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Cytotoxicity of various DOX formulations toward A549 cells and A549/Adr cells. Notes: (A) A549 cells cultured for 48 h. (B) A549 cells cultured for 72 h. (C) A549/Adr cells cultured for 48 h. (D) A549/Adr cells cultured for 72 h. n=3; *P<0.05; **P<0.01. The error bars represent standard deviation. Abbreviations: CUR, curcumin; DOX, doxorubicin; (DOX + CUR)–PMs, polymeric micelles loaded with DOX and CUR; ND, no difference.
Source publication
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Purpose
A new type of polymeric micelle (PM) was assembled using a polyethylene glycol (PEG)-linked (PEGylated) amphiphilic copolymer and d-tocopheryl PEG1000 succinate (TPGS1000). The micelles were used to deliver doxorubicin (DOX) and curcumin (CUR) for alleviating multidrug resistance (MDR) in lung cancer cells while enhancing the therapeutic ef...
Citations
... Prevention of DOX resistance and/or side effect has been searched to enhance DOX efficacy. A new type of nanomicelles loaded with doxorubicin and curcumin was used to attenuate DOX resistance in lung cancer cell line, A549/Adr cells [16]. Many plant extracts have also been employed to enhance DOX efficacy and decrease its drug resistance. ...
Objectives:
This research aims to comparatively investigate the capability of resveratrol (RES) and RES analogues, oxyresveratrol (Oxy-RES) and dihydrooxyresveratrol (DHoxy-RES), to potentiate doxorubicin (DOX) effects against lung carcinoma epithelial cells.
Methods:
All experiments were performed on lung carcinoma cell lines (A549) with DOX combination between DOX and RES or RES analogues. Cell viability or growth inhibitory effect was assessed by MTT assay and genes associated with survival and metastasis were monitored by real-time polymerase chain reaction (RT-PCR).
Results:
DOX obviously demonstrated cytotoxic and anti-metastatic activities against A549 cells. Expression of gene-associated with both activities was potentiated by RES and RES analogues. Oxy-RES showed highest capability to potentiate DOX effects. DHoxy-RES showed nearly no effect to DOX activities.
Conclusions:
These results provided an important basis of DOX combination with RES analogues, especially Oxy-RES, for better therapeutic effect. Further studies in human should be performed on exploring combination of DOX and Oxy-RES.
... Suppression of lipid peroxidation processes also plays a role in the process [21,22]. In addition, quercetin has an anti-inflammatory effect [23,24] and shows its own antitumor activity [25]. Therefore, the co-administration of DOX and polyphenols with antioxidant activity such as quercetin can be assumed to limit the chemotherapeutic cardiotoxicity while maintaining its cytostatic properties. ...
Background:
One of the therapeutic limitations of the use of doxorubicin (DOX) as an anticancer drug is its cardiotoxicity. Its hydrophilicity also causes difficulties in achieving sustained release. The simultaneous delivery with the well-known natural antioxidant quercetin could ameliorate its cardiotoxicity. Thus, the main aim of this work is to study the potential of carboxylated and non-carboxylated mesoporous silica MCM-41 nanoparticles for double loading of the hydrophilic doxorubicin hydrochloride and hydrophobic quercetin (Q) in one nanocarrier with a modified release pattern to reduce the cardiotoxic side effects of doxorubicin in vitro.
Methods:
The methods included the modification of MCM-41, single and double loading of modified and non-modified MCM-41, physicochemical characterization, in vitro release tests and kinetic study, and in vitro cell viability studies.
Results:
Doxorubicin and quercetin were successfully double-loaded with encapsulation efficiency (EE) of 43 ± 4.1% and 37 ± 4.5%, respectively, in native MCM-41. The post-synthetic carboxylation led to 49 ± 4.3% EE (DOX) and 36 ± 4.0% (Q) and double lowering of the cardiotoxicity on H9c2 (IC50 = 5.96 µm). Sustained release profiles over 72 h were achieved.
Conclusions:
A successful procedure was proposed for the efficient double loading of a hydrophilic drug and a hydrophobic drug. The carboxy-modified double-loaded nanosystems demonstrate a decreased in vitro cardiotoxicity of doxorubicin and can be considered as a potential chemotherapeutic formulation.
... PEG micelles have shown some ability to deliver both DOX and CUR to DOX-resistant A549/Adr cells and synergistically reverse their DOX resistance [54]. In vivo studies have confirmed that micelles have the ability to increase DOX or CUR plasma concentrations and prolong their respective circulation in the bloodstream [54]. ...
... PEG micelles have shown some ability to deliver both DOX and CUR to DOX-resistant A549/Adr cells and synergistically reverse their DOX resistance [54]. In vivo studies have confirmed that micelles have the ability to increase DOX or CUR plasma concentrations and prolong their respective circulation in the bloodstream [54]. PEG-stabilized Dox NPs also exhibit long blood circulation time, good biocompatibility and stability, fast release in acidic environment, and high accumulation in tumors. ...
... DOX is a non-selective cytotoxic drug and has many side effects [11]. Clinical use of DOX is often associated with severe side effects, namely hepatotoxicity [66,67], nephrotoxicity [10,35,47,48,[66][67][68].] and dose-dependent cardiotoxicity [28,54,55,66,67]. Chemotherapy also causes damage to normal tissues of the bone marrow, gastrointestinal tract, neurons and auditory tissues, etc. [67]. ...
The aim of the work was to review literature data on combined nanochemotherapy using the example of two drugs ̶doxorubicin and curcumin. Special attention was paid to the use of substances with synergistic properties in one nanoparticle, capable to penetrate into living cell.
The method of combined chemotherapy of nanopreparations improves processing efficiency. The technique of using nanocontainers with synergistic drugs in combination with ligands reduces the side effects of chemotherapy drugs.
Results. Literature data indicate that the use of nanopreparations contributes the rapid creation and use of synergistic combinations that were purposefully delivered to target cells, reducing dosage due to precise targeting. A promising direction of nanomedicine is the creation of multifunctional nanomaterials based on several active drugs having synergistic properties, with the simultaneous use of their enhancers and the strategy of active targeting. These structures enabled targeted and controlled penetration of medicinal compounds into the localization of pathological processes, reducing drugs toxicity for normal cells.
Conclusions. Combined chemotherapy using polymers and nanoparticles with ligands, in which synergistic drugs are included, ensures to reduce side effects and doses of chemotherapy drugs, and helps to overcome multiple drug resistance as well.
... The resistance of human tumors to many chemotherapeutic agents is referred to as multiple drug resistance (MDR) [13,21]. Acquired resistance is the main obstacle to successful cancer treatment [20,22,23]. ...
... DOX has obvious advantages due to its significant efficacy and low cost [32]. It has demonstrated potential antitumor activity against various cancer cells [21], but unlike other chemotherapeutic agents such as cisplatin, paclitaxel, docetaxel, etoposide, and oxaliplatin, the efficacy of DOX is limited due to the ability of cancer cells to acquire chemoresistance [21,27,28,32,42,43]. Doxorubicin has proven itself as a highly effective antitumor agent used for the treatment of a wide range of oncological diseases [44]. ...
... DOX has obvious advantages due to its significant efficacy and low cost [32]. It has demonstrated potential antitumor activity against various cancer cells [21], but unlike other chemotherapeutic agents such as cisplatin, paclitaxel, docetaxel, etoposide, and oxaliplatin, the efficacy of DOX is limited due to the ability of cancer cells to acquire chemoresistance [21,27,28,32,42,43]. Doxorubicin has proven itself as a highly effective antitumor agent used for the treatment of a wide range of oncological diseases [44]. ...
The aim of the work was to review the literature data regarding the prospects for the creation and use of multifunctional fluorescent two-dye nanosystems, which enable investigating the distribution of fluorescent components with significant acceleration of the study and introduction of nanomedicines into practice. Special attention is paid to the use of two substances with hydrophobic and hydrophilic properties in one nanoparticle (NP), capable of penetrating a living cell. The method of fluorescence confocal microscopy enables observation of the nanoscale dynamics of distribution and stability of drugs over time. The concomitant use of doxorubicin (DOX) and curcumin (CUR) in single nanoparticle causes synergism in the action of medical drugs, and their own fluorescence makes it possible to use them as multifunctional fluorescent nanosystems.
Results. Data from the literature indicate that the use of two or more fluorescent dyes provide an advantage over other, more expensive methods when studying the penetration and distribution of NPs in living samples. The use of nanocarriers is an effective way to significantly increase the bioavailability of those drugs, which are poorly soluble in water. A promising direction of nanomedicine is the creation of complex bio-compatible multifunctional nanomaterials based on several active drugs, with the simultaneous use of their enhancers and the strategy of active targeting. Such recent structures enable targeted and controlled penetration of medicinal compounds into the sites of localization of pathological processes, reducing the toxicity of drugs to normal cells.
Conclusions. The use of the fluorescence microscopy method, as exemplified by the two dyes, DOX and CUR, enables to trace the stages of interaction of loaded DOX and CUR nanoparticles with cultured cells, and their release from NPs to determine their amount and localization in organelles cells.
... 41−45 Researchers have explored the co-delivery of DOX and CUR for the treatment of cancers, such as colon cancer, 46,47 breast cancer, 48 and lung cancer. 49 Experimental results in the literature have demonstrated that DOX and CUR have excellent synergistic effects on cancer cells. 50,51 As such, CUR and DOX are chosen as the model drugs for the MMHR. ...
... The drug release of micelles and nanomicelle-microsphere complexes was determined by dynamic membrane dialysis. One milliliter of the DOX-loaded micelle solution or the nanomicelle-microsphere complex suspension (500 µg DOX equivalent) was transferred into dialysis bags (MWCO = 3500 Da) and then immersed in 100 mL of PBS (pH 7.4, 0.01 M) containing 0.1% (v/v) Tween 80 [34]. The release system was incubated at 37 • C with stirring at 100 rpm under dark conditions. ...
Lung cancer is the second-most common cancer and has the highest mortality among all cancer types. Nanoparticle (NP) drug delivery systems have been used to improve the therapeutic effectiveness of lung cancer, but rapid clearance and poor targeting limit their clinical utility. Here, we developed a nanomicelle-microsphere composite, in which doxorubicin (DOX) was loaded with spermine (Spm) modified poly (ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) micelles, and then the nanomicelles were noncovalently adsorbed on the surface of poly (lactic-co-glycolic acid) (PLGA) microspheres. The attachment was confirmed by scanning electron microscopy and confocal microscopy. In vitro cell experiments, MTT assays and intracellular uptake assays were used to demonstrate the cytotoxicity and the cellular uptake of micelles in A549 cells. In vivo biodistribution studies were conducted, an orthotopic lung cancer implantation model based on C57BL/6 mice was established, and then real-time fluorescence imaging analysis was used to study the targeted efficacy of the complex. A nanomicelle-microsphere composite was successively constructed. Moreover, Spm-modified micelles significantly enhanced cytotoxicity and displayed more efficient cellular uptake. Notably, an orthotopic lung cancer implantation model based on C57BL/6 mice was also successively established, and in vivo biodistribution studies confirmed that the complex greatly improved the distribution of DOX in the lungs and displayed notable tumor targeting. These results suggested that the nanomicelle-microsphere composite has potential application prospects in the targeted treatment of lung cancer.
... Inhibition of tumor growth. [108] Doxorubicin (with curcumin encapsulated in U-11 targeting nanoparticle) ...
... Doxorubicin, which is notorious for its cardiotoxicity, is also challenged by multidrug resistance development [107]. These problems were improved with a nanomicelle delivery system encapsulating both doxorubicin and curcumin, which was responsible for promoting endocytosis and increasing drug-release capacity, while being harmless to the normal cells in vitro and in vivo [107][108][109]. ...
... With the proper choice of excipients, the stability of curcumin could also be improved, where the nanomaterials could protect the compound from degradation. In fact, several reports illustrated that the application of nanoformulation in curcumin combination therapy has successfully demonstrated the enhanced aqueous solubility for better delivery [195], reversing multidrug resistance [108] and ensuring the distinctive biodistribution of therapeutic agents [107,196]. On the other hand, the nanoformulation of curcumin could also be designed to target a specific site of the body, to deliver an even higher dose of the compound to the site of action, instead of distributing to other organs. ...
The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.
... Micelle was assembled using D-tocopheryl polyethylene glycol (1000) succinate. They investigated the internalization of 17 nm NPs on A549 cell line, using series of blockers such as chlorpromazine, β-cyclodextrin, indomethacin, and quercetin to inhibit and disrupt the ClaME and CavME pathways, and in result, they have found out that the β-cyclodextrin inhibits at a greater extent in comparison to another blocker, by depletion of cholesterol in the plasma membrane, which is one of the main components for the CavME pathway [195]. Endocytosis of oleoyl alginate ester NPs of size 50 nm/120 nm, 420 nm, and 730 nm was carried out with ClaME, CavME, and macropinocytosis respectively by Caco-2 (human colon adenocarcinoma) cell line [196]. ...
Background
Efficient and controlled internalization of NPs into the cells depends on their physicochemical properties and dynamics of the plasma membrane. NPs-cell interaction is a complex process that decides the fate of NPs internalization through different endocytosis pathways.
Objective
The aim of this review is to highlight the physicochemical properties of synthesized nanoparticles (NPs) and their interaction with the cellular-dynamics and pathways like phagocytosis, pinocytosis, macropinocytosis, clathrin, and caveolae-mediated endocytosis and the involvement of effector proteins domain such as clathrin, AP2, caveolin, Arf6, Cdc42, dynamin and cell surface receptors during the endocytosis process of NPs.
Method
An electronic search was performed to explore the focused reviews and research articles on types of endocytosis and physicochemical properties of nanoparticles and their impact on cellular internalizations. The search was limited to peer-reviewed journals in the PubMed database.
Results
This article discusses in detail how different types of NPs and their physicochemical properties such as size, shape, aspect ratio, surface charge, hydrophobicity, elasticity, stiffness, corona formation, surface functionalization changes the pattern of endocytosis in the presence of different pharmacological blockers. Some external forces like a magnetic field, electric field, and ultrasound exploit the cell membrane dynamics to permeabilize them for efficient internalization with respect to fundamental principles of membrane bending and pore formation.
Conclusion
This review will be useful to attract and guide the audience to understand the endocytosis mechanism and their pattern with respect to physicochemical properties of NPs to improve their efficacy and targeting to achieve the impactful outcome in drug-delivery and theranostics applications.
... The lower water solubility of curcumin has led to the use of methods like micelles and nanocapsules for effective permeation and release. Adriamycin resistant A549/ADR lung cancer cell line showed a reversal of resistance to doxorubicin on treatment with polymeric micelles loaded with doxorubicin and curcumin [65] . ...
Curcumin, a polyphenol, has a wide range of biological properties such as anticancer, antibacterial, antitubercular, cardioprotective and neuroprotective. Moreover, the anti-proliferative activities of Curcumin have been widely studied against several types of cancers due to its ability to target multiple pathways in cancer. Although Curcumin exhibited potent anticancer activity, its clinical use is limited due to its poor water solubility and faster metabolism. Hence, there is an immense interest among researchers to develop potent, water-soluble, and metabolically stable Curcumin analogs for cancer treatment. While drug resistance remains a major problem in cancer therapy that renders current chemotherapy ineffective, curcumin has shown promise to overcome the resistance and re-sensitize cancer to chemotherapeutic drugs in many studies. In the present review, we are summarizing the role of curcumin in controlling the proliferation of drug-resistant cancers and development of curcumin-based therapeutic applications from cell culture studies up to clinical trials.
... Additionally, clinical trials have demonstrated that CUR showed negligible toxicity in humans at an administration dose of up to 12 g/day, indicating excellent biocompatibility [29][30][31]. Although codelivery of CUR and chemotherapeutic drugs has exhibited enhanced antitumor efficacy in MDR cells and animal models, the drug release behavior under specific stimuli, pharmacokinetics and systemic toxicity have not been revealed clearly [32,33]. ...
Aim: This work aims to develop an injectable nano-drug delivery system to overcome tumor multidrug resistance (MDR). Methods: A drug delivery nanoplatform based on PEGylated PLGA with glutathione (GSH) responsivity was constructed for dual delivery of doxorubicin and curcumin (termed DCNP), and its MDR reversal efficiency was studied in vitro and in vivo. Results: The DCNPs exhibited a rapid drug release profile under high GSH concentration and could enhance the cellular uptake and cytotoxicity of doxorubicin to MDR cancer cells. Moreover, the DCNPs showed better biocompatibility, longer blood circulation and enhanced antitumor efficiency compared with free drugs. Conclusion: The GSH-responsive nanocarrier is believed to be a promising candidate for overcoming tumor MDR.
