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Nanomedicine: A pragmatic approach for tackling melanoma skin cancer
... The delivery of nanoparticles using FRα has shown similar results in other subtypes of solid tumors. Prajapat et al. found that delivery of immunotherapeutic and targeted agents using nanoparticle technology has promise in reducing the loss of appropriate targeting and specificity for tumor cells in melanomas [33]. Wang et al. showed that not only is FRα useful for diagnosing lung cancer, but it can also be useful in detecting lung-cancer recurrence [34]. ...
... Singh et al. generated novel planetary ball milled (PBM) nanoparticles encapsulating resveratrol (RES) and docetaxel and combined with folic acid, which lowered resistance to docetaxel through inhibition of drug efflux [31]. Nanoparticle technology has also explored improved delivery of immunotherapy for melanoma treatment [33]. Chemotherapies that exploit FRα can be made more effective because drug conjugates can target FRα. ...
Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate. Folate is taken up by the cell via this receptor, which also targeted by many cancer agents due to the over-expression of the receptor by cancer cells. FR is a membrane-bound glycosyl-phosphatidylinositol (GPI) anchor glycoprotein encoded by the folate receptor 1 (FOLR1) gene. FR plays a significant role in DNA synthesis, cell proliferation, DNA repair, and intracellular signaling, all of which are essential for tumorigenesis. FR is more prevalent in cancer cells compared to normal tissues, which makes it an excellent target for oncologic therapeutics. FRα is found in many cancer types, including ovarian cancer, non-small-cell lung cancer (NSCLC), and colon cancer. FR is widely used in antibody drug conjugates, small-molecule-drug conjugates, and chimeric antigen-receptor T cells. Current oncolytic therapeutics include mirvetuximab soravtansine, and ongoing clinical trials are underway to investigate chimeric antigen receptor T cells (CAR-T cells) and vaccines. Additionally, FRα has been used in a myriad of other applications, including as a tool in the identification of tumor types, and as a prognostic marker, as a surrogate of chemotherapy resistance. As such, FRα identification has become an essential part of precision medicine.
... 6,7 Therefore, in this study we want to make nanoparticles from melanoma cancer cells, hoping that the nanoparticles can be attached and fused inside the melanoma cancer cells, to enhance the action of anticancer drugs and make the drugs more effective by directly targeting the cancer cells and destroy cancer cells. 8 In recent years, astaxanthin has been confirmed by various medical and biotechnology researchers to have excellent anti-oxidation, vision improvement, immunity enhancement, and even excellent anti-tumor abilities, a large number of related healthcare and nutrition products have gradually come into the market. [9][10][11][12][13][14] Hence, we decided to use astaxanthin as a precursor drug to inhibit melanoma and use melanoma cancer cells as nano-carriers, hoping to achieve the purpose of effective treatment of melanoma. ...
Background
Recently, the use of the tumor or its secretions as drug carriers has gradually become popular, with the advantages of high biocompatibility and enhanced drug delivery to specific cells. Melanoma is the most malignant tumor of all skin cancers; it is the most metastatic and, therefore, the most difficult to treat. The main purpose of this study is to develop nanovesicles with tumor cell membrane secretion properties to encapsulate target substances to enhance the therapeutic effect of cancer.
Methods
Astaxanthin was selected as an anticancer drug due to our previous research finding that astaxanthin has extremely high antioxidant, anti-ultraviolet damage, and anti-tumor properties. The manufacturing method of the astaxanthin nanovesicle carrier is to mix melanoma cells and astaxanthin in an appropriate ratio and then remove the genetic material and inflammatory factors of cancer cells by extrusion.
Results
In terms of results, after the co-culture of astaxanthin nanovesicles and melanoma cancer cells, it was confirmed that the ability of astaxanthin nanovesicles to inhibit the growth and metastasis of melanoma cancer cells was significantly better than the same amount of astaxanthin alone, and it had no effect on normal Human cells are also effective. There was no apparent harm on normal cells, indicating the ability of the vesicles to be selectively transported.
Conclusion
Our findings illustrated the potential of astaxanthin nanovesicles as an anticancer drug.
This analysis explores the principal regulatory concerns linked to nanomedicines and gene vaccines, including the complexities involved and the perspectives on how to navigate them. In the realm of nanomedicines, ensuring the safety of nanomaterials is paramount due to their unique characteristics and potential interactions with biological systems. Regulatory bodies are actively formulating guidelines and standards to assess the safety and risks associated with nanomedicine products, emphasizing the need for standardized characterization techniques to accurately gauge their safety and effectiveness. Regarding gene vaccines, regulatory frameworks must be tailored to address the distinct challenges posed by genetic interventions, necessitating special considerations in safety and efficacy evaluations, particularly concerning vector design, target specificity, and long-term patient monitoring. Ethical concerns such as patient autonomy, informed consent, and privacy also demand careful attention, alongside the intricate matter of intellectual property rights, which must be balanced against the imperative of ensuring widespread access to these life-saving treatments. Collaborative efforts among regulatory bodies, researchers, patent offices, and the private sector are essential to tackle these challenges effectively, with international cooperation being especially crucial given the global scope of nanomedicine and genetic vaccine development. Striking the right balance between safeguarding intellectual properties and promoting public health is vital for fostering innovation and ensuring equitable access to these ground-breaking technologies, underscoring the significance of addressing these regulatory hurdles to fully harness the potential benefits of nanomedicine and gene vaccines for enhancing healthcare outcomes on a global scale.
Niosomes are vesicular nanocarriers, biodegradable, relatively non-toxic, stable, and inexpensive, that provide an alternative for lipid-solid carriers (e.g., liposomes). Niosomes may resolve issues related to the instability, fast degradation, bioavailability, and insolubility of different drugs or natural compounds. Niosomes can be very efficient potential systems for the specific delivery of anticancer, antioxidant, anti-inflammatory, antimicrobial, and antibacterial molecules. This review aims to present an overview of their composition, the most common formulation techniques, as well as of recent utilizations as delivery systems in cancer therapy.
In the last decade, investigators have put significant efforts to develop several diagnostic and therapeutic strategies against cancer. Many novel nanoplatforms, including lipidic, metallic, and inorganic nanocarriers, have shown massive potential at preclinical and clinical stages for cancer diagnosis and treatment. Each of these nano-systems is distinct with its own benefits and limitations. The need to overcome the limitations of single-component nano-systems, improve their morphological and biological features, and achieve multiple functionalities has resulted in the emergence of hybrid nanoparticles (HNPs). These HNPs integrate multicomponent nano-systems with diagnostic and therapeutic functions into a single nano-system serving as promising nanotools for cancer theragnostic applications. Chitosan (CS) being a mucoadhesive, biodegradable, and biocompatible biopolymer, has emerged as an essential element for the development of HNPs offering several advantages over
conventional nanoparticles including pH-dependent drug delivery, sustained drug release, and enhanced nanoparticle stability. In addition, the free protonable amino groups in the CS backbone offer flexibility to its structure, making it easy for the modification and functionalization of CS, resulting in better drug targetability
and cell uptake. This review discusses in detail the existing different oncology-directed CS-based HNPs including their morphological characteristics, in-vitro/in-vivo outcomes, toxicity concerns, hurdles in clinical translation, and future prospects.
Background and Purpose
Safe and effective drug delivery is crucial for the treatment of cancer, which is quite impossible to achieve through traditional methods. Among all types of cancer, skin melanoma is known for its aggressive metastasizing ability and an unprecedented higher degree of lethalness, limiting the overall therapeutic efficacy. Here, we focus on the different types of nanomaterials (NMs) and their drug delivery applications against melanoma.
Experimental Approach
All relevant publications, including research papers, reviews, chapters and patents, were assessed using search engines such as Scopus and PubMed, up to the end of August of 2023. The keywords used in the search were: nanomaterials, melanoma, drug delivery routes for melanoma, and nanomaterial-based drug delivery systems (DDS). Most of the publications out of 234 cited in this review are from the last five years.
Key Results
The recent advancement and mechanism of action of various NMs against melanoma, including inorganic metallic and carbon-based NMs, organic polymeric and lipid-based NMs, and cell-derived vesicles are discussed. We also focus on the application of different NMs in the delivery of therapeutic agents for melanoma therapy. In addition, the skin and melanoma, genetic mutation and pathways for melanoma, conventional treatment options, and delivery routes for therapeutic agents are also discussed briefly.
Conclusion
There are few NM-based DDS developed in the lab set up recently. The findings of this review will pave the path for the development of NM-based DDS on an industrial scale and help in the better management of skin melanoma.
Cancer is responsible for high mortality rates worldwide, representing a serious health problem. In this sense, melanoma corresponds to the most aggressive type of skin cancer, being the cause of the highest death rates. Therapeutic strategies for the treatment of melanoma remain limited, with problems associated with toxicity, serious side effects, and mechanisms of resistance. The potential of natural products for the prevention and treatment of melanoma has been reported in different studies. Among these compounds, naphthoquinones (1,2-naphthoquinones and 1,4-naphthoquinones) stand out for their diverse pharmacological properties, including their antitumor activity. Thus, this review covers different studies found in the literature on the application of natural naphthoquinones targeting melanoma, providing information regarding the mechanisms of action investigated for these compounds. Finally, we believe that this review provides a comprehensive basis for the use of natural naphthoquinones against melanoma and that it may contribute to the discovery of promising compounds, specifically naphthoquinones, aimed at the treatment of this cancer.
Curcumin possesses remarkable chemotherapeutic activity owing to its anti-inflammatory and anti-oxidant properties. Purpose of the research work was to prepare curcumin-loaded nanoparticles of Eudragit E 100 for topical skin applications through a simple, cost-effective method of nanoprecipitation. Resultant formulation will enhance the water solubility, permeability and bioactivity of curcumin. The particle size and morphology were investigated by dynamic light scattering and electron microscopy. The encapsulation efficiency, drug loading, in vitro drug release were determined by UV spectroscopy. In vitro drug release was conducted at acidic and neutral pH. The interaction of drug with polymers was investigated by Fourier-transform infrared spectroscopy. Ex vivo skin penetration study was conducted using vertical Franz diffusion cell to assess the potential of curcumin nanoparticles to cross the stratum corneum. In vivo evaluation was done in mice model. Results illustrated that particles were in nanometers (˂ 120 nm), with narrow size distribution, spherical in shape and with encapsulation efficiency of more than 75%. Drug release demonstrated the acid-responsive behavior of curcumin nanoparticles while ex vivo permeation and in vivo studies show prominent results of the formulation. It can be concluded from the results that curcumin nanoparticles have a potential to be designed successfully in future as a topical dosage form for the treatment of skin cancer. The present research work concludes that Eudragit E100 can fulfill the requirements related to delivery of curcumin for topical use for the local treatment of skin cancer.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized‐stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized‐stage diagnoses (from 17% in 2004 to 28% in 2018) and 3‐year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.
The aim of this study was to prepare and evaluate α-mangostin-loaded polymeric nanoparticle gel (α-MNG-PLGA) formulation to enhance α-mangostin delivery in an epidermal carcinoma. The poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed using the emulsion-diffusion-evaporation technique with a 3-level 3-factor Box-Behnken design. The NPs were characterized and evaluated for particle size distribution, zeta potential (mV), drug release, and skin permeation. The formulated PLGA NPs were converted into a preformed carbopol gel base and were further evaluated for texture analysis, the cytotoxic effect of PLGA NPs against B16-F10 melanoma cells, and in vitro radical scavenging activity. The nanoscale particles were spherical, consistent, and average in size (168.06 ± 17.02 nm), with an entrapment efficiency (EE) of 84.26 ± 8.23% and a zeta potential of -25.3 ± 7.1 mV. Their drug release percentages in phosphate-buffered solution (PBS) at pH 7.4 and pH 6.5 were 87.07 ± 6.95% and 89.50 ± 9.50%, respectively. The release of α-MNG from NPs in vitro demonstrated that the biphasic release system, namely, immediate release in the initial phase, was accompanied by sustained drug release. The texture study of the developed α-MNG-PLGA NPs gel revealed its characteristics, including viscosity, hardness, consistency, and cohesiveness. The drug flux from α-MNG-PLGA NPs gel and α-MNG gel was 79.32 ± 7.91 and 16.88 ± 7.18 µg/cm2/h in 24 h, respectively. The confocal study showed that α-MNG-PLGA NPs penetrated up to 230.02 µm deep into the skin layer compared to 15.21 µm by dye solution. MTT assay and radical scavenging potential indicated that α-MNG-PLGA NPs gel had a significant cytotoxic effect and antioxidant effect compared to α-MNG gel (p < 0.05). Thus, using the developed α-MNG-PLGA in treating skin cancer could be a promising approach.
Photodynamic therapy is one of the more unique cancer treatment options available in today’s arsenal against this devastating disease. It has historically been explored in cutaneous lesions due to the possibility of focal/specific effects and minimization of adverse events. Advances in drug delivery have mostly been based on biomaterials, such as liposomal and hybrid lipoidal vesicles, nanoemulsions, microneedling, and laser-assisted photosensitizer delivery systems. This review summarizes the most promising approaches to enhancing the photosensitizers’ transdermal delivery efficacy for the photodynamic treatment for cutaneous pre-cancerous lesions and skin cancers. Additionally, discussions on strategies and advantages in these approaches, as well as summarized challenges, perspectives, and translational potential for future applications, will be discussed.
Photodynamic therapy (PDT) has been used as an anti-tumor treatment method for a long time and photosensitizers (PS) can be used in various types of tumors. Originally, light is an effective tool that has been used in the treatment of diseases for ages. The effects of combination of specific dyes with light illumination was demonstrated at the beginning of 20th century and novel PDT approaches have been developed ever since. Main strategies of current studies are to reduce off-target effects and improve pharmacokinetic properties. Given the high interest and vast literature about the topic, approval of PDT as the first drug/device combination by the FDA should come as no surprise. PDT consists of two stages of treatment, combining light energy with a PS in order to destruct tumor cells after activation by light. In general, PDT has fewer side effects and toxicity than chemotherapy and/or radiotherapy. In addition to the purpose of treatment, several types of PSs can be used for diagnostic purposes for tumors. Such approaches are called photodynamic diagnosis (PDD). In this Review, we provide a general overview of the clinical applications of PDT in cancer, including the diagnostic and therapeutic approaches. Assessment of PDT therapeutic efficacy in the clinic will be discussed, since identifying predictors to determine the response to treatment is crucial. In addition, examples of PDT in various types of tumors will be discussed. Furthermore, combination of PDT with other therapy modalities such as chemotherapy, radiotherapy, surgery and immunotherapy will be emphasized, since such approaches seem to be promising in terms of enhancing effectiveness against tumor. The combination of PDT with other treatments may yield better results than by single treatments. Moreover, the utilization of lower doses in a combination therapy setting may cause less side effects and better results than single therapy. A better understanding of the effectiveness of PDT in a combination setting in the clinic as well as the optimization of such complex multimodal treatments may expand the clinical applications of PDT.
Aims
Skin cancer is the most widespread cancer worldwide, mainly caused by exposure to ultraviolet radiation (UV) in sunlight. Utilizing topical preventive agents in routinely daily used cosmetics may prevent UV-related skin damages and skin cancers. γ-Oryzanol (GO) is a natural component derived from rice bran oil, with potential antioxidant and skin anti-aging properties.
Main methods
We biologically thorough studied the antioxidant and anticancer effects of GO in vitro to found the effective signaling pathways, then evaluated the sun protection factor of prepared formulation, and finally investigated the long-term preventive effects of GO-loaded nanoethosomes (GO-NEs) against UVB-induced skin cancer in mice.
Key findings
GO-NEs could effectively prevent UVB-induced skin cancer.
Significance
Our results suggest that GO-NEs could be utilized as an innovative ingredient in cosmetics.
The increasing prevalence of cancer, a disease in which rapid and uncontrollable cell growth causes complication and tissue dysfunction, is one of the serious and tense concerns of scientists and physicians. Nowadays, cancer diagnosis and especially its effective treatment have been considered as one of the biggest challenges in health and medicine in the last century. Despite significant advances in drug discovery and delivery, their many adverse effects and inadequate specificity and sensitivity, which usually cause damage to healthy tissues and organs, have been great barriers in using them. Limitation in the duration and amount of these therapeutic agents’ administration is also challenging. On the other hand, the incidence of tumor cells that are resistant to typical methods of cancer treatment, such as chemotherapy and radiotherapy, highlights the intense need for innovation, improvement, and development in antitumor drug properties. Liposomes have been suggested as a suitable candidate for drug delivery and cancer treatment in nanomedicine due to their ability to store drugs with different physical and chemical characteristics. Moreover, the high flexibility and potential of liposome structure for chemical modification by conjugating various polymers, ligands, and molecules is a significant pro for liposomes not only to enhance their pharmacological merits but also to improve the effectiveness of anticancer drugs. Liposomes can increase the sensitivity, specificity, and durability of these anti-malignant cell agents in the body and provide remarkable benefits to be applied in nanomedicines. We reviewed the discovery and development of liposomes focusing on their clinical applications to treat diverse sorts of cancers and diseases. How the properties of liposomal drugs can be improved and their opportunity and challenges for cancer therapy were also considered and discussed.
Graphic abstract
Polyphenols such as curcumin (Cur) and resveratrol (Res) have been recently shown to have potential to inhibit proliferation of highly aggressive melanoma cells. This study was designed to investigate the feasibility of a topical delivery system, using a solid lipid nanoparticles (SLNs) loaded delivery systems, that can enhance the skin penetration and anti-cancer efficacy of combination of these polyphenols. Negatively charged Cur-Res SLNs with a mean diameter of 180.2 ± 7.7 nm were prepared using high shear homogenization method. Cur-Res SLNs were found to be stable up to 2 weeks under 4°C. The in vitro release study showed that Res was released five time more than curcumin. The permeability of resveratrol was about 1.67 times that of curcumin from the SLN-gel formulation which was significantly (p < 0.05) lower than from SLN suspension. More than 70% of Cur-Res SLNs were bound to skin locally in a skin binding study suggesting potentially utility of Cur-Res SLNs in the treatment of localized melanoma. In fact, the electrical cell-substrate impedance sensing (ECIS) measurements suggested that Cur-Res combination has potential to stop cell migration of B16F10 melanoma cells. Furthermore, both, Cur-Res SLNs and Cur-Res solution at the ratio of 3:1 demonstrated a strong synergistic inhibition of SK-MEL-28 melanoma cell proliferation. Further evaluation of Cur-Res SLNs in vivo melanoma models are warranted to establish the clinical utility of Cur-Res formulations in melanoma therapy.
Graphical abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide‐binding proteins GNAQ/GNA11, and loss of the BRACA1‐associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies. Attempts to utilise the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors which are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualised tumour profiling. It would also be important to characterise UM tumours to differentiate the potential drivers of progression from those in other types of cancers. The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM‐specific treatments feasible.
Malignant melanoma is a life-threatening form of skin cancer with a low response rate to single-agent chemotherapy. Although combined therapies of metformin (MET) and doxorubicin (DOX) are effective in treating a variety of cancers, including breast cancer, their different physicochemical properties and administration routines reduce the effective co-accumulation of both drugs in tumors. Nanoparticles (NPs) have been demonstrated to potentially improve drug delivery efficiency in cancer therapy of, for example, liver and lung cancers. Hence, in this study, we prepared pH-sensitive, biocompatible, tumor-targeting NPs based on the conjugation of biomaterials, including sodium alginate, cholesterol, and folic acid (FCA). As expected, since cholesterol and folic acid are two essentials, but insufficient, substrates for melanoma growth, we observed that the FCA NPs specifically and highly effectively accumulated in xenograft melanoma tumors. Taking advantage of the FCA NP system, we successfully co-delivered a combination of MET and DOX into melanoma tumors to trigger pyroptosis, apoptosis, and necroptosis (PANoptosis) of the melanoma cells, thus blocking melanoma progression. Combined, the establishment of such an FCA NP system provides a promising vector for effective drug delivery into melanoma and increases the possibility and efficiency of drug combinations for cancer treatment.
Chemotherapy has limited success in the treatment of malignant melanoma due to fast development of drug resistance and the low bioavailability of chemotherapeutic drugs. Resveratrol (RES) is a natural polyphenol with recognized preventive and therapeutic anti-cancer properties. However, poor RES solubility hampers its bioactivity, thus creating a demand for suitable drug delivery systems to improve it. This work aimed to assess the potential of RES-loaded mesoporous silica nanoparticles (MSNs) for human melanoma treatment. RES was efficiently loaded (efficiency > 93%) onto spheroidal (size~60 nm) MSNs. The encapsulation promoted the amorphization of RES and enhanced the release in vitro compared to non-encapsulated RES. The RES release was pH-dependent and markedly faster at pH 5.2 (acid environment in some tumorous tissues) than at pH 7.4 in both encapsulated and bulk forms. The RES release from loaded MSNs was gradual with time, without a burst effect, and well-described by the Weibull model. In vitro cytotoxicity studies on human A375 and MNT-1 melanoma cellular cultures showed a decrease in the cell viability with increasing concentration of RES-loaded MSNs, indicating the potent action of the released RES in both cell lines. The amelanotic cell line A375 was more sensitive to RES concentration than the melanotic MNT-1 cells.
Purpose
A near-infrared (NIR)-triggered trans-activating transcriptional activator (TAT)-based targeted drug delivery system for the combined chemo/photothermal therapy of melanoma, namely, TAT-TSL-TMZ (temozolomide)/IR820, was developed for the first time.
Methods
TAT-TSL-TMZ/IR820 liposomes were synthesized via thin-film dispersion and sonication. IR820 and TMZ were encased in the inner layer and lipid bilayer of the liposomes, respectively.
Results
Dynamic light scattering results showed that the liposomes had an average hydrodynamic size of 166.9 nm and a zeta potential of −2.55 mV. The encapsulation rates of TMZ and IR820 were 35.4% and 28.6%, respectively. The heating curve obtained under near-infrared (NIR) laser irradiation showed that TAT-TSL-TMZ/IR820 liposomes had good photothermal conversion efficiency. The in vitro drug release curve revealed that NIR laser irradiation could accelerate drug release from TAT-TSL-TMZ/IR820 liposomes. The results of inverted fluorescence microscopy and flow cytometry proved that the uptake of TAT-TSL-TMZ/IR820 liposomes by human melanoma cells (MV3 cells) was concentration-dependent and that the liposomes modified with membrane peptides were more likely to be ingested by cells than unmodified liposomes. Confocal laser scanning microscopy indicated that TAT-TSL-TMZ/IR820 liposomes entered MV3 cells via endocytosis and was stored in lysosomes. In addition, TAT-TSL-TMZ/IR820 liposomes exposed to NIR laser showed 89.73% reduction in cell viability.
Conclusion
This study investigated the photothermal conversion, cell uptake, colocation and chemo/photothermal effect of TAT-TSL-TMZ/IR820 liposomes.
Carbon is one of the most abundant elements on Earth. In addition to the well-known crystallographic modifications such as graphite and diamond, other allotropic carbon modifications such as graphene-based nanomaterials and carbon nanotubes have recently come to the fore. These carbon nanomaterials can be designed to help deliver or target drugs more efficiently and to innovate therapeutic approaches, especially for cancer treatment, but also for the development of new diagnostic agents for malignancies and are expected to help combine molecular imaging for diagnosis with therapies. This paper summarizes the latest designed drug delivery nanosystems based on graphene, graphene quantum dots, graphene oxide, reduced graphene oxide and carbon nanotubes, mainly for anticancer therapy.
[This corrects the article DOI: 10.1155/2014/895986.].
This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2‐fold to 3‐fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2‐fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
Simple Summary
The incidence of cutaneous malignant melanoma is increasing worldwide. Despite available modern therapeutical options, long-term survival of patients in advanced stages of the disease remains rather limited until now. Detailed insights into etiopathogenesis and mechanisms of tumour progression enable physicians to manipulate distinct molecular structures and pathways therapeutically and so treat the tumour. Unfortunately, the acquisition of therapeutic resistance frequently terminates these therapeutical interventions. The presented special issue is focusing on the research and therapeutic experience of leading scientists, and it summarises the state of the art of targeted therapy of melanoma and suggests the new perspectives of the treatment of disease.
Nanotechnology has been extensively studied and exploited for cancer treatment as nanoparticles can play a significant role as a drug delivery system. Compared to conventional drugs, nanoparticle-based drug delivery has specific advantages, such as improved stability and biocompatibility, enhanced permeability and retention effect, and precise targeting. The application and development of hybrid nanoparticles, which incorporates the combined properties of different nanoparticles, has led this type of drug-carrier system to the next level. In addition, nanoparticle-based drug delivery systems have been shown to play a role in overcoming cancer-related drug resistance. The mechanisms of cancer drug resistance include overexpression of drug efflux transporters, defective apoptotic pathways, and hypoxic environment. Nanoparticles targeting these mechanisms can lead to an improvement in the reversal of multidrug resistance. Furthermore, as more tumor drug resistance mechanisms are revealed, nanoparticles are increasingly being developed to target these mechanisms. Moreover, scientists have recently started to investigate the role of nanoparticles in immunotherapy, which plays a more important role in cancer treatment. In this review, we discuss the roles of nanoparticles and hybrid nanoparticles for drug delivery in chemotherapy, targeted therapy, and immunotherapy and describe the targeting mechanism of nanoparticle-based drug delivery as well as its function on reversing drug resistance.
Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)—an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma—in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4⁺ and CD8⁺ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
Purpose
Melanoma is the most aggressive form of skin cancer. Chemotherapy at a late stage fails due to low accumulation in tumors, indicating the need for targeted therapy.
Materials and methods
To increase drug uptake by tumor cells, we have targeted doxorubicin-containing liposomes using a T-cell receptor (TCR)-like antibody (scFv G8 and Hyb3) directed against melanoma antigen A1 (MAGE-A1) presented by human leukocyte antigen A1 (M1/A1). With the use of flow cytometry and confocal microscopy, we have tested our formulation in vitro. In vivo pharmacokinetics was done in tumor-free nu/nu mice, while biodistribution and efficacy study was done in nu/nu mice xenograft.
Results
We demonstrated two to five times higher binding and internalization of these immunoliposomes by M1⁺/A1⁺ melanoma cells in vitro in comparison with nontargeted liposomes. Cytotoxicity assay showed significant tumor cell kill at 10 µM doxorubicin (DXR) for targeted vs nontargeted liposomes. In vivo pharmacokinetics of nontargeted and targeted liposomes were similar, while accumulation of targeted liposomes was 2- to 2.5-fold and 6.6-fold enhanced when compared with nontargeted liposomes and free drug, respectively. Notably, we showed a superior antitumor activity of MAGE-A1-targeted DXR liposomes toward M1⁺/A1⁺ expressing tumors in mice compared with the treatment of M1⁻/A1⁺ tumors. Our results indicate that targeted liposomes showed better cytotoxicity in vitro and pharmacokinetics in vivo.
Conclusion
Liposomes decorated with TCR-mimicking scFv antibodies effectively and selectively target antigen-positive melanoma. We showed that DXR-loaded liposomes coupled to anti-M1/-A1 scFv inflict a significant antitumor response. Targeting tumor cells specifically promotes internalization of drug-containing nanoparticles and may improve drug delivery and ultimately antitumor efficacy. Our data argue that targeting MAGE in A1 context, by nanosized carriers decorated with TCR-like antibodies mimicking scFv, can be used as a theragnostic platform for drug delivery, immunotherapy, and potentially imaging, and diagnosis of melanoma.
The poly (lactic‐co‐glycolic acid) nanoparticle (PLGA NP) has been widely used in the biomedical field. However, it is insensitive to degradation upon laser irradiation, resulting in a limited increase in drug release, which compromises the therapeutic efficacy. To actively promote drug release, the biphasic α‐tocopheryl succinate (TPGS) functionalized PLGA NPs (PTNPs) are developed by introducing TPGS into the aqueous and organic phase to generate pores in the PLGA core during preparation. Paclitaxel and indocyanine green are encapsulated in the PTNPs to realize chemo‐photothermal combined therapy, and PTNPs are delivered through dissolving microneedles (DMNs) for local treatment in melanoma. PTNPs show enhanced drug release and improved cytotoxicity due to their greater ability in inhibiting cell microtubule depolymerization. In vivo tumor suppression investigation and ki‐67 immunohistochemical staining of tumor tissue further show the superiority of PTNPs loaded DMNs against tumor growth, and photothermal therapy synergistically enhances the chemotherapeutic effect of PTNPs. Moreover, the living imaging of mice demonstrates that the drug is successfully retained in the tumor tissue to avoid it entering into the circulation and producing adverse effects. Therefore, the PTNPs loaded DMNs show a favorable prospect in the treatment of superficial tumor.
Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Almost 70-80% of cases of BC are curable at the early non-metastatic stage. BC is a heterogeneous disease with different molecular subtypes. Around 70% of breast tumors exhibit estrogen-receptor (ER) expression and endocrine therapy is used for the treatment of these patients. However, there are high chances of recurrence in the endocrine therapy regimen. Though chemotherapy and radiation therapy have substantially improved survival rates and treatment outcomes in BC patients, there is an increased possibility of the development of resistance and dose-limiting toxicities. Conventional treatment approaches often suffer from low bioavailability, adverse effects due to the non-specific action of chemotherapeutics, and low antitumor efficacy. Nanomedicine has emerged as a conspicuous strategy for delivering anticancer therapeutics in BC management. It has revolutionized the area of cancer therapy by increasing the bioavailability of the therapeutics and improving their anticancer efficacy with reduced toxicities on healthy tissues. In this article, we have highlighted various mechanisms and pathways involved in the progression of ER-positive BC. Further, different nanocarriers delivering drugs, genes, and natural therapeutic agents for surmounting BC are the spotlights of this article.
Amongst the several nano-drug delivery systems, lipid or polymer-based core–shell nanocapsules (NCs) have garnered much attention of researchers owing to its multidisciplinary properties and wide application. NCs are structured core–shell systems in which the core is an aqueous or oily phase protecting the encapsulated drug from environmental conditions, whereas the shell can be lipidic or polymeric. The core is stabilized by surfactant/lipids/polymers, which control the release of the drug. The presence of a plethora of biocompatible lipids and polymers with the provision of amicable surface modifications makes NCs an ideal choice for precise drug delivery. In the present article, multiple lipidic and polymeric NC (LNCs and PNCs) systems are described with an emphasis on fabrication methods and characterization techniques. Far-reaching applications as a carrier or delivery system are demonstrated for oral, parenteral, nasal, and transdermal routes of administration to enhance the bioavailability of hard-to-formulate drugs and to achieve sustained and targeted delivery. This review provide in depth understanding on core–shell NC’s mechanism of absorption, surface modification, size tuning, and toxicity moderation which overshadows the drawbacks of conventional approaches. Additionally, the review shines a spotlight on the current challenges associated with core–shell NCs and applications in the foreseeable future.Graphical Abstract
The gene therapy is an alternative approach to melanoma treatments due to several drug resistance that this type of cancer developed and to perform an efficiently in vivo gene therapy the use of vectors is generally required. The non-viral vectors can guarantee the biological effect of DNA or RNA, increasing their stability and uptake, also, presenting lesser adverse effects and immunogenicity than viral-based ones, however, to perform an in vivo gene therapy there are plenty of challenges to be faced. This review, considering the fact that there is no ideal non-viral vector for melanoma gene therapy, but rather, there are several possibilities that bring us relevant and illustrative contributions on the magnitude of this subject, points out the main challenges to perform gene therapy from non-viral vectors for the melanoma skin cancer, focusing on the most studied strategies to overcome them. In this way it was considered as challenges: the administration route and the vector choice; aspects in the non-viral vectors’ preparation process; effectiveness and safety, and pre-clinical and clinical aspects.
Melanoma is an aggressive malignancy deriving from melanocytes, which is characterized by high tendency of metastases and mortality rate. Current therapies for melanoma, like chemotherapy, immunotherapy and targeted therapy, have the problem of systemic exposure of drugs, which will lead to many side effects and premature degradation of drugs. The resulting low drug accumulation at the lesion limits the therapeutic effect on melanoma and makes the cure rate low. As an emerging drug delivery system, microneedles (MNs) can efficiently deliver drugs through the skin, increase the drug distribution in deeper tumor sites and minimize the leakage of therapeutic drugs into adjacent tissues, thus improving the therapeutic effect. In addition, compared with traditional drug delivery methods, MN-based drug delivery system has the advantages of simplicity, safety and little pain. So MNs can be developed for the treatment of melanoma, which can relieve the pain of patients and improve the survival rate. This review aims to introduce an update on the progress of MNs as an innovative strategy for melanoma, especially when MNs combining with different therapies against melanoma, such as chemotherapy, targeted therapy, immunotherapy, photothermal therapy (PTT), photodynamic therapy (PDT) and synergic therapy.
Hematological malignancy like lymphoma originates in lymph tissues and has a propensity to spread across other organs. Managing such tumors is challenging as conventional strategies like surgery and local treatment are not plausible options and there are high chances of relapse. The advent of novel targeted therapies and antibody-mediated treatments has proven revolutionary in the management of these tumors. Although these therapies have an added advantage of specificity in comparison to the traditional chemotherapy approach, such treatment alternatives suffer from the occurrence of drug resistance and dose-related toxicities. In past decades, nanomedicine has emerged as an excellent surrogate to increase the bioavailability of therapeutic moieties along with a reduction in toxicities of highly cytotoxic drugs. Nanotherapeutics achieve targeted delivery of the therapeutic agents into the malignant cells and also have the ability to carry genes and therapeutic proteins to the desired sites. Furthermore, nanomedicine has an edge in rendering personalized medicine as one type of lymphoma is pathologically different from others. In this review, we have highlighted various applications of nanotechnology-based delivery systems based on lipidic, polymeric and inorganic nanomaterials that address different targets for effectively tackling lymphomas. Moreover, we have discussed recent advances and therapies available exclusively for managing this malignancy.
The suitability of poly(lactic acid-co-glycolic acid) (PLGA) as sustained drug delivery vehicle for melanoma treatment has been revealed through paclitaxel (PTX) encapsulated PLGA nanoparticles (NPs) and PLGA film. The efficacy of PLGA-PTX formulations in different forms has been compared using both in vitro and in vivo melanoma model. Drug release from both the delivery systems has been compared using in vitro drug release assay and eventual chemotherapeutic effects indicate greater impact of NPs as compared to film due to higher surface area and better encapsulation efficiency. In vitro application of PLGA-PTX NPs and film led to significantly reduced melanoma cell proliferation. These results are successfully extrapolated in mice melanoma model causing considerable reduction in melanoma tumor volume and expression of melanoma inhibitory activity protein as compared to pure drug and control group. The greatest advantage of the sustained drug delivery systems is visualized in the form of least damage to vital organs such as liver, kidney and spleen as confirmed through histopathological examination. Liver and kidney function tests using blood serum also indicate least side effects in the groups treated with PTX encapsulated PLGA film and NPs as compared to pure PTX. The present study demonstrates the significance of PLGA as sustained drug delivery vehicle and its application in melanoma tumor treatment.
The present work deals with the development of metformin-loaded ethosomes for localized treatment of melanoma and wound healing. Different ethosomal formulations were prepared using different concentrations of ethanol adopting injection technique. The developed formulations were investigated for entrapment efficiency, ex-vivo skin permeation, vesicle size, morphology and permeation kinetics. The optimized formulation was loaded in 5 % carbomer gel that was evaluated for skin permeation, cytotoxic effect against melanoma mice B16 cell line and for wound healing action. Ethosomes having 30 % v/v ethanol displayed superior entrapment for metformin % (55.3±0.07) ; and a highly efficient permeation via mice skin (85.8±3.7). The related carbomer ethosomal gel exhibited higher skin permeation compared to the untreated metformin gel (P < 0.001). The metformin ethosomes had a substantial antiproliferative activity against melanoma B16 cells compared to corresponding metformin solution as shown by the lower IC50 values (56.45±1.47 and 887.3±23.2, respectively, P<0.05) and tumour cell viability (P<0.05). The ethosomal system had a significant wound healing action in mice (80.5±1.9%) that was superior to that of the marketed product Mebo® ointment (56±1 %), P<0.05.
This ethosomal system demonstrated outstanding induction of the mRNA levels of growth factors (IGF-1, FGF-1, PDGF-B and TGF-β) that are essential in the healing process. Those findings were supported by histopathologic examination of wound sections of different treated groups. Thus, the study proved that metformin ethosomes as a promising drug delivery system and a conceivable therapeutic approach for treatment of melanoma and wound healing.
Objectives
Mycosynthesis offers a benevolent alternative for the synthesis of Silver Nanoparticles (AgNPs) when compared to the conventional physical and chemical methods. Fungi secrete enormous amounts of proteins and enzymes that act as reducing and capping agents in AgNPs synthesis.
Methods
AgNPs were synthesized using extracellular fungal extract of Fusarium incarnatum. The reaction mixture was optimized using different parameters to obtain better yield. Anti-melanogenic activity of fungal extract, AgNPs and standard drug (Kojic acid) was evaluated against Human skin melanoma SK-MEL-3 cells. AgNPs were synthesized at 30 °C, pH 5 and 1 mM AgNO3 concentration. Then optimization and the characterization were done by UV–Vis, FTIR, XRD, Zeta potential and H-TEM techniques.
Results
The average size of AgNPs was 10 nm and predominantly spherical in shape. Myco-synthesized AgNPs showed significant anti-melanogenic activity against human skin melanoma SK-MEL-3 cells with an IC50 value of 17.70 μg/ml. The concentration of AgNPs required to inhibit SK-MEL-3 cells was lower than the concentrations of F. incarnatum extract and standard Kojic acid.
Conclusion
Spherical AgNPs with and average size of 4 nm were synthesized using fungal extract of F. incarnatum. Mycosynthesized AgNPs can be considered as effective anti-melanogenic agents owing to their impressive activity against skin melanoma.
The potent photodynamic properties of Hypericin (Hyp) elicit a range of light-dose dependant anti-tumor activities. However, it is hampered by its low water solubility. Therefore, the administration of Hyp into biological systems requires drug carriers that would enable sufficient bioavailability. Stimuli-triggered nanocarriers, which are sensitive to endogenous or exogenous stimuli, have become an attractive replacement for conventional therapeutic regimens. Herein, we produced optimized Hyp thermosensitive liposomes (Hyp-TSL), which are self-assembled from DPPC, DSPC, DSPE-PEG2000. Hyp-TSL displayed a hydrodynamic diameter below 100 nm with an adequate encapsulation efficiency of 94.5 % and good colloidal stability. Hyp-TSL exhibited thermal sensitivity over a narrow range with a phase transition temperature of 41.1°C, in which liposomal destruction was evident in AFM images after elevated temperature above the phase transition temperature. The uptake of TSL-Hyp into MDA-MB-231 cells was significantly increased with hyperthermic treatment of 42°C when compared to the uptake at a normal physiological temperature of 37°C. Consequent enhancement of cellular reactive oxygen species was observed after hyperthermic treatment at 42°C. Hyp-TSL half-maximal inhibitory concentration was reduced by 3.8 fold after hyperthermic treatment at 42°C in comparison to treatment at 37°C. Hyp-TSL were considered safe for intravenous applications as compared by hemocompatibility studies, where coagulation time was less than 50 s and hemolytic potential was less than 10 %. Conclusively, the enhancement in tumor drug availability was correlated with improved therapeutic outcomes.
Photoactivated chemotherapy (PACT) is an emerging strategy for targeted cancer therapy. Strained Ru complexes with pseudo-octahedral geometry may undergo photo-induced ligand dissociation, forming aquated photoproducts that are significantly more cytotoxic compared to the precursor complex. The complexes investigated were the strained complex [Ru(bpy)2BC]Cl2 (where bpy = 2,2′-bipyridine and BC = bathocuproine) and its unstrained control [Ru(bpy)2phen]Cl2 (where phen = 1,10-phenanthroline). The uptake of [Ru(bpy)2BC]Cl2, assessed by ICP/MS, started immediately post-incubation and plateaued after 24 h. Active transport was found as the main mode of intracellular transport. Cell viability assays on A375 cells indicated a mean phototoxicity index of 340-fold, and the effect was shown to be primarily mediated by the aquated photoproducts rather than the dissociating ligands. A significant increase in ROS production and DNA damage was also observed. Flow cytometry confirmed the induction of early apoptosis at 48 h that proceeds to late apoptosis/necrosis by 72 h post-treatment. Western blot analysis of pro- and anti-apoptotic proteins revealed that apoptosis was mediated through an interplay between the intrinsic and extrinsic pathways, as well as autophagy and via inhibition of the MAPK and PI3K pathways. In conclusion, this study demonstrates that [Ru(bpy)2BC]Cl2 is a multi-mechanistic PACT drug which exhibits promising anticancer potential.
Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics — including issues associated with specificity, delivery and tolerability — and focus on promising emerging approaches that aim to boost their success. Over the past decade, several RNA-based therapies have gained FDA approval. Additional noncoding RNA (ncRNA)-based therapeutic approaches — targeting microRNAs and long ncRNAs — are now also gaining interest. Here, Calin and co-authors assess the hurdles facing the clinical translation of ncRNA-based therapeutics and highlight promising emerging solutions to address these issues.
Photodynamic Therapy (PDT) is a medical modality that has been applied against several types of cancer, macular degeneration, pointed condyloma, actinic keratosis as well as infections caused by fungi, viruses, and bacteria. When PDT is applied against microorganisms, the technique is called as antimicrobial photodynamic therapy (aPDT). PDT/aPDT principle involves the association of a light source (performed by a LASER, LED, and optical fiber), a non-toxic photosensitizer (PS), and molecular oxygen dissolved in the tissue of interest. The photosensitizer is excited by a light source of a specific wavelength which, in the presence of oxygen, generate high-cytotoxic reactive oxygen species (ROS) as well as superoxide anion (O2·−), hydroxyl radical (HO·), hydrogen peroxide (H2O2) and singlet oxygen (¹O2). These species cause damage to tumor cells and vasculatures by apoptosis, necrosis, and activating the immune responses. Among the main advantages of PDT is the specificity. This is guaranteed by the preferential accumulation of the photosensitizer in the cells of interest and the targeting of the lighting system without compromising healthy tissues. Additionally, it is a cheaper and less invasive than most known treatment, such as surgery, chemotherapy, and radiotherapy. Several classes of photosensitizers have been proposed for application in PDT treatment. It is necessary to mention phthalocyanines, porphyrins, bacteriochlorins, chlorines, chlorophyll-based compounds, phenothiazinium salts, and xanthene dyes. Generally, better PS compounds are hydrophobic once they accumulate in the interest tumors most effectively. However, the direct application of these in the body is harmful once PS can precipitate in the body, forming aggregates. Additionally, the pre-solubilization in an organic solvent before the application is not recommended once these are high toxicity in the cell. In this way, strategies have been proposed to solubilize hydrophobic PS in aqueous solutions and increase their biocompatibility. One of the most successful is the incorporation of PS in nanocarrier systems such as liposomes, copolymeric micelles, cyclodextrins, gold nanoparticles, microemulsions, self-assembled peptide-based nanomaterials, and others. Each nanocarrier has this specificity in order of its vantages and advantages. The main objective of this chapter is the description of PDT principles and understands more about formulations that have been used for PDT treatment.
Cancer is a leading cause of death throughout the world. Melanoma is a skin cancer with a significant impact on global public health. Application of nanotechnology in the field of cancer diagnosis, drug delivery, imaging and therapy, has the most attractive approach as nanoparticles reach target sites easily due to their unique properties. Previous studies have shown that titanium dioxide nanotubes (TNT) and quercetin are effective anticancer agents. However, conjugated TNT with quercetin (TNT–Qu) as a combinational treatment is unexplored yet. This study is aimed to explore the anticancer activity of TNT, quercetin, and TNT–Qu in B16F10 melanoma skin cancer cells. TNT–Qu significantly inhibited proliferation at 25 µg/mL of IC 50 lower than quercetin (34 µg/mL) and TNT alone (72 µg/mL). TNT–Qu treatment inhibited migration and significantly induced 60.29% apoptosis in melanoma cells when compared to TNT (14.14%) or quercetin (44.86%) alone treatment. Furthermore, quercetin and TNT–Qu decreased the reactive oxygen species and superoxide levels due to quercetin's antioxidant properties. TNT–Qu treatment arrested 55.5% cells in G2/M phase more than quercetin (30.7%) or pristine TNT (3.7%) treatment. The molecular mechanism of TNT–Qu on melanoma cells revealed that it enhanced the cleaved caspase-3 levels and induced more apoptosis than TNT or quercetin alone. Hence, Novel TNT–Qu exhibited enhanced anticancer properties and could be a potential therapeutic combinational molecule for the treatment of skin cancer. Schematic representation of the proposed mechanism of TNT, quercetin and TNT–Qu inducing apoptosis in B16F10 melanoma cells. TNT–Qu enhanced the cleaved caspase-3 and induced caspase-dependent apoptosis. Importantly, it down-regulates the ROS and dysfunctions mitochondria and enhances the DNA fragmentation.
The primary course of melanoma treatment involves surgery in association with chemotherapy. One potential agent is vinorelbine (VNR). While it displays anti-proliferative activity against melanoma cell lines, it presents a low oral bioavailability and intravenous administration often causes irritation, phlebitis and pain at the injection site. The aim of this study was to develop Pluronic® F-127 (PF-127) hydrogels containing VNR for the transdermal route of administration. Hydrogels composed of either 15% (G15), 20% (G20), 23% (G23) or 25% (G25) PF-127 aqueous solutions were loaded with a VNR propylene glycol solution. Their release and permeation profiles for VNR were evaluated in a Franz diffusion cell. In addition, their rheological behavior, visual aspect during storage and the in silico prediction of VNR absorption using GastroPlus® were evaluated. The G20 and G23 formulations showed similar release and permeation profiles with the G20 demonstrating a higher permeation of VNR at 8h (p<0.05) and cumulative permeated drug amount of 495.2 ± 46.7 μg/cm² at 24h. Further, their activity was tested on the melanoma cell lines SK-MEL28 and MV-3 to evaluate cell viability and proliferation. At VNR concentrations of 75 and 100 μg/mL, cell viability of both melanoma cells was lower in the presence of the G20 formulation than G23 after 24h of treatment although the proliferation profiles were similar. When combined with an in silico pharmacokinetic model, the results suggest that the transdermal administration of VNR could be a promising alternative to intravenous administration and that the G20 formulation would be an excellent candidate for the direct application onto melanomas.
In recent years, polymeric micelles have been extensively utilized in pre-clinical studies for delivering poorly soluble chemotherapeutic agents in cancer. Polymeric micelles are formed via self-assembly of amphiphilic polymers in facile manners. The wide availability of hydrophobic and, to some extent, hydrophilic polymeric blocks allow researchers to explore various polymeric combinations for optimum loading, stability, systemic circulation, and delivery to the target cancer tissues. Moreover, polymeric micelles could easily be tailor-made by increasing and decreasing the number of monomers in each polymeric chain. Some of the widely accepted hydrophobic polymers are poly(lactide) (PLA), poly(caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), polyesters, poly(amino acids), lipids. The hydrophilic polymers used to wrap the hydrophobic core are poly(ethylene glycol), poly(oxazolines), chitosan, dextran, and hyaluronic acids. Drugs could be conjugated to polymers at the distal ends to prepare pharmacologically active polymeric systems that impart enhanced solubility and stability of the conjugates and provide an opportunity for combination drug delivery. Their nano-size enables them to accumulate to the tumor microenvironment via the Enhanced Permeability and Retention (EPR) effect. Moreover, the stimuli-sensitive breakdown provides the micelles an effective means to deliver the therapeutic cargo effectively. The tumor micro-environmental stimuli are pH, hypoxia, and upregulated enzymes. Externally applied stimuli to destroy micellar disassembly to release the payload include light, ultrasound, and temperature. This article delineates the current trend in developing polymeric micelles combining various block polymeric scaffolds. The development of stimuli-sensitive micelles to achieve enhanced therapeutic activity are also discussed.
Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.
Dermatological applications of phloretin are restricted by its poor aqueous solubility. Nanotechnology has been proposed as strategy to increase the apparent drug solubility in aqueous media. This study aimed to develop, characterize, and evaluate the antitumoral effects and safety of polymeric nanocapsules containing phloretin (NCPhl). Further, to incorporate NC-Phl in an innovative semi-solid formulation (HG-NCPhl) to evaluate its performance using porcine skin model. NC-Phl was prepared and the effects in MRC5, HACAT, and SK-mel28 cells were evaluated. Hydrogels were prepared with Lecigel ® and characterized for their nanotechnological properties, adhesion (in vitro washability), and penetration/permeation studies in porcine skin. NC-Phl had a cytotoxic effect against Sk-Mel-28 cells and the population doubling time was increased upon treatment with NC-Phl for longer culture periods; notably when cells were treated for 72 h and then followed for 7 days after the treatment was removed (p < 0.05). HG-NC-Phl was considered adhesive and had a higher capacity to penetrate all skin layers compared with HG-Phl (p < 0.05). The innovative hydrogel HGNC-Phl promoted a drug-reservoir in the stratum corneum and higher penetration of the flavonoid into the epidermis. Therefore, this approach can be considered as a platform to establish versatile dermatological solutions for both cosmeceutics and melanoma therapy.
Aim
The aim of the study was to formulate, characterize, and evaluate the resveratrol-loaded cubosomes (RC) through topical application.
Background
Resveratrol (RV) is a nutraceutical compound that has exciting pharmacological potential in different diseases including cancers. Many studies of resveratrol have been reported for anti-melanoma activity. Due to its low bioavailability, the activities of resveratrol are strongly limited. Hence, an approach with nanotechnology has been done to increase its activity through transdermal drug delivery.
Objective
To formulate, characterize, and evaluate the resveratrol-loaded cubosomes (RC). To evaluate resveratrol-loaded cubosomal gel (RC-Gel) for its topical application.
Methods
RC was formulated by homogenization technique and optimized using a 2-factor 3-level factorial design. Formulated RCs were characterized for particle size, zeta potential, and entrapment efficiency. Optimized RC was evaluated for in vitro release and stability study. Optimized RC was further formulated into cubosomal gel (RC-Gel) using carbopol and evaluated for drug permeation and deposition. Furthermore, developed RC-Gel was evaluated for its topical application using skin irritancy, toxicity, and in vivo local bioavailability studies.
Results
The optimized RC indicated cubic-shaped structure with mean particle size, entrapment efficiency, and zeta potential were 113±2.36 nm, 85.07 ± 0.91%, and -27.40 ± 1.40 mV respectively. In vitro drug release of optimized RC demonstrated biphasic drug release with the diffusion-controlled release of resveratrol (RV) (87.20 ± 2.25%). The RC-Gel demonstrated better drug permeation and deposition in mice skin layers. The composition of RC-Gel has been proved non-irritant to the mice skin. In vivo local bioavailability study depicted the good potential of RC-Gel for skin localization.
Conclusion
The RC nanoformulation proposes a promising drug delivery system for melanoma treatment simply through topical application.
Transdermal drug delivery exhibited encouraging prospects, especially through superficial drug administration routes. However, only a few limited lipophilic drug molecules could cross the skin barrier, those are with low molecular weight and rational Log P value. Microneedles (MNs) can overcome these limitations to deliver numerous drugs into the dermal layer by piercing the outermost skin layer of the body. In the case of superficial cancer treatments, topical drug administration faces severely low transfer efficiency, and systemic treatments are always associated with side effects and premature drug degradation. MN-based systems have achieved excellent technical capabilities and been tested for pre-clinical chemotherapy, photothermal therapy, photodynamic therapy, and immunotherapy. In this review, we will focus on the features, progress, and opportunities of MNs in the anticancer drug delivery system. Then, we will discuss the strategies and advantages in these works and summarize challenges, perspectives, and translational potential for future applications.
The therapeutic efficacy of most chemotherapeutic drugs is hampered by low water solubility, poor stability, serious side effects, and lack of tumor selectivity. To solve these issues, chondroitin sulfate (CS)-based redox-responsive nanoparticles were developed. The amphiphilic polymer, CS-alpha-tocopherol succinate (TOS) (CS-CYS-TOS), was constructed by conjugating TOS on the CS backbone via cystamine (CYS) as a redox-sensitive linker, which could self-assemble to form polymeric nanoparticles in phosphate buffer saline (PBS). The resulting nanoparticles had low critical aggregation concentration (CAC) of 0.027 to 0.040 mg/mL, small size, and narrow size distribution. The docetaxel (DTX)-loaded nanoparticles were fabricated by the sonication method with high drug loading (DL) of 17.06% ± 0.97. The dynamic light scattering (DLS) and transmission electron microscope (TEM) had shown spherical nanoparticles with a size of 170.7 nm ± 2.8 and ∼160 nm, respectively, and zeta potential of -26.5 mV ± 1.5. The results of the reduction-triggered disassembly behavior study and in vitro release study revealed the redox-sensitive potential of CS-CYS-TOS nanoparticles. The nanoparticles exhibited time-dependent qualitative and quantitative uptake by melanoma cells. The Sulforhodamine B (SRB) assay indicated the safety of carrier material and enhanced anti-tumor activity of DTX-loaded nanoparticles. The in vivo biological performance of nanoparticles in tumor-bearing mice was evaluated and DTX/CS-CYS-TOS nanoparticles were superior in terms of tumor volume inhibition than other formulations. This nanoparticulate system responded to the reducing conditions in tumor cells, released drugs quickly and thoroughly, thereby improved the efficacy of chemotherapy.
The objective of this investigation was to develop dual drug-loaded nanostructured lipid carrier (NLC) gel of quercetin and resveratrol to enhance their disposition in dermal and epidermal layers. The optimization of the lipidic phase, i.e., liquid lipid and solid lipid was done on the basis of the solubility of quercetin & resveratrol in lipids in the preformulation stage. NLC formulation was optimized by Central composite rotatable design (CCRD). The NLC formulation contained lipid binary mixture (1.0% w/w) and Cremophor RH40 (5% w/v) as a surfactant and had a particle size of 191 nm ± 5.20, polydispersity index (PDI) of 0.33 ± 0.01, zeta potential (ZP) of -10.00 mV ± 0.30 and entrapment efficiency (EE) of 92.85 ± 0.25% (quercetin), 89.05 ± 0.18% (resveratrol) respectively. The flux and permeability coefficient of quercetin and resveratrol from NLC gel were found to be 14.09 µg/cm²/h, 3.70 µg/cm²/h and 7.21 × 10⁻² cm/h, 4.69 × 10⁻² cm/h respectively. Dermatokinetic studies revealed that there was a significant increase in the CSkin max and AUC0-8h in skin treated with NLC gel as compared to skin treated with conventional gel, which was prepared using carbopol 934 (1.5% w/w). Further, all claims of dermatokinetic studies were proved by confocal microscopic (CLMS) studies, which revealed that the disposition of combinatorial NLC gel was higher (∼3 folds) as compared to the conventional gel. Furthermore, skin treated with NLC gel and untreated skin were analysed by FTIR and DSC spectra to understand the permeation dynamics of NLC gel. The cytotoxic effect of combinatorial NLC gel and the conventional gel assessed in human epidermoid carcinoma (A431) cell line by MTT assay, revealed that IC50 of NLC gel and the conventional gel was 86.50 µM and 123.64 µM respectively. Thus, these results disclosed that NLC gel could be used as a potential carrier for the delivery of quercetin & resveratrol into deeper layers of the skin and can serve as a promising formulation for treatment of skin cancer.
Nanoparticles offer new opportunities for the treatment of skin diseases. The barrier function of the skin poses a significant challenge for nanoparticles to permeate into the tissue, although the barrier is partially compromised in case of injury or inflammation, as in the case of skin cancer. This may facilitate the penetration of nanoparticles. Extensive research has gone into developing nanoparticles for topical delivery; however, relatively little progress has been made in translating them to the clinic for treating skin cancers. We summarize the types of skin cancers and practices in current clinical management. The review provides a comprehensive outlook of the various nanoparticle technologies tested for topical therapy of skin cancers and summarizes the obstacles that impede its progress from the bench-to-bedside. The review also aims to provide an understanding of the pathways that govern nanoparticle penetration into the skin and a critical analysis of the approaches used to study nanoparticle interactions within the tissue.
Hypericin (Hyp) is considered a promising photosensitizer for Photodynamic Therapy (PDT) due its high hydrophobicity, affinity for cell membranes, low toxicity and high photooxidation activity. In this study, Hyp photophysical properties and photodynamic activity against melanoma B16-F10 cells were optimized using DPPC liposome (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) as a drug delivery system. This nanoparticle is used as cell membranes biomimetic model and solubilizes hydrophobic drugs. Hyp oxygen singlet lifetime (τ) in DPPC was approximately 2 fold larger than in P-123 micelles (PluronicTM surfactants), reflecting a more hydrophobic environment provided by the DPPC liposome. On the other hand, singlet oxygen quantum yield (ΦΔ1O2) in DPPC and in P-123 were similar; Hyp molecules were preserved as monomers. Hyp/DPPC liposome aqueous dispersion was stable for fluorescence emission and liposome diameter for at least 5 days at 30 oC. However, the liposomes collapsed after lyophilization/rehydration process, which was resolved by adding the lyoprotectant Trehalose to liposome the dispersion prior to lyophilization. Cell viability of the Hyp/DPPC formulation was assessed against the healthy HaCat cells and high-metastatic melanoma B16-F10 cells. Hyp incorporated in the DPPC carrier presented higher selectivity index than Hyp sample previously solubilized in ethanol under illumination effect. Moreover, the IC50 was lower for Hyp in DPPC than for Hyp pre-solubilized in ethanol. These results enable the formulation Hyp/DPPC for future biomedical applications in PDT treatment
Objectives. To determine the effect of new therapies and trends toward reduced mortality rates of melanoma.
Methods. We reviewed melanoma incidence and mortality among Whites (the group most affected by melanoma) in 9 US Surveillance, Epidemiology, and End Results registry areas that recorded data between 1986 and 2016.
Results. From 1986 to 2013, overall mortality rates increased by 7.5%. Beginning in 2011, the US Food and Drug Administration approved 10 new treatments for metastatic melanoma. From 2013 to 2016, overall mortality decreased by 17.9% (annual percent change [APC] = −6.2%; 95% confidence interval [CI] = −8.7%, −3.7%) with sharp declines among men aged 50 years or older (APC = −8.3%; 95% CI = −12.2%, −4.1%) starting in 2014. This recent, multiyear decline is the largest and most sustained improvement in melanoma mortality ever observed and is unprecedented in cancer medicine.
Conclusions. The introduction of new therapies for metastatic melanoma was associated with a significant reduction in population-level mortality. Future research should focus on developing even more effective treatments, identifying biomarkers to select patients most likely to benefit, and renewing emphasis on public health approaches to reduce the number of patients with advanced disease.
Nanotechnology-based advances in nanosponges have impacted the field of drug delivery of biomacromolecules to maximize therapeutic efficacy along with minimizing its untoward effects. Several approaches have been exploited not only to develop nanosponges for targeted and controlled drug delivery but also for photothermal therapy, blood purification, and solubility enhancement. Nanosponges have emerged as a tool of nanotechnology in the field of drug delivery. In order to achieve specific targeted delivery, these tiny sponges can circulate around the body until they encounter its target site to release the drug in a controlled and programmed manner. Recently, various software-based approaches have also been used for the optimization of nanosponges. There are several applications of nanosponges such as increased bioavailability, stability, reduced irritancy and many more. This review attempts to elaborate on merits and demerits, methods of preparation, characterization, optimization approaches, applications, and recent advances in nanosponges.
Skin cancer is a high burden disease with a high impact on global health. Conventional therapies have several drawbacks; thus, the development of effective therapies is required. In this context, nanotechnology approaches are an attractive strategy for cancer therapy because they enable the efficient delivery of drugs and other bioactive molecules to target tissues with low toxic effects. In this review, nanotechnological tools for skin cancer will be summarized and discussed. First, pathology and conventional therapies will be presented, followed by the challenges of skin cancer therapy. Then, the main features of developing efficient nanosystems will be discussed, and next, the most commonly used nanoparticles (NPs) described in the literature for skin cancer therapy will be presented. Subsequently, the use of NPs to deliver chemotherapeutics, immune and vaccine molecules and nucleic acids will be reviewed and discussed as will the combination of physical methods and NPs. Finally, multifunctional delivery systems to codeliver anticancer therapeutic agents containing or not surface functionalization will be summarized.
In the last one-decade numbers of review and research, articles have been published on niosomes. This shows the interest of researchers in niosomes because of the advantages offered by them over other vesicular carrier systems. Niosomes formation occurs when non-ionic surfactant vesicles assemble themselves. There are several factors like the type of non-ionic surfactant used, method of preparation, the temperature of hydration, etc. which affect the niosome formation. In this review article, we have made an attempt to incorporate all the basic details of niosomes like various methods of preparation, different types of niosomes, factors affecting their formation, characterization of niosome, their applications, routes of administration as well as the advancements taken place in the field of niosomal research with a literature review of research done in the last decade.