis routes with their limitations have been discussed in detail. Overall, this chapter explains the current scenario of engineering stimuli responsive drug delivery system and application of bioinspired systems with their significant impact in nanomedicine.
Introduction: The use of herbal compounds in cancer therapy has great potential to promote the efficacy of current cancer therapeutic strategies. Herbal compounds were successfully reported to enhance tumor cells sensitization to the action of chemo-, hormonal- and gene-therapeutic agents via different mechanisms. Herbal ingredients can affect different signaling pathways, reduce the toxic side effects or inhibit the efflux of anticancer drugs.
Areas covered: This review will discuss the delivery of herbal compounds with other cancer treatments such as hormonal, small molecule inhibitors and inorganic hybrids to tumor cells. An overview of physicochemical properties of herbal components that require intelligent design of combo-nanomedicines for efficient co-delivery of those herbal-derived and other anticancer agents was discussed. Nanocarriers provide various benefits to overcome the shortcomings of the encapsulated herbal compounds including improved solubility, increased stability and enhanced tumor targeting. Different nanocarrier systems were the focus of this review.
Expert opinion: Multifunctional nanocarrier systems encapsulating herbal and different anticancer drugs showed to be a wonderful approach in the treatment of cancer enabling the co-delivery of anticancer drugs with versatile modes of action in an accurate manner in an attempt to enhance the efficacy, benefit from the synergism between the drugs as well as to minimize the development of multi-drug resistance. The main challenge point is the early detection and management of any developed adverse effect.
Polymeric nanocapsules are vesicular drug delivery systems composed of an inner oily reservoir surrounded by polymeric membranes. Nanocapsules have various advantages over other nanovesicular systems such as providing controlled drug release properties. We discuss the recent advances in polymeric shell-oily core nanocapsules, illustrating the different types of polymers used and their implementation. Nanocapsules can be utilized for many purposes, especially encapsulation of highly lipophilic drugs. They have been shown to have variable applications, especially in cancer therapy, due to the ability of the polymeric shell to direct the loaded drugs to their target sites, as well as their high internalization efficacy. Those productive applications guaranteed their high potential as drug delivery systems. However, their clinical development is still in an early stage.
Hyaluronic acid (HA), an important component of the extracellular matrix, has high water solubility and biocompatibility, and good application prospects in biomedicine. Especially in tumour treatment, prodrug polymer micelles prepared from HA and chemotherapeutics can increase water solubility, prolong drug release time, improve organ distribution and therapeutic effects, and show good tumour targeting and biocompatibility. Therefore, this study introduces strategies for using HA to prepare prodrug polymer micelles and discusses recent research on HA prodrug micelles for antitumor applications.
The polysaccharide-based biomaterials hyaluronic acid (HA) and chondroitin sulfate (CS) have aroused great interest for use in drug delivery systems for tumor therapy, as they have outstanding biocompatibility and great targeting ability for cluster determinant 44 (CD44). In addition, modified HA and CS can self-assemble into micelles or micellar nanoparticles (NPs) for targeted drug delivery. This review discusses the formation of HA- and CS-based NPs, and various types of CS-based NPs including CS-drug conjugates, CS-polymer NPs, CS-small molecule NPs, polyelectrolyte nanocomplexes (PECs), CS-metal NPs, and nanogels. We then focus on the applications of HA- and CS-based NPs in tumor chemotherapy, gene therapy, photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and immunotherapy. Finally, this review is expected to provide guidelines for the development of various HA- and CS-based NPs used in multiple cancer therapies.
A successful drug delivery to a specific site relies on two essential factors including; efficient entrapment of the drug within the carrier and successful delivery of drug- loaded nanocarrier to the target site without opsonisation or drug release in the circulation before reaching the organ of interest. Lactoferrin (LF) is a glycoprotein belonging to the transferrin (TF) family which can bind to TF receptors (TFRs) and LF membrane internalization receptors (LFRs) highly expressed on the cell surface of both highly proliferating cancer cells and blood brain barrier (BBB), which in turn can facilitate its accessibility to the cell nucleus. This merit could be exploited to develop actively targeted drug delivery systems that can easily cross the BBB or internalize into tumor cells. In this review, the most recent advances of utilizing LF as an active targeting ligand for different types of nanocarriers including: inorganic nanoparticles, dendrimers, synthetic biodegradable polymers, lipid nanocarriers, natural polymers, and nanoemulstions will be highlighted. Collectively, LF seems to be a promising targeting ligand in the field of nanomedicine.
Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.
Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion–diffusion–evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity.
Protein nanocarriers possess unique merits including minimal cytotoxicity, numerous renewable sources, and high drug-binding capability. In opposition to delivery carriers utilizing hydrophilic animal proteins, hydrophobic plant proteins (e.g, zein) have great tendency in fabricating controlled-release particulate carriers without additional chemical modification to stiffen them, which in turn evades the use of toxic chemical crosslinkers. Moreover, zein is related to a class of alcohol-soluble prolamins and generally recognized as safe (GRAS) carrier for drug delivery. Various techniques have been adopted to fabricate zein-based nanoparticulate systems including phase separation coacervation, spray-drying, supercritical anti-solvent approach, electrospinning and self-assembly. This manuscript reviews the recent advances in the zein-based colloidal nano-carrier systems such as nanospheres, nanocapsules, micelles and nanofibers with a special focus on their physicochemical characteristics and drug delivery applications.
ABSTRACT
Purpose In the current work, we propose a combined delivery
nanoplatform for letrozole (LTZ) and celecoxib (CXB).
Methods Multi-reservoir nanocarriers were developed by
enveloping protamine nanocapsules (PRM-NCs) within
drug-phospholipid complex bilayer.
Results Encapsulation of NCs within phospholipid bilayer
was confirmed by both size increase from 109.7 to 179.8 nm
and reduction of surface charge from +19.0 to +7.78 mV.
The multi-compartmental core-shell structure enabled biphasic
CXB release with initial fast release induced by complexation
with phospholipid shell followed by prolonged release
from oily core. Moreover, phospholipid coating provided
protection for cationic PRM-NCs against interaction with
RBCs and serum proteins enabling their systemic administration.
Pharmacokinetic analysis demonstrated prolonged
circulation and delayed clearance of both drugs after intravenous
administration into rats. The superior anti-tumor efficacy
of multi-reservoir NCs was manifested as powerful cytotoxicity
against MCF-7 breast cancer cells and marked reduction
in the mammary tumor volume in Ehrlich ascites bearing
mice compared with free LTZ-CXB combination.
Moreover, the NCs induced apoptotic caspase activation
and marked inhibition of aromatase expression and angiogenic
marker, VEGF as well as inhibition of both NFκB and
TNFα.
Conclusions Multi-reservoir phospholipid shell coating
PRM-NCs could serve as a promising nanocarrier for parenteral
combined delivery of LTZ and CXB.
Background:
Micellization provides numerous merits for the delivery of water insoluble anti-cancer therapeutic agents including a nanosized 'core-shell' drug delivery system. Recently, hydrophobically-modified polysaccharides and proteins are attracting much attention as micelle forming polymers to entrap poorly soluble anti-cancer drugs.
Method:
By virtue of their small size, the self-assembled micelles can passively target tumor tissues via enhanced permeation and retention effect (EPR). Moreover, the amphiphilic micelles can be exploited for active-targeted drug delivery by attaching specific targeting ligands to the outer micellar hydrophilic surface.
Results:
Here, we review the conjugation techniques, drug loading methods, physicochemical characteristics of the most important amphiphilic polysaccharides and proteins used as anti-cancer drug delivery systems. Attention focuses on the mechanisms of tumor-targeting and enhanced anti-tumor efficacy of the encapsulated drugs. This review will highlight the remarkable advances of hydrophobized polysaccharide and protein micelles and their potential applications as anti-cancer drug delivery nanosystems.
Conclusion:
Micellar nanocarriers fabricated from amphiphilic natural polymers hold great promise as vehicles for anti-cancer drugs.
Herein, we report the synthesis of a library of new s-triazine polyamides containing glycine and thioglycolic acid. The reaction of s-triazine dicarboxylic acid derivatives with ethylenediamine, benzidine, piperazine, or p-phenylenediamine, afforded the target designed s-triazine polyamides. The thermal properties of the polymers were evaluated by different techniques, and the thermodynamic parameters of the decomposition processes were evaluated. The feasibility of the synthesized polymers as drug nanodelivery systems was investigated. The nanoparticles were loaded with celecoxib (CXB), an anti-inflammatory drug with a highly promising anti-cancer effect, resulting in high entrapment efficiency levels (62.3-99.8%) with good drug loading in the range 1.58-4.19%. After 48 h, 46.90, 64.20, 57.81, 53.95, and 49.43% of CXB was released from polymeric NPs 26, 43, 44, 45, and 46, respectively, demonstrating a sustained drug release profile. Notably, free CXB, and CXB-loaded polymeric NPs CXB-43, CXB-45, and CXB-46 demonstrated considerable reduction in cell viability in a dose-dependent manner. © 2016 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
Background:
There is a broad range of biological, chemical and physical hurdles for drugs to reach the brain. Nanoparticulate drug delivery systems hold tremendous potential for diagnosis and treatment of brain disorders, including the capacity of crossing the blood-brain barrier and accessing to the brain after systemic administration. Thus, nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti-Alzheimer's drugs, protease inhibitors, and several macromolecules into the brain. Moreover, nanoparticles may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution.
Methods:
The current review highlights the latest advances achieved in developing drug-loaded polysaccharide and protein nanocarriers for brain delivery. The nanoparticles are discussed with respect to their formulation aspects, advantages, limitations, as well as the major outcomes of the in vitro and in vivo investigations. Modification of the nanoparticle surface with specific brain targeting ligands or by coating with certain surfactants for enhanced brain delivery is also reviewed. In addition, the mechanisms of the nanoparticle-mediated drug transport across the BBB are also discussed in this review.
Results:
A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable. Therefore, nanocarriers fabricated from natural polymers including polysaccharides and proteins are particularly interesting.
Conclusion:
Meeting requirements such as low cytotoxicity, abundant surface functional groups, high drug binding capacity and significant uptake into the targeted cells, natural polymer-based nanocarriers represent promising candidates for efficient drug and gene delivery to the brain.
Novel polyelectrolyte complex nanoparticles (AAP/LCS NPs) were prepared in this study and these were produced by mixing negatively charged auricularia auricular polysaccharide (AAP) with positively charged low molecular weight chitosan (LCS) in an aqueous medium. The AAP was extracted and purified from auricularia auricular, and then characterized by micrOTOF-Q mass spectrometry, UV/Vis spectrophotometry, moisture analyzer and SEM. The yield, moisture, and total sugar content of the AAP was 4.5%, 6.2% and 90.12% (w/w), respectively. The AAP sample was water-soluble and exhibited white flocculence. The characteristics of AAP/LCS NPs, such as the particle size, zeta potential, morphology, FT-IR spectra, DSC were investigated. The results obtained revealed that the AAP/LCS NPs had a spherical shape with a diameter of 223nm and a smooth surface, and the results of the FT-IR spectra and DSC investigations indicated that there was an electrostatic interaction between the two polyelectrolyte polymers. Bovine serum albumin (BSA, pI=4.8) and bovine hemoglobin (BHb, pI=6.8) were used as model drugs to investigate the loading and release features of the AAP/LCS NPs. The results obtained showed that the AAP/LCS NPs had a higher entrapment efficiency (92.6%) for BHb than for BSA (81.5%). The cumulative release of BSA and BHb from AAP/LCS NPs after 24h in vitro was 95.4% and 91.9%, respectively. The in vitro release demonstrated that AAP/LCS NPs provided a sustained release matrix suitable for the delivery of protein drugs. These studies demonstrate that AAP/LCS NPs have a very promising potential as a delivery system for protein drugs
Ethyl carbamate (EC); urethane is a chemical carcinogen (IARC group 2A). It has been commonly found in the fermented food and beverages. EC induced cancerous lesion in different sites due to the formation of active metabolite; vinyl carbamate (VC). The current study aims to investigate the potential risk of cancerous lesions in small and repeated exposure of ethyl carbamate in BALB/C mice. Three groups of BALBL/C mice were treated for 120 days included untreated control; group treated with a single dose of urethane (1.5 g/kg B.w/i.p) at a day one; group treated with repeated doses, the first at a day one and a second at day sixty (1.5g/ kg B.w/i.p). Ethyl carbamate (EC) exposure showed sever changes of serum biochemical markers, apoptosis markers, inflammatory cytokines as well as lipid peroxide formation in lung homogenate, these changes were pronounced in repeated exposure to ethyl carbamate. In addition, histological examinations revealed that epithelial changes in pulmonary tissues were advanced in animals treated with repeated doses of ethyl carbamate. These findings indicate that repeated exposure to ethyl carbamate of fermented foods and beverages is an additional risk for lung cancer due to permanent mitochondrial dysfunction and increase the cellular mitotic activity.
Ethyl carbamate (EC); urethane is a chemical carcinogen (IARC group 2A). It has been commonly found in the fermented food and beverages. EC induced cancerous lesion in different sites due to the formation of active metabolite; vinyl carbamate (VC). The current study aims to investigate the potential risk of cancerous lesions in small and repeated exposure of ethyl carbamate in BALB/C mice. Three groups of BALBL/C mice were treated for 120 days included untreated control; group treated with a single dose of urethane (1.5 g/kg B.w/i.p) at a day one; group treated with repeated doses, the first at a day one and a second at day sixty (1.5g/ kg B.w/i.p). Ethyl carbamate (EC) exposure showed sever changes of serum biochemical markers, apoptosis markers, inflammatory cytokines as well as lipid peroxide formation in lung homogenate, these changes were pronounced in repeated exposure to ethyl carbamate. In addition, histological examinations revealed that epithelial changes in pulmonary tissues were advanced in animals treated with repeated doses of ethyl carbamate. These findings indicate that repeated exposure to ethyl carbamate of fermented foods and beverages is an additional risk for lung cancer due to permanent mitochondrial dysfunction and increase the cellular mitotic activity.
Chitosan (CS) nanoparticles for the oral delivery of the protein, Human Serum Albumin (HSA) were prepared by two techniques (precipitation and ionic gelation) together with two anions (sodium sulfate or tripolyphosphate, TPP). HSA was loaded with CS nanoparticles by adsorption or entrapment loading protocols. The highest HSA association efficiency (93.43%) and loading capacity (58.65%) were obtained using ionic gelation technique with 0.1% w/v TPP as a crosslinker. The particle size of CS-HSA nanoparticles ranged between 100-320 nm with a high specific surface area (703-903 m2/g) and porosity (1060.99-1350.95 e-3ml/g). Incubation of nanoparticles with lysozyme led to a reduction of 243 nm in particle size within 3 h. CS nanoparticles was redispersible after one month storage. CS/TPP nanoparticles prepared by precipitation/protein entrapment technique slowly released 10.34% HSA over 5 days which is suitable for vaccine or protein delivery while 86.54% of HSA was released from nanoparticles prepared by precipitation/ protein adsorption technique after 8 hr which is suitable for rapid drug release. Using ionic gelation technique, CS/ TPP nanoparticles released 22.47-38.65% HSA over 5 days at 7:1 to 3:1 CS/TPP mass ratio, respectively. Both techniques retained the structural integrity of HSA after preparation and release processes which was proven via gel electrophoresis.
The aim of this study was to produce fine particles with different corrugated degree of surface by spray-drying and to investigate the effect of surface morphology on in vitro aerosol performance of the particles within HFA 134a based metered dose formulations. Compositions of rizatriptan and scutellarin were spray-dried using different spray-drying parameters, and particles were suspended within HFA 134a. The surface morphology were determined using scanning electron microscopy (SEM), whilst the aerodynamic performance of MDIs was evaluated using a next generation pharmaceutical impactor. The surface morphology of spray-dried particles could vary from smooth to moderately corrugated, and to raisin-like depending upon spray-drying parameters and preparation compositions. In general, increasing inlet temperature, decreasing feed concentration and/or adding leucine to the feed solution tended to increase the corrugated degree of particle surface. Deposition results indicated that raisin-like particle based MDIs for all compositions of the two drugs produced significantly better aerodynamic performance in terms of fine particle fractions and mass median aerodynamic diameters relative to the formulations of the corresponding smooth or slightly corrugated particles when the particle compositions were the same. The present results demonstrated that wrinkled particles increased fine particle fractions within surfactant-free MDI formulations.
In this study, spray-dried alfuzosin hydrochloride (ALF)-loaded casein (CAS) nanoparticles were successfully used for the preparation of a swellable floating matrix via direct compression. The developed NIR calibration model was able to assess ALF and CAS levels in five different batches of drug-loaded nanoparticles. The calibration and prediction plots exhibited good linearity with correlation coefficients of more than 0.9. The standard error of calibration and cross-validation was less than 5% of the measured values, confirming the accuracy of the model. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the NIR partial least squares regression model. The un-crosslinked tablet demonstrated a substantial weight gain (317 % after 2h) and completely disintegrated after 3-4h whereas both 10 and 40 % w/w genipin-crosslinked tablets showed lower weight gain (114 and 42 % after 2h, respectively). A rapid floating of the tablets within 5-15min (compared to 45min for the marketed tablet) was observed, with maintained floating for 24h. Marketed and prepared tablets succeeded to prolong ALF release for 24h. The development of drug-loaded CAS nanoparticles using spray-drying represents a new alternative for the preparation of swellable floating tablets for prolonged drug release.
Copyright © 2015. Published by Elsevier B.V.
Protein-based nanocarriers have gained considerable attention as colloidal carrier systems for the delivery of anticancer drugs. Protein nanocarriers possess various advantages including their low cytotoxicity, abundant renewable sources, high drug-binding capacity, and significant uptake into the targeted tumor cells. Moreover, the unique protein structure offers the possibility of site-specific drug conjugation and tumor targeting using various ligands modifying the surface of protein nanocarriers. In this chapter, we highlight the most important applications of protein nanoparticles (NPs) for the delivery of anticancer drugs. We examine the various techniques that have been utilized for the preparation of anticancer drug-loaded protein NPs. Finally, the current chapter also reviews the major outcomes of the in vitro and in vivo investigations of surface-modified tumor-targeted protein NPs.
© 2015 Elsevier Inc. All rights reserved.
Cytochrome P450 (CYP450) inhibition by the bioactive molecules of dietary supplements or herbal products leading to greater potential for toxicity of co-administered drugs. The present study was aimed to compare the inhibitory potential of selected common dietary bioactive molecules (Gallic acid, Ellagic acid, β-Sitosterol, Stigmasterol, Quercetin and Rutin) on CYP3A4 and CYP2D6 to assess safety through its inhibitory potency and to predict interaction potential with co-administered drugs. CYP450-CO complex assay was carried out for all the selected dietary bioactive molecules in isolated rat microsomes. CYP450 concentration of the rat liver microsome was found to be 0.474 nmol/mg protein, quercetin in DMSO has shown maximum inhibition on CYP450 (51.02 ± 1.24 %) but less when compared with positive control (79.02 ± 1.61 %). In high throughput fluorometric assay, IC50 value of quercetin (49.08 ± 1.02–54.36 ± 0.85 μg/ml) and gallic acid (78.46 ± 1.32–83.84 ± 1.06 μg/ml) was lower than other bioactive compounds on CYP3A4 and CYP2D6 respectively but it was higher than positive controls (06.28 ± 1.76–07.74 ± 1.32 μg/ml). In comparison of in vitro inhibitory potential on CYP3A4 and CYP2D6, consumption of food or herbal or dietary supplements containing quercetin and gallic acid without any limitation should be carefully considered when narrow therapeutic drugs are administered together.
Nanoparticles are extensively studied for drug delivery and are proving to be effective in drug delivery and the diagnostic field. Drug delivery to lungs has its advantages over other routes of administration. Inhalable powders consisting of nanoparticles is gaining much interest in respiratory research and clinical therapy. Particle engineering technique is a key factor to develop inhalable formulations that can successfully deliver drug with improved therapeutic effect and enhanced targeting. Inhalable nanoparticles in the solid-state dry powders for targeted pulmonary delivery offers unique advantages and is an exciting new area of research. Nasal delivery of inhalable nanoparticulate powders is gaining research attention recently, particularly in vaccine applications, systemic drug delivery in the treatment of pain, and non-invasive brain targeting. Fundamental aspects and recent advancements along with future prospects of inhalable powders consisting of nanoparticles in the solid-state for respiratory delivery are presented.
Copyright © 2015. Published by Elsevier Inc.
Most respiratory infections, diseases and allergic reactions have varying degrees of inflammation. Inflammation is a natural immunodefensive response to the presence of allergens or foreign particles that come into contact or affect the cells and tissues within the respiratory tract. The three main types of therapeutic drug classes available for anti-inflammatory and anti-allergy effects are corticosteroids, antihistamines and decongestants. Corticosteroid drugs for pulmonary inhalation and/or nasal delivery include beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Antihistamine drugs for nasal delivery include azelastine and olopatadine. Two common decongestants available are oxymetazoline and phenylephrine. Another therapeutic class, the anticholinergic agents, such as ipratropium bromide and tiotropium bromide, are used in pulmonary delivery in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease. The mast cell stabilizer therapeutic class, cromolyn sodium, can be used to prevent and relieve nasal allergic symptoms. Additionally cromolyn sodium was the first dry powder inhaler product for pulmonary drug delivery several decades ago and currently is on the market as a pressurized metered dose inhaler for pulmonary inhalation delivery. Based on the devices used in pulmonary drug delivery, this route can be subdivided into three categories; namely nebulizers, pressurized metered dose inhalers, and dry powder inhalers. Nasal delivery of anti-inflammatory and antiallergy drugs is most commonly available commercially in an aqueous spray form. This article comprehensively reviews and discusses different kinds of drugs used for anti-inflammatory and anti-allergic effects via the pulmonary and nasal delivery route, as well as their mechanisms of action, marketed products, disease state indications while highlighting drug delivery and therapeutic aspects.
The interaction of particles with cells is known to be strongly influenced by particle size, but little is known about the interdependent role that size, shape, and surface chemistry have on cellular internalization and intracellular trafficking. We report on the internalization of specially designed, monodisperse hydrogel particles into HeLa cells as a function of size, shape, and surface charge. We employ a top-down particle fabrication technique called PRINT that is able to generate uniform populations of organic micro- and nanoparticles with complete control of size, shape, and surface chemistry. Evidence of particle internalization was obtained by using conventional biological techniques and transmission electron microscopy. These findings suggest that HeLa cells readily internalize nonspherical particles with dimensions as large as 3 μm by using several different mechanisms of endocytosis. Moreover, it was found that rod-like particles enjoy an appreciable advantage when it comes to internalization rates, reminiscent of the advantage that many rod-like bacteria have for internalization in nonphagocytic cells.
• PRINT
• shape
• size
• surface charge
Milk, especially colostrum, contains different kinds of macromolecules abundantly, such as immunoglobulin G (IgG), lactoferrin (Lf), transferrin (Tf), and growth factors. These are essential for the development and maintenance of health, which greatly depends on the absorption and transportation of macromolecules to the target organs. To evaluate the macromolecular transport, and concentrations in plasma and cerebrospinal fluid (CSF), colostrum was fed to newborn calves followed by milk and milk replacer, and maintained up to the 4th week under farm conditions. Plasma and CSF were collected at different times, and were analyzed for Lf, Tf, IgG and iron concentrations. Lf, Tf and IgG concentrations were steeply increased in plasma and CSF after colostrum feeding, and fluctuating patterns were observed during the experiments. Furthermore, intraduodenal administration of bovine Lf alone in young calf experiments revealed that the Lf concentration reached a peak at 4 hr, and was 7 and 4 times higher than preadministration in plasma and CSF, respectively. To explore the transport mechanism of Lf into CSF in young calves, epithelial membranes of the choroid plexus were prepared and a binding assay for Lf receptors (Lf-R) was carried out with 125I-Lf. The saturation kinetics revealed that the Bmax of epithelial membranes was 26.15 nmol/mg protein with a Kd of 0.11 microM, which also showed that Lf-R is saturable and specific. Scatchard plot transformation showed the presence of a single type of Lf-R in the choroid plexus. These results suggest that Lf is transported into the CSF through receptor mediated transcytosis in young calves, and that Lf may play an important role(s) in brain function.
Cardiotoxic side-effects of doxorubicin limit the clinical use of this anti-cancer agent. Iron chelators have been studied as protectors against doxorubicin-induced cardiotoxicity. These iron chelators do not provide optimal protection and have certain drawbacks. We therefore looked for new protectors and decided that these new compounds should combine iron chelating and antioxidant activity. Flavonoids appeared to possess those combined iron chelating and antioxidant properties. Quantum chemical evaluation of radical stabilization and determination of physico-chemical properties of a series of flavonoids brought our attention to the semi-synthetic flavonoid 7-monohydroxyetylrutoside (monoHER). Both in vitro (using an electrically paced mouse left atrium model) and in vivo (using a mouse ECG telemetry model) experiments corroborated the protective effect of monoHER. MonoHER also showed anti-inflammatory properties. A subsequent clinical phase I study showed that an i.v. dose of 1,500mg/m2 is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.
Aim:
Multireservoir nanocarriers were fabricated for delivering antineoplastic drug cocktail from herbal and fungal origin. Monascus yellow pigments (MYPs), monascin and ankaflavin, were isolated from red-mold rice, and incorporated within casein micelles (CAS MCs) along with the herbal drug, resveratrol (RSV). Both drugs (MYPs and RSV) were simultaneously incorporated into the hydrophobic core of CAS MCs. Alternatively, MYPs-loaded CAS MCs were enveloped within RSV-phytosomal bilayer elaborating multireservoir nanocarriers.
Results:
Cytotoxicity studies confirmed the superiority of multireservoir nanocarriers against MCF-7 breast cancer cells. The in vivo antitumor efficacy was revealed by reduction of the tumor volume and growth biomarkers.
Conclusion:
Multireservoir CAS nanocarriers for codelivery of both MYPs and RSV may be promising alternative to traditional breast cancer therapy.
There is progressive evolution in the use of inhalable drug delivery systems (DDSs) for lung cancer therapy. The inhalation route offers many advantages, being non-invasive method of drug administration as well as localized delivery of anti-cancer drugs to tumor tissue. This article reviews various inhalable colloidal systems studied for tumor-targeted drug delivery including polymeric, lipid, hybrid and inorganic nanocarriers. The active targeting approaches for enhanced delivery of nanocarriers to lung cancer cells were illustrated. This article also reviews the recent advances of inhalable microparticle-based drug delivery systems for lung cancer therapy including bioresponsive, large porous, solid lipid and drug-complex microparticles. The possible strategies to improve the aerosolization behavior and maintain the critical physicochemical parameters for efficient delivery of drugs deep into lungs were also discussed. Therefore, a strong emphasis is placed on the approaches which combine the merits of both nanocarriers and microparticles including inhalable nanocomposites and nanoaggregates and on the optimization of such formulations using the proper techniques and carriers. Finally, the toxicological behavior and market potential of the inhalable anti-cancer drug delivery systems are discussed.
Aim:
Oral administration of exemestane (EXM) and resveratrol (RES) for breast cancer therapy has been limited by their poor solubility and low permeability.
Methods:
In this study, these issues were tackled using zein nanocapsules (ZNCs) for oral EXM/RES codelivery combining drug solubilization within oily core and resistance to digestion via hydrophobic protein shell. Furthermore, higher oral stability and sustained release could be enabled by glutaraldehyde crosslinking of zein shell.
Results & conclusion:
EXM/RES-ZNCs showed enhanced cytotoxicity against MCF-7 and 4T1 breast cancer cells compared with free drug combination with higher selectivity to cancer cells rather than normal fibroblasts. In vivo, crosslinked EXM/RES-ZNCs markedly reduced the percentage increase of Ehrlich ascites mammary tumor volume in mice by 2.4-fold compared with free drug combination.
Despite several reports have revealed the beneficial effect of co-administration of COX-2 inhibitors with aromatase inhibitors in managing postmenopausal breast cancer; no nanocarriers for such combined delivery have been developed till now. Therefore, protamine nanocapsules (PMN-NCs) have been developed to co-deliver letrozole (LTZ) that inhibits aromatase-mediated estrogen biosynthesis and celecoxib (CXB) that synergistically inhibits aromatase expression. Inspired by the CD44-mediated tumor targeting ability of hyaluronate (HA), we developed HA-coated PMN-NCs (HA-NCs) via electrostatic layer-by-layer assembly. Moreover, multi-compartmental PEGylated phospholipid-CXB complex bilayer enveloping PMN-NCs (PEG-NCs) were designed for conferring biphasic CXB release from the phospholipid corona and oily core as well as enabling passive-targeting. The NCs demonstrated excellent stability, prolonged circulation and could be scaled up with the aid of spray-drying technology. Hemolysis, serum stability and cytotoxicity studies confirmed the superiority of combined LTZ-CXB nano-delivery. Mechanistically, the NCs especially HA-NCs and PEG-NCs demonstrated precious anti-tumor effects in vivo revealed as reduction in the tumor volume and aromatase level, increased apoptosis, as well as inhibition of VEGF, NF-κB and TNF-α augmented by histopathological and immunohistochemical studies. Overall, our approach provided for the first time a potential strategy for targeted LTZ-CXB combined therapy of hormone-dependent breast cancer via singular nanocapsule delivery system.
The airways of most people with cystic fibrosis are colonized with biofilms of the Gram-negative, opportunistic pathogen Pseudomonas aeruginosa. Delivery of antibiotics directly to the lung in the form of dry powder aerosols offers the potential to achieve high local concentrations directly to the biofilms. Unfortunately, current aerosolised antibiotic regimes are unable to efficiently eradicate these biofilms from the airways. We investigated the ability of the innate antimicrobial, lactoferrin, to enhance the activity of two aminoglycoside antibiotics (tobramycin and gentamicin) against biofilms of P. aeruginosa strain PAO1. Biofilms were prepared in 96 well polystyrene plates. Combinations of the antibiotics and various lactoferrin preparations were spray dried. The bacterial cell viability of the various spray dried combinations was determined. Iron-free lactoferrin (apo lactoferrin) induced a 3-log reduction in the killing of planktonic cell by the aminoglycoside antibiotics (p < 0.01) and also reduced both the formation and persistence of P. aeruginosa biofilms (p < 0.01). Combinations of lactoferrin and an aminoglycoside displays potential as an effective new therapeutic strategy in the treatment of P. aeruginosa biofilms infections such as those typical of the CF lungs.
Pegylated liposomal doxorubicin (Lipo-Dox) is one of the few clinically used cancer nanomedicines. Here we show that tumor-homing, redox-responsive and reversibly crosslinked multifunctional biodegradable polymersomes are a better alternative to liposomes for Dox delivery. Cyclic peptide cNGQGEQc-decorated polymersomes (cNGQ-PS) are easily prepared with a small size and high Dox loading. Dox-loaded cNGQ-PS (cNGQ-PS-Dox) shows superb stability with minimal drug leakage under physiological conditions while spontaneous disassembly and quick drug release in response to 10mM glutathione. MTT assays, flow cytometry and confocal microscopy clearly display efficient receptor-mediated internalization of cNGQ-PS-Dox, fast intracellular drug release, and high antitumor activity in α3β1 integrin-overexpressing A549 lung cancer cells. Intriguingly, cNGQ-PS-Dox presents a remarkably high maximum-tolerated dose of over 100mg/kg, over 6-fold higher than Lipo-Dox. The in vivo pharmacokinetics and biodistribution studies reveal that cNGQ-PS-Dox has a long circulation time and significantly enhanced tumor accumulation (8.60%ID/g) as compared to Lipo-Dox and non-targeting PS-Dox controls. Notably, cNGQ-PS-Dox shows superior treatment of both subcutaneous and orthotopic A549 human lung cancer bearing nude mice to Lipo-Dox, resulting in effective tumor suppression, significantly improved survival time, and markedly reduced adverse effects. cNGQ-PS appears to be a clinically viable system for targeted lung cancer chemotherapy.
Gemcitabine is one of the most potent anticancer agents acting on a wide range of solid tumors, however, its use is limited by short half life and high dose leading to serious side effects. The present investigation describes the development and characterization of folate functionalized gemcitabine loaded bovine serum albumin nanoparticles (Fa-Gem-BSANPs). The nanoparticles were prepared by desolvation cross-linking technique and characterized for various parameters including morphology, particle size, zeta potential, drug loading and release profile. The particle size of Gem-BSANPs and Fa-Gem-BSANPs was found to be 159.1±5.29 and 208.7±1.80nm, respectively. DSC and XRD analysis indicated amorphous nature of the drug within the particles. The encapsulated gemcitabine exhibited less hemolytic properties as compared to native drug. The anticancer activity of Fa-Gem-BSANPs was evaluated in folate receptor over expressing cell lines (Ovcar-5 and MCF-7) and folate receptor deficient cell line (MIAPaCa-2). The Fa-Gem-BSANPs showed superior anticancer activity as compared to Gem-BSANPs in Ovcar-5 and MCF-7 cells while no significant difference in cytotoxicity was found with MIAPaCa-2 cells. Confocal microscopy indicated facilitated intracellular uptake of Fa-Gem-BSANPs in MCF-7, which in turn result in a higher potential for apoptosis. Further, Fa-Gem-BSANPs exhibited improved anti-tumor activity in Ehrlich solid tumor model in mice. In conclusion, our study indicates that folate functionalized nanoparticles confer enhance cellular uptake and cytotoxicity for gemcitabine.
Copyright © 2015. Published by Elsevier B.V.
Nanomaterials promise to improve disease diagnosis and therapy through effective delivery of drugs, genes, biomolecules and imaging agents to specific subcellular targets. In order to optimize nanomaterial design for this purpose, a comprehensive understanding of how these materials are taken up and transported within the cell is required. In this review, we discuss the endocytic pathways employed by different types of nanoparticles with emphasis on their surface modification. The use of pharmacological inhibition to probe internalization and intracellular trafficking pathways of nanoparticles is critically evaluated. Finally, approaches to target-specific delivery of therapeutics into the cytoplasm and nucleus are addressed.
Chondroitin sulfate-g-poly(ε-caprolactone) (CP) copolymers were synthesized via atom transfer radical addition (ATRA). The CP copolymers self-assembled into micelles in water and the micelles could be used to encapsulate a hydrophobic anticancer drug, camptothecin (CPT), in the core for tumor targeting delivery. The physicochemical properties of the micelles and CPT-loaded micelles were thoroughly characterized. For the in vitro test, the CPT release, the protection of the lactone ring of CPT from hydrolysis, and the cellular uptake of CPT were studied. The cell-killing and apoptosis-inducing effects using the CPT-loaded micelles were significantly better than using free CPT against CRL-5802 cells. The micellar internalization into CRL-5802 cells was primarily via CD44 and clathrin dual-mediated endocytosis. For the in vivo test, the therapeutic efficacy of the CPT-loaded micelles was studied in a non-small cell lung cancer xenograft animal model. The CPT-loaded micelles showed good inhibition in tumor growth as compared with a commercial product, CPT-11, in CRL-5802 tumor-bearing mice. The in vitro and in vivo data suggested the CP-based micelles are promising anticancer drug vehicles for lung cancer targeting.
Nanotechnology in drug delivery has been manifested into nanoparticles that can have unique properties both in vitro and in vivo, especially in targeted drug delivery to tumors. Numerous nanoparticle formulations have been designed and tested to great effect in small animal models, but the translation of the small animal results to clinical success has been limited. Successful translation requires revisiting the meaning of nanotechnology in drug delivery, understanding the limitations of nanoparticles, identifying the misconceptions pervasive in the field, and facing inconvenient truths. Nanoparticle approaches can have real impact in improving drug delivery by focusing on the problems at hand, such as enhancing their drug loading capacity, affinity to target cells, and spatiotemporal control of drug release.
Inhalable highly porous large PLGA microparticles with incorporated doxorubicin and surface-attached with TRAIL (TRAIL/Dox PLGA MP) were fabricated using a w/o/w double emulsification method using ammonium bicarbonate as a gas-foaming agent for the treatment of lung cancer. The TRAIL/Dox PLGA MP produced were highly porous and 11.5 ± 0.4 μm in diameter, and the loading efficiencies of Dox and TRAIL were 86.5 ± 6.5% and 91.8 ± 2.4%, respectively. TRAIL and doxorubicin were gradually released by TRAIL/Dox PLGA over 7 days, and pulmonary administration resulted in the deposition of TRAIL/Dox PLGA MP in mouse lungs, and they remained in situ for up to a week. The anti-tumor efficacy of pulmonary administered TRAIL/Dox PLGA MP was evaluated in a BALB/c nu/nu mice mouse model of H226 cell metastasis. Tumors in H226-implanted mice treated with TRAIL/Dox PLGA MP were markedly smaller and fewer in number than mice treated with TRAIL or Dox PLGA MP alone. Furthermore, this improved performance was found to be due to the synergistic apoptotic effects of the two drugs. We believe that TRAIL/Dox PLGA MP offer a promise of a sustained-release, long-acting, inhalable anti-lung cancer agent. Furthermore, the synergism observed between TRAIL and doxorubicin suggests that the doxorubicin dosage could be substantially reduced and its side effects minimized.
Understanding the influence of process conditions on the properties of pharmaceutical products is critical to their optimal and cost-effective design and manufacture. The aim of this study was to investigate the effect of changing processing variables on the physical properties of spray-dried mannitol and co-spray-dried mannitol/disodium cromoglycate (DSCG) formulations intended for therapeutic inhalation. A 24 full factorial design was performed to assess the consequences of altering the following spray-drying parameters: feed flow rate, nozzle gas flow rate, drying gas inlet temperature, and aspirator capacity (drying gas flow rate). Aqueous solutions of mannitol and mannitol/DSCG were spray-dried using a laboratory-scale spray dryer, and the products were characterized in terms of particle size distribution, powder yield, and particle morphology. These physical properties were found to be affected mainly by two processing variables: nozzle gas flow rate and drying gas inlet temperature. In addition, optimal conditions for the production of inhalable mannitol powders were obtained, generating a yield of 90% by weight of round and smooth particles with a volume median diameter of 4.28 μm. Mannitol/DSCG formulations co-spray-dried in the same conditions had similar characteristics. The results of this study can be applied to controlled formulation of various spray-dried powders for inhalation.
Aim:
To develop polymeric-ceramic nanocarriers (NCs) in order to achieve oral delivery of the anticancer neutraceutical iron-saturated bovine lactoferrin (Fe-bLf) protein.
Materials & methods:
Fe-bLf or paclitaxel (Taxol®) were adsorbed onto calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate. The Fe-bLf or Taxol-loaded NCs indicated as AEC-CP-Fe-bLf or AEC-CP-Taxol NCs, respectively, were made by combination of ionic gelation and nanoprecipitation. Size distribution, morphology, internalization and release profiles of the NCs were studied along with evaluation of in vitro and in vivo anticancer activities and compared with paclitaxel.
Results:
AEC-CP-Fe-bLf NCs obtained spherical morphology and showed enhanced endocytosis, transcytosis and anticancer activity in Caco-2 cells in vitro. AEC-CP-Fe-bLf NCs were supplemented in an AIN 93G diet and fed to mice in both prevention and treatment human xenograft colon cancer models. AEC-CP-Fe-bLf NCs were found to be highly significantly effective when given orally, as a pretreatment, 1 week before Caco-2 cell injections. None of the mice from the AEC-CP-Fe-bLf NC-fed group developed tumors or showed any signs of toxicity, while the mice fed the control AIN 93G diet showed normal tumor growth. Fe-bLf or Taxol, when given orally in a diet as nanoformulations post-tumor development, showed a significant regression in the tumor size with complete inhibition of tumor growth later, while intratumoral injection of Taxol just delayed the growth of tumors. The pharmacokinetic and bioavailability studies indicated that nanoformulated Fe-bLf was predominantly present on tumor cells compared to non-nanoformulated Fe-bLf. Fe-bLf-loaded NCs were found to help in absorption of iron and thus may have utility in enhancing the iron uptake during iron deficiency without interfering with the absorption of calcium.
Conclusion:
With the promising results of our study, the future potential of NC-loaded Fe-bLf in chemoprevention and in the treatment of human colon cancer, deserves further investigation for translational research and preclinical studies of other malignancies.
Lactoferrin, a single chain cationic glycoprotein, present in the secondary granules of neutrophils, acts as a negative feedback regulator of myelopoiesis. Specific receptors for lactoferrin were detected on the surface of different hematopoietic cell types. The influence of lactoferrin on cell growth in culture has been reported. Interactions of lactoferrin with DNA were also demonstrated.
In the present paper we confirm the presence of lactoferrin specific binding sites on K562 cells and we estimate the number of binding sites and the dissociation constant. By Western blotting analysis performed on K562 lysates we find a band of about 120 kDa responsible for specific binding of lactoferrin. We also show that lactoferrin, after binding at the cell surface, is internalized in a temperature dependent way and is immunologically detectable as a DNA‐linked protein in nuclear extracts. © 1992 Wiley‐Liss, Inc.
Amoitone B, as a new derivative of cytosporone B, has been proved to be a natural agonist for Nur77. It exhibits remarkable anticancer activity in vivo and has the potential to be a therapeutic agent for cancer treatment. However, the poor solubility and dissolution rate result in low therapeutic index for injection and low bioavailability for oral administration, therefore limiting its application. In order to magnify the clinical use of Amoitone B, nanocrystal was selected as an application technology to solve the above problems. In this study, the optimized Amoitone B nanocrystals with small and uniform particle size were successfully prepared by microfluidization method and investigated by morphology, size distribution, and zeta potential. The differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed there was no crystalline state changed in the size reduction process. For Amoitone B nanocrystals, an accelerated dissolution velocity and increased saturation solubility were achieved in vitro and a markedly different pharmacokinetic property in vivo was exhibited with retarded clearance and magnified AUC compared with Amoitone B solution. These results implied that developing Amoitone B as nanocrystals is a promising choice for intravenous delivery and further application for cancer therapy.
Doxorubicin-loaded highly porous large PLGA microparticles (Dox PLGA MPs) were prepared using a w/o/w double emulsification method using ammonium bicarbonate effervescent salt. The prepared Dox PLGA MPs were characterized by particle size analysis, scanning electron microscopy, and confocal microscopy. In vitro cytotoxicity to B16F10 melanoma cells and lung deposition in C57BL/6 mice were examined, and finally the anti-tumor efficacy of pulmonary administered Dox PLGA MPs was evaluated in a mouse model of B16F10 melanoma metastasis. Results showed that Dox PLGA MPs were highly porous, had high encapsulation efficiency, and good aerosolization characteristics. Doxorubicin was gradually released from Dox PLGA MPs over 2 weeks, and after pulmonary administration, Dox PLGA MPs were deposited in lungs and remained in situ for up to 14 days. Furthermore, exposure to Dox PLGA MPs killed B16F10 cells in vitro within 24 h. In particular, tumors in B16F10-implanted mice treated with Dox PLGA MPs were remarkably smaller in terms of mass and number than those in non-treated B16F10-implanted mice. We believe that doxorubicin-loaded highly porous large PLGA microparticles have great potential as a long-term inhalation agent for the treatment of lung cancer.
To develop a polymer-anticancer drug conjugate, we employed gelatin nanoparticles (GPs) as carriers of cisplatin (CDDP) with anticipated improved therapeutic effect and reduced side effects. The anticancer activities of CDDP-incorporated in GPs (GP–Pt) with biotinylated-EGF (bEGF) modification (GP–Pt–bEGF) were studied. GP–Pt–bEGF with EGFR affinity produced much higher Pt concentrations in A549 cells (high EGFR expression) than in HFL1 cells (low EGFR expression). An in vitro anticancer study showed that GP–Pt–bEGF was more potent than free CDDP or GP–Pt because of its rapid effect on the cell cycle as well as a lower IC50 (1.2 μg/ml) that inhibits A549 cell growth. PI staining showed that cells treated with GP–Pt-bEGF for only 4 h had the highest sub-G1 population.The CDDP formulations – free CDDP, GP–Pt, and GP–Pt–bEGF – were given by intratumorous injections to SCID mice in a subcutaneous model. This treatment showed that GP–Pt–bEGF had stronger anti-tumor activity and was less toxic than free CDDP in vivo. Mice treated with GP–Pt–bEGF showed slight body weight loss, whereas free CDDP treatment at the same dose caused a body weight loss of 20–30%. Furthermore, these formulations were given to mice with lung cancer via aerosol delivery. This treatment showed that inhaled GP–Pt–bEGF could target EGFR-overexpressing cells to achieve high cisplatin dosage in cancerous lungs.To summarize, gelatin nanoparticles loaded with CDDP and decorated with EGF tumor-specific ligand were successfully developed. Their in vitro and in vivo targeting ability and anticancer effect were confirmed. The aerosol delivery of the nanodrug carrier was demonstrated. Simple aerosol delivery of targeted drug carriers may prove useful for the clinical treatment of lung cancer patients.
Matrix systems based on biocompatible and biodegradable polymers like the United States Food and Drug Administration (FDA)-approved polymer poly(DL-lactide-co-glycolide acid) (PLGA) are promising for the delivery of small interfering RNA (siRNA) due to favorable safety profiles, sustained release properties and improved colloidal stability, as compared to polyplexes. The purpose of this study was to design a dry powder formulation based on cationic lipid-modified PLGA nanoparticles intended for treatment of severe lung diseases by pulmonary delivery of siRNA. The cationic lipid dioleoyltrimethylammoniumpropane (DOTAP) was incorporated into the PLGA matrix to potentiate the gene silencing efficiency. The gene knock-down level in vitro was positively correlated to the weight ratio of DOTAP in the particles, and 73% silencing was achieved in the presence of 10% (v/v) serum at 25% (w/w) DOTAP. Optimal properties were found for nanoparticles modified with 15% (w/w) DOTAP, which reduced the gene expression with 54%. This formulation was spray-dried with mannitol into nanocomposite microparticles of an aerodynamic size appropriate for lung deposition. The spray-drying process did not affect the physicochemical properties of the readily re-dispersible nanoparticles, and most importantly, the in vitro gene silencing activity was preserved during spray-drying. The siRNA content in the powder was similar to the theoretical loading and the siRNA was intact, suggesting that the siRNA is preserved during the spray-drying process. Finally, X-ray powder diffraction analysis demonstrated that mannitol remained in a crystalline state upon spray-drying with PLGA nanoparticles suggesting that the sugar excipient might exert its stabilizing effect by sterical inhibition of the interactions between adjacent nanoparticles. This study demonstrates that spray-drying is an excellent technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local delivery of biologically active siRNA directly to the lung tissue.
It is demonstrated that nanoparticulate PEC with a crosslinked shell sustains DOX release and increases DOX activity against cancer cells. CSMA was synthesized to prepare PEC with chitosan. The double bonds among CSMA were used to form a shell crosslink. The released DOX from DOX-loaded PECs against human cancer KB cells and A549 cells were qualitatively traced by confocal laser scanning microscopy and flow cytometry, and quantitatively measured by capillary electrophoresis. All the results implied the DOX-loaded PEC with a crosslinked shell had the best anti-cancer potency of free DOX and the DOX-loaded PEC prepared from pure chondroitin sulfate and chitosan in both the cell lines.
Differing stages of chronic obstructive pulmonary disease (COPD) are characterized by differing radioaerosol images. Localized aerosol hot spots in the lungs in advanced COPD may correspond to flow-limiting segments. Avoidance of such localized deposition could be an important factor in the effective administration of therapeutic aerosols.
Determine if wet milling technology could be used to formulate water insoluble antitumor agents as stabilized nanocrystalline drug suspensions that retain biological effectiveness following intravenous injection.
The versatility of the approach is demonstrated by evaluation of four poorly water soluble chemotherapeutic agents that exhibit diverse chemistries and mechanisms of action. The compounds selected were: piposulfan (alkylating agent), etoposide (topoisomerase II inhibitor), camptothecin (topoisomerase I inhibitor) and paclitaxel (antimitotic agent). The agents were wet milled as a 2% w/v solids suspension containing 1% w/v surfactant stabilizer using a low energy ball mill. The size, physical stability and efficacy of the nanocrystalline suspensions were evaluated.
The data show the feasibility of formulating poorly water soluble anticancer agents as physically stable aqueous nanocrystalline suspensions. The suspensions are physically stable and efficacious following intravenous injection.
Wet milling technology is a feasible approach for formulating poorly water soluble chemotherapeutic agents that may offer a number of advantages over a more classical approach.
Cigarette smoking has been clearly and unambiguously identified as a direct cause of cancers of the oral cavity, oesophagus, stomach, pancreas, larynx, lung, bladder, kidney and leukaemia, especially acute myeloid leukaemia. Additionally, cigarette smoking is a direct cause of ischaemic heart disease (the commonest cause of death in western countries), respiratory heart disease, aortic aneurysm, chronic obstructive lung disease, stroke, pneumonia and cirrhosis and cancer of the liver. Cigarette smoking can kill in 24 different ways and, although smoking protects against several fatal and non-fatal conditions, the adverse effect of smoking on health is largely negative. In developed countries as a whole, tobacco is responsible for 24% of all male deaths and 7% of all female deaths: these figures rise to over 40% in men in some countries of central and eastern Europe and to 17% in women in the United States. The average loss of life of smokers is 8 years.
The polyphenolic antioxidants, consumed as an integral part of vegetables, fruits and beverages, are suggested as possessing anticarcinogenic properties. In the present study we have looked into the anticarcinogenic potential of plant polyphenols ellagic acid (EA) and quercetin against N-nitrosodiethylamine-induced lung tumorigenesis in mice. Ellagic acid was able to significantly reduce tumour incidence to 20% from the control value of 72.2%. Similarly, tumour burden was also decreased, although not significantly, from 3.15 to 2.5. Quercetin (QR) caused the tumour incidence to decrease from 76.4% to 44.4% when fed until the third dose of carcinogen. Both of the polyphenols suppressed the tumour incidence mainly by acting at the initiation phase of the carcinogenesis, since continuing the feeding of polyphenols until the termination of the experiment did not cause any apparent change in tumour incidence or tumour burden. Besides this, ellagic acid was found to be a better chemopreventor than quercetin. In order to search for their mechanism of action, the effect of feeding of these compounds on reduced glutathione (GSH), an important endogenous antioxidant, and on lipid peroxidation was investigated. Both ellagic acid and QR caused a significant increase in GSH and decrease in NADPH- and ascorbate-dependent lipid peroxidation. Ellagic acid was found to be more effective in decreasing the lipid peroxidation and increasing the GSH. This may be one of the reasons for its observed better anticarcinogenic property as compared to quercetin.
The potential cytotoxic and anti-proliferative activities of ellagic acid (a naturally occurring bioactive compound in berries, grapes, and nuts) was evaluated using human umbilical vein endothelial cells (HUVEC), normal human lung fibroblast cells HEL 299, Caco-2 colon, MCF-7 breast, Hs 578T breast, and DU 145 human prostatic cancer cells. Ellagic acid at concentration in the range 10-100 micromol/L did not affect the viability of normal fibroblast cells during a 24-hour incubation. An increase in adenosine triphosphate (ATP) bioluminescence of approximately 18-21% was observed in normal cells incubated with ellagic acid. In contrast, ellagic acid at 1-100 micromol/L dose-dependently inhibited HUVEC tube formation and proliferation on a reconstituted extracellular matrix and showed strong anti-proliferative activity against the colon, breast, and prostatic cancer cell lines investigated. The most sensitive cells were the Caco-2, and the most resistant were the breast cancer cells. Ellagic acid induced cancer cell death by apoptosis as shown by the microscopic examination of cell gross morphology. Ellagic acid induced reduced cancer cell viability as shown by decreased ATP levels of the cancer cells. After 24 hours incubation of 100 micromol/L of ellagic acid with Caco-2, MCF-7, Hs 578T, and DU 145 cancer cells, ellagic acid suppressed fetal bovine serum (FBS) stimulation of cell migration. The apoptosis induction was accompanied by a decreased in the levels of pro-matrix metalloproteinase-2 (pro-MMP-2 or gelatinase A), pro-matrix metalloproteinase-9 (pro-MMP-9 or gelatinase B), and vascular endothelial growth factor (VEGF(165)) in conditioned media. The results suggest that ellagic acid expressed a selective cytotoxicity and anti-proliferative activity, and induced apoptosis in Caco-2, MCF-7, Hs 578T, and DU 145 cancer cells without any toxic effect on the viability of normal human lung fibroblast cells. It was also observed that the mechanism of apoptosis induction in ellagic acid-treated cancer cells was associated with decreased ATP production, which is crucial for the viability of cancer cells.
The current study aimed to quantify the different degree of particle surface corrugation and correlate it to the aerosol performance of powders.
Powders of different degree of surface corrugation were prepared by spray drying under varying conditions. The solid-state properties of the powders including particle size, morphology, crystal form, true density, and moisture content were characterized. The degree of surface corrugation was quantified by the surface fractal dimension (Ds) obtained by light scattering. The aerosol performance was studied by dispersing the powders using the Rotahaler at 60 L/min into a multi-stage liquid impinger. Fine particle fraction (FPF) was expressed as the wt% of BSA particles of size < or =5 microm in the aerosol.
Four powders of increasing degree of particle surface corrugation were prepared, with Ds ranging from 2.06 for the least corrugated to 2.41 for the most corrugated. The powders had a similar size distribution (VMD 3 microm, span 1.4-1.5) and solid-state properties. Increasing the surface corrugation, Ds, slightly from 2.06 to 2.18 enhanced the FPF significantly from 27% to 41%. This was explained by the reduced area of contacts and increased separation distance between the particles. Further increase of corrugation (Ds > or = 2.18) did not improve FPF.
Powders with varying degrees of corrugation were successfully obtained by spray drying with their surface roughness quantified by fractal analysis. It was shown that only a relatively small degree of surface corrugation was sufficient to accomplish a considerable improvement in the aerosol performance of the powder.
In this study, we examined the effects of the food antioxidants, alkyl gallates, on the function of P-glycoprotein (P-gp) and elucidated the importance of alkyl chains and gallic acid moieties on the activity of P-gp. We examined the effects of three alkyl (n-butyl, n-octyl and n-dodecyl) gallates and their related compounds on the cellular accumulation and efflux of rhodamine 123 and daunorubicin in P-gp overexpressing KB-C2 cells. Alkyl gallates increased the cellular accumulation of these P-gp substrates dependent on their alkyl chain lengths by inhibiting the efflux of the substrates. n-Dodecylresorcinol also increased the accumulation, but its effect was less than that of n-dodecyl gallate. However, either lauric acid or n-dodecyl-beta-d-maltoside, which does not have a phenol group, did not increase the accumulation. The results indicated that both the gallic acid moiety and a long alkyl chain play important roles in the modification of P-gp function. The cytotoxicity of daunorubicin was recovered in the presence of alkyl gallates possibly due to their inhibition of P-gp function.
In this study lactoferrin (Lf) was investigated as a targeting ligand for receptor-mediated gene delivery to human bronchial epithelial cells. A high number of lactoferrin receptors (LfRs) were detected on bronchial epithelial (BEAS-2B), but not on alveolar epithelial (A549) cells by fluorescence microscopy and FACS measurements, suggesting potential targeting selectivity for bronchial epithelial cells. Molecular conjugates with ratios of Lf to branched polyethylenimine 25 kDa (PEI) ranging from 4:1 to 1:40 (mol/mol) were synthesized and analyzed for complexation of plasmid DNA (pDNA), transfection efficiency, and cytotoxicity. Whereas particle size increased with the degree of Lf coupling from 45 to 225 nm, surface charge was not significantly influenced. Transfection studies on BEAS-2B cells revealed that Lf-PEI 1:20 exhibited the highest luciferase gene expression which was 5-fold higher at an N/P ratio (molar ratio of PEI nitrogen to pDNA phosphate) of 4 than PEI and could be inhibited by an excess of free Lf. With A549 cells, no significant enhancement in transfection efficiency between Lf-PEI/pDNA and PEI/pDNA complexes could be observed. Increasing the degree of Lf coupling to PEI resulted in reduced transfection efficiency in both alveolar and bronchial epithelial cells. Cell viability assays resulted in significantly lower cellular toxicity of Lf-PEI/pDNA compared with PEI/pDNA complexes. We suggest that Lf represents a potent targeting ligand for receptor-mediated gene delivery to bronchial epithelial cells and might be a promising candidate for lung gene transfer in vivo.
To investigate whether ellagic acid (EA) has a possible protective effect against cisplatin (CP)-induced negative changes in epididymal sperm characteristics and the histologic structure of testis and prostate associated with oxidative stress in rats.
Experimental study.
Firat University Medical School Experimental Research Center, Elazig, Turkey.
Eight-week-old adult male Sprague Dawley rats (n = 24).
Cisplatin was administered to rats at a single dose of 7 mg/kg IP. Ellagic acid was administered both separately and simultaneously with CP by gavage daily for 10 days at the dose of 10 mg/kg.
Reproductive organ weights, epididymal sperm characteristics, and histopathologic structure of testes and ventral prostate were determined along with malondialdehyde (MDA) and glutathione (GSH) levels and glutathione-peroxidase (GSH-Px) and catalase (CAT) activities of plasma, sperm, and testicular tissue.
Ellagic acid ameliorated the CP-induced reductions in weights of testes, epididymides, seminal vesicles, and prostate along with epididymal sperm concentration and motility. Additionally, EA decreased the CP-induced increments in abnormalities of sperm. Whereas CP increased the MDA levels of plasma, sperm, and testicular tissue, it decreased the GSH-Px and CAT activities in the study samples compared with the control group. The administration of EA to CP-treated rats decreased the MDA level and increased GSH-Px and CAT activities in these samples. Cisplatin caused degeneration, necrosis, interstitial edema, and reduction in germinative cell layer thickness and rarely reduction in spermatogenic activity in some seminiferous tubules. The CP-induced changes in histopathologic findings of testis were partially reversed by treatment with EA. No significant changes were observed in the histopathologic structure of the prostate among any of groups.
Ellagic acid has a protective effect against testicular toxicity caused by CP. This protective effect of EA seems to be closely involved with the suppressing of oxidative stress.