Treatment avenues for age-related macular degeneration: Breakthroughs and bottlenecks.

Age-related macular degeneration (AMD) is a significant factor contributing to serious vision loss in adults above 50. The presence of posterior segment barriers serves as chief roadblocks in the delivery of drugs to treat AMD. The conventional treatment strategies use is limited due to its off-targeted distribution in the eye, shorter drug residence, poor penetration and bioavailability, fatal side effects, etc. The above-mentioned downside necessitates drug delivery using some cutting-edge technology including diverse nanoparticulate systems and microneedles (MNs) which provide the best therapeutic delivery alternative to treat AMD efficiently. Furthermore, cutting-edge treatment modalities including gene therapy and stem cell therapy can control AMD effectively by reducing the boundaries of conventional therapies with a single dose. This review discusses AMD overview, conventional therapies for AMD and their restrictions, repurposed therapeutics and their anti-AMD activity through different mechanisms, and diverse barriers in drug delivery for AMD. Various nanoparticulate-based approaches including polymeric NPs, lipidic NPs, exosomes, active targeted NPs, stimuli-sensitive NPs, cell membrane-coated NPs, inorganic NPs, and MNs are explained. Gene therapy, stem cell therapy, and therapies in clinical trials to treat AMD are also discussed. Further, bottlenecks of cutting-edge (nanoparticulate) technology-based drug delivery are briefed. In a nutshell, cutting-edge technology-based therapies can be an effective way to treat AMD.

Unravelling the success of transferosomes against skin cancer: Journey so far and road ahead.

Skin cancer remains one of the most prominent types of cancer. Melanoma and non-melanoma skin cancer are commonly found together, with melanoma being the more deadly type. Skin cancer can be effectively treated with chemotherapy, which mostly uses small molecular medicines, phytoceuticals, and biomacromolecules. Topical delivery of these therapeutics is a non-invasive way that might be useful in effectively managing skin cancer. Different skin barriers, however, presented a major obstacle to topical cargo administration. Transferosomes have demonstrated significant potential in topical delivery by improving cargo penetration through the circumvention of diverse skin barriers. Additionally, the transferosome-based gel can prolong the residence of drug on the skin, lowering the frequency of doses and their associated side effects. However, the choice of appropriate transferosome compositions, such as phospholipids and edge activators, and fabrication technique are crucial for achieving improved entrapment efficiency, penetration, and regulated particle size. The present review discusses skin cancer overview, current treatment strategies for skin cancer and their drawbacks. Topical drug delivery against skin cancer is also covered, along with the difficulties associated with it and the importance of transferosomes in avoiding these difficulties. Additionally, a summary of transferosome compositions and fabrication methods is provided. Furthermore, topical delivery of small molecular drugs, phytoceuticals, and biomacromolecules using transferosomes and transferosomes-based gel in treating skin cancer is discussed. Thus, transferosomes can be a significant option in the topical delivery of drugs to manage skin cancer efficiently.

Enhancing the oral bioavailability of fisetin: polysaccharide-based self nano-emulsifying spheroids for colon-targeted delivery.

Fisetin (FS) is a flavonoid that possesses antioxidant and anti-inflammatory properties against ulcerative colitis. FS shows poor dissolution rate and permeability. An attempt has been made to develop colon-targeted solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of FS. Initially, liquid (L) SNEDDS were prepared by loading FS into isotropic mixture of L-SNEDDS was prepared using Labrafil M 1944 CS, Transcutol P, and Tween 80. These L-SNEDDS were further converted into solid (S) SNEDDS by mixing the isotropic mixture with 1:1:1 ratio of guar gum (GG), xanthan gum (XG) and pectin (PC) [GG:XG:PC (1:1:1)]. Aerosil-200 (A-200) was added to enhance their flow characteristics. Further, they were converted into spheroids by extrusion-spheronization technique. The solid-state characterization of S-SNEDDS was done by SEM, DSC, and PXRD, which revealed that the crystalline form of FS was converted into the amorphous form. In the dissolution study, S-SNEDDS spheroids [GG:XG:PC (1:1:1)] exhibited less than 20% drug release within the first 5 h, followed by rapid release of the drug between the 5th and 10th h, indicating its release at colonic site. The site-specific delivery of FS to colon via FS-S-SNEDDS spheroids was confirmed by conducting pharmacokinetic studies on rats. Wherein, results showed delay in absorption of FS loaded in spheroids up to 5 h and achievement of Cmax at 7h, whereas L-SNEDDS showed rapid absorption of FS. Furthermore, FS-L-SNEDDS and FS-S-SNEDDS spheroids [GG:XG:PC (1:1:1)] increased oral bioavailability of FS by 6.86-fold and 4.44-fold, respectively, as compared to unprocessed FS.

Unlocking the secrets: Volatile Organic Compounds (VOCs) and their devastating effects on lung cancer.

Lung cancer (LCs) is still a serious health problem globally, with many incidences attributed to environmental triggers such as Volatile Organic Compounds (VOCs). VOCs are a broad class of compounds that can be released via various sources, including industrial operations, automobile emissions, and indoor air pollution. VOC exposure has been linked to an elevated risk of lung cancer via multiple routes. These chemicals can be chemically converted into hazardous intermediate molecules, resulting in DNA damage and genetic alterations. VOCs can also cause oxidative stress, inflammation, and a breakdown in the cellular protective antioxidant framework, all of which contribute to the growth of lung cancer. Moreover, VOCs have been reported to alter critical biological reactions such as cell growth, apoptosis, and angiogenesis, leading to tumor development and metastasis. Epidemiological investigations have found a link between certain VOCs and a higher probability of LCs. Benzene, formaldehyde, and polycyclic aromatic hydrocarbons (PAHs) are some of the most well-researched VOCs, with comprehensive data confirming their cancer-causing potential. Nevertheless, the possible health concerns linked with many more VOCs and their combined use remain unknown, necessitating further research. Identifying the toxicological consequences of VOCs in LCs is critical for establishing focused preventative tactics and therapeutic strategies. Better legislation and monitoring mechanisms can limit VOC contamination in occupational and environmental contexts, possibly reducing the prevalence of LCs. Developing VOC exposure indicators and analyzing their associations with genetic susceptibility characteristics may also aid in early identification and targeted therapies.

Applications and advancements of nanoparticle-based drug delivery in alleviating lung cancer and chronic obstructive pulmonary disease.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties. This picture was generated with BioRender.

Unravelling the role of microneedles in drug delivery: Principle, perspectives, and practices.

In recent year, the research of transdermal drug delivery systems has got substantial attention towards the development of microneedles (MNs). This shift has occurred due to multifaceted advantages of MNs as they can be utilized to deliver the drug deeper to the skin with minimal invasion, offer successful delivery of drugs and biomolecules that are susceptible to degradation in gastrointestinal tract (GIT), act as biosensors, and help in monitoring the level of biomarkers in the body. These can be fabricated into different types based on their applications as well as material for fabrication. Some of their types include solid MNs, hollow MNs, coated MNs, hydrogel forming MNs, and dissolving MNs. These MNs deliver the therapeutics via microchannels deeper into the skin. The coated and hollow MNs have been found successful. However, they suffer from poor drug loading and blocking of pores. In contrast, dissolving MNs offer high drug loading. These MNs have also been utilized to deliver vaccines and biologicals. They have also been used in cosmetics. The current review covers the different types of MNs, materials used in their fabrication, properties of MNs, and various case studies related to their role in delivering therapeutics, monitoring level of biomarkers/hormones in body such as insulin. Various patents and clinical trials related to MNs are also covered. Covered are the major bottlenecks associated with their clinical translation and potential future perspectives.

Concurrent oral delivery of non-oncology drugs through solid self-emulsifying system for repurposing in hepatocellular carcinoma.

OBJECTIVE: The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC) treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs. SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations. METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as ketoconazole (KCZ), disulfiram (DSR), tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier), which was developed and characterized. RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 pmol), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The DTX inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm), and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss). CONCLUSION: The current study revealed a non-oncology drug combination effective against HCC. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.

Nanostructured Lipid Carrier-Based Gel for Repurposing Simvastatin in Localized Treatment of Breast Cancer: Formulation Design, Development, and In Vitro and In Vivo Characterization.

Simvastatin (SMV) is noticed as a repurposed candidate to be effective against breast cancer (BC). However, poor solubility, dose-limiting toxicities, and side effects are critical hurdles in its use against BC. The above drawbacks necessitate the site-specific (localized) delivery of SMV via suitable nanocarriers. Therefore, the present study intended to develop SMV nanostructured lipid carrier (NLC)-based gel using carbopol-934 as a gelling agent to achieve local delivery and improve patient compliance while combating BC. The SMV NLCs were fabricated by melt-emulsification ultrasonication technique using stearic acid as solid lipid, olive oil (OO) as liquid lipid, tween 20 as a surfactant, and PEG-200 as a co-surfactant, and optimized by Box-Behnken design. The optimized SMV-loaded NLCs displayed % entrapment efficiency of 91.66 ± 5.2% and particle size of 182 ± 11.9 nm. The pH of NLC-based gels prepared using a 2.0% w/v of carbopol-934 was found in the range of 5.3-5.6 while the viscosity was in the range of 5.1-6.6 Pa.S. Besides, NLC-based gels exhibited higher and controlled SMV release (71-76%) at pH 6.8 and (78-84%) at pH 5.5 after 48 h than SMV conventional gel (37%) at both pH 6.8 and 5.5 after 48 h. The ex vivo permeation of SMV from NLC-based gel was 3.8 to 4.5 times more than conventional gel. Notably, SMV-loaded NLCs displayed ameliorated cytotoxicity than plain SMV against MCF-7 and MDA-MB-231 BC cells. No substantial difference was noticed in the cytotoxicity of NLC-based gels and pure SMV against both cell lines. The SMV NLC-based gel exhibited the absence of skin irritation in vivo in the mice following topical application. In addition, the histopathological study revealed no alteration in the mice skin anatomy. Furthermore, the SMV-loaded NLCs and NLC-based gels were stable for 6 months at refrigerator conditions (4°C ± 2°C). Thus, the present research confirms that NLC-based gel can be a safe, efficacious, and novel alternative to treat BC.

Co-crystal nanoarchitectonics as an emerging strategy in attenuating cancer: Fundamentals and applications.

Cancer ranks as the second foremost cause of death in various corners of the globe. The clinical uses of assorted anticancer therapeutics have been limited owing to the poor physicochemical attributes, pharmacokinetic performance, and lethal toxicities. Various sorts of co-crystals or nano co-crystals or co-crystals-laden nanocarriers have presented great promise in targeting cancer via improved physicochemical attributes, pharmacokinetic performance, and reduced toxicities. These systems have also demonstrated the controlled cargo release and passive targeting via enhanced permeation and retention (EPR) effect. In addition, regional delivery of co-crystals via inhalation and transdermal route displayed remarkable potential in targeting lung and skin cancer effectively. However, more research is required on the use of co-crystals in cancer and their commercialization. The present review mainly emphasizes co-crystals as emerging avenues in the treatment of various cancers by modulating the physicochemical and pharmacokinetic attributes of approved anticancer therapeutics. The worth of co-crystals in cancer treatment, computational paths in the co-crystals screening, diverse experimental techniques of co-crystals fabrication, and sorts of co-crystals and their noteworthy applications in targeting cancer are also discussed. Besides, the game changer approaches like nano co-crystals and co-crystals-laden nanocarriers, and co-crystals in regional delivery in cancer are also explained with reported case studies. Furthermore, regulatory directives for pharmaceutical co-crystals and their scale-up, and challenges are also highlighted with concluding remarks and future initiatives. In essence, co-crystals and nano co-crystals emerge to be a promising strategy in overwhelming cancers through improving anticancer efficacy, safety, patient compliance, and reducing the cost.

Antioxidant, Antidiabetic and Lipid Profiling of Spermadicyton Suaveolens in Streptozotocin (STZ) Induced Diabetic Rats

ABSTRACT Diabetes is a life-threatening disease, and currently available synthetic medicines for treating diabetes are associated with various side effects. Therefore, there is an unmet need to develop herbal remedies against diabetes as an alternative to synthetic medicines. Although local healers use the roots of Spermadicyton suaveolens (SS) to manage diabetes, there is negligible research to validate its antidiabetic properties. The present investigation aims to the assess the antioxidant, antidiabetic, and antihyperlipidemic potential of the ethanolic extract of S. Suaveolen's roots (EESS) on streptozotocin (STZ) induced diabetic rats. The extract was screened for in vitro antioxidant and antidiabetic activity. The in vivo antidiabetic potential of EESS (at 200 and 400 mg/kg) was studied on STZ-induced diabetic rats for 20 days. The EESS displayed significant (p<0.05) antidiabetic and antioxidant properties. The administration of 200 mg/kg and 400 mg/kg EESS in STZ-induced diabetic rats significantly reduced hyperglycemia, and restored antioxidant enzymes and lipid profile-a high density lipoprotein (HDL) increased by the administration of a single dose of streptozotocin. Thus, EESS could be a promising herbal medicine in the treatment of diabetes and hyperlipidemia

Harnessing the dual role of polysaccharides in treating gastrointestinal diseases: As therapeutics and polymers for drug delivery.

Polysaccharides (PS) represent a broad class of polymer-based compounds that have been extensively researched as therapeutics and excipients for drug delivery. As pharmaceutical carriers, PS have mostly found their use as adsorbents, suspending agents, as well as cross-linking agents for various formulations such as liposomes, nanoparticles, nanoemulsions, nano lipid carriers, microspheres etc. This is due to inherent properties of PS such as porosity, steric stability and swellability, insolubility in pH. There have been emerging reports on the use of PS as therapeutic agent due to its anti-inflammatory and anti-oxidative properties for various diseases. In particular, for Crohn's disease, ulcerative colitis and inflammatory bowel disease. However, determining the dosage, treatment duration and effective technology transfer of these therapeutic moieties have not occurred. This is due to the fact that PS are still at a nascent stage of development to a full proof therapy for a particular disease. Recently, a combination of polysaccharide which act as a prebiotic and a probiotic have been used as a combination to treat various intestinal and colorectal (CRC) related diseases. This has proven to be beneficial, has shown good in vivo correlation and is well reported. The present review entails a detailed description on the role of PS used as a therapeutic agent and as a formulation pertaining to gastrointestinal diseases.

Nanoparticulate drugs and vaccines: Breakthroughs and bottlenecks of repurposing in breast cancer.

Breast cancer (BC) is a highly diagnosed and topmost cause of death in females worldwide. Drug repurposing (DR) has shown great potential against BC by overcoming major shortcomings of approved anticancer therapeutics. However, poor physicochemical properties, pharmacokinetic performance, stability, non-selectivity to tumors, and side effects are severe hurdles in repurposed drug delivery against BC. The variety of nanocarriers (NCs) has shown great promise in delivering repurposed therapeutics for effective treatment of BC via improving solubility, stability, tumor selectivity and reducing toxicity. Besides, delivering repurposed cargos via theranostic NCs can be helpful in the quick diagnosis and treatment of BC. Localized delivery of repurposed candidates through apt NCs can diminish the systemic side effects and improve anti-tumor effectiveness. However, breast tumor variability and tumor microenvironment have created several challenges to nanoparticulate delivery of repurposed cargos. This review focuses on DR as an ingenious strategy to treat BC and circumvent the drawbacks of approved anticancer therapeutics. Various nanoparticulate avenues delivering repurposed therapeutics, including non-oncology cargos and vaccines to target BC effectively, are discussed along with case studies. Moreover, clinical trial information on repurposed medications and vaccines for the treatment of BC is covered along with various obstacles in nanoparticulate drug delivery against cancer that have been so far identified. In a nutshell, DR and drug delivery of repurposed drugs via NCs appears to be a propitious approach in devastating BC.

Drug repurposing: An emerging strategy in alleviating skin cancer.

Skin cancer is one of the most common forms of cancer. Several million people are estimated to have affected with this condition worldwide. Skin cancer generally includes melanoma and non-melanoma with the former being the most dangerous. Chemotherapy has been one of the key therapeutic strategies employed in the treatment of skin cancer, especially in advanced stages of the disease. It could be also used as an adjuvant with other treatment modalities depending on the type of skin cancer. However, there are several shortfalls associated with the use of chemotherapy such as non-selectivity, tumour resistance, life-threatening toxicities, and the exorbitant cost of medicines. Furthermore, new drug discovery is a lengthy and costly process with minimal likelihood of success. Thus, drug repurposing (DR) has emerged as a new avenue where the drug approved formerly for the treatment of one disease can be used for the treatment of another disease like cancer. This approach is greatly beneficial over the de novo approach in terms of time and cost. Moreover, there is minimal risk of failure of repurposed therapeutics in clinical trials. There are a considerable number of studies that have reported on drugs repurposed for the treatment of skin cancer. Thus, the present manuscript offers a comprehensive overview of drugs that have been investigated as repurposing candidates for the efficient treatment of skin cancers mainly melanoma and its oncogenic subtypes, and non-melanoma. The prospects of repurposing phytochemicals against skin cancer are also discussed. Furthermore, repurposed drug delivery via topical route and repurposed drugs in clinical trials are briefed. Based on the findings from the reported studies discussed in this manuscript, drug repurposing emerges to be a promising approach and thus is expected to offer efficient treatment at a reasonable cost in devitalizing skin cancer.

Inhalation delivery of repurposed drugs for lung cancer: Approaches, benefits and challenges.

Lung cancer (LC) is one of the leading causes of mortality accounting for almost 25% of cancer deaths throughout the world. The shortfall of affordable and effective first-line chemotherapeutics, the existence of resistant tumors, and the non-optimal route of administration contribute to poor prognosis and high mortality in LC. Administration of repurposed non-oncology drugs (RNODs) loaded in nanocarriers (NCs) via inhalation may prove as an effective alternative strategy to treat LC. Furthermore, their site-specific release through inhalation route using an appropriate inhalation device would offer improved therapeutic efficacy, thereby reducing mortality and improving patients' quality of life. The current manuscript offers a comprehensive overview on use of RNODs in LC treatment with an emphasis on their inhalation delivery and the associated challenges. The role of NCs to improve lung deposition and targeting of RNODs via inhalation are also elaborated. In addition, information about various RNODs in clinical trials for the treatment of LC, possibility for repurposing phytoceuticals against LC via inhalation and the bottlenecks associated with repurposing RNODs against cancer are also highlighted. Based on the reported studies covered in this manuscript, it was understood that delivery of RNODs via inhalation has emerged as a propitious approach. Hence, it is anticipated to provide effective first-line treatment at an affordable cost in debilitating LC from low and middle-income countries (LMIC).

Podophyllotoxin-polyacrylic acid conjugate micelles: improved anticancer efficacy against multidrug-resistant breast cancer.

BACKGROUND: Podophyllotoxin (PPT) is a naturally occurring compound obtained from the roots of Podophyllum species, indicated for a variety of malignant tumors such as breast, lung, and liver tumors. This toxic polyphenol (PPT) exhibited significant activity against P-glycoprotein (P-gp) mediated multidrug-resistant (MDR) cancer cells. However, extremely poor water solubility, a narrow therapeutic window, and high toxicity have greatly restricted the clinical uses of PPT. Therefore, the present research was aimed to synthesize the water-soluble ester prodrug of PPT with polyacrylic acid (PAA), a water-soluble polymer by Steglich esterification reaction, and to screen it for assay, solubility, in vitro hemolysis, in vitro release, and in vitro anticancer activity. RESULTS: The Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy results revealed the successful synthesis of podophyllotoxin-polyacrylic acid conjugate (PPC). The assay and saturation solubility of the prodrug is found to be 64.01 ± 4.5% and 1.39 ± 0.05 mg/mL (PPT equivalent) respectively. The PPC showed CMC (critical micelle concentration) of 0.430 mg/mL in distilled water at room temperature. The PPC micelles showed a mean particle size of 215 ± 11 nm with polydispersity index (PDI) of 0.193 ± 0.006. Further, the transmission electron microscope (TEM) results confirmed the self-assembling character of PPC into micelles. The PPC caused significantly less hemolysis (18.6 ± 2.9%) than plain PPT solution. Also, it demonstrated significantly (p < 0.01) higher in vitro cytotoxicity against both sensitive as well as resistance human breast cancer cells (MCF-7 and MDA MB-231) after 48 h of treatment. CONCLUSION: The obtained study results clearly revealed the notable in vitro anticancer activity of PPT following its esterification with PAA. However, further in vivo studies are needed to ascertain its efficacy against a variety of cancers.

Polymeric Mixed Micelles: Improving the Anticancer Efficacy of Single-Copolymer Micelles.

Mixed micelles self-assembled from two or more dissimilar block copolymers provide a direct and convenient approach to improved drug delivery. The present review is focused on mixed micelles (prepared from block copolymers only) for various drug delivery applications along with their merits over single-copolymer micelles. Presented are the physicochemical properties of mixed and single-copolymer micelles, various stimuli-responsive mixed micelles for the treatment of cancer, interesting combinations of multifunctional mixed micelles along with their in vitro and in vivo performance, and the potential of mixed micelles as a gene delivery system. Finally, the performance of mixed micelles in preclinical and clinical testing is explained. In addition, the interaction of mixed micelles with cancer cells and the biosafety of mixed micelles are summarized. The in vitro and in vivo performance presented here clearly reveals that the mixed-micelle approach has a wider scope than that of the single-copolymer micelle approach and directs researchers to focus on this approach to delivery of drugs/gene/biologics for various applications.

Polymeric Mixed Micelles: Improving the Anticancer Efficacy of Single-Copolymer Micelles.

Mixed micelles self-assembled from two or more dissimilar block copolymers provide a direct and convenient approach to improved drug delivery. The present review is focused on mixed micelles (prepared from block copolymers only) for various drug delivery applications along with their merits over single-copolymer micelles. Presented are the physicochemical properties of mixed and single-copolymer micelles, various stimuli-responsive mixed micelles for the treatment of cancer, interesting combinations of multifunctional mixed micelles along with their in vitro and in vivo performance, and the potential of mixed micelles as a gene delivery system. Finally, the performance of mixed micelles in preclinical and clinical testing is explained. In addition, the interaction of mixed micelles with cancer cells and the biosafety of mixed micelles are summarized. The in vitro and in vivo performance presented here clearly reveals that the mixed-micelle approach has a wider scope than that of the single-copolymer micelle approach and directs researchers to focus on this approach to delivery of drugs/gene/biologics for various applications.

Mixed Micelles as Nano Polymer Therapeutics of Docetaxel: Increased In vitro Cytotoxicity and Decreased In vivo Toxicity.

BACKGROUND: Docetaxel (DTX) has been used to treat several types of cancers, but it has provided pharmaceutical challenges due to its poor water solubility and toxicities associated with the co-solvents (tween-80 and ethanol). Nanopolymer therapeutics can be engineered to deliver anticancer agent specifically to cancer cells, thereby leaving normal healthy cells unaffected by toxic drugs such as DTX. The objective of the present study was to synthesize the polyacrylic acid (PAA)-DTX conjugate (PAADC) and preparation of nanopolymer therapeutics such as PAADC/DSPE-mPEG2000 mixed micelles (PAADC-DP MMs). METHODS: The prepared PAADC-DP MMs were characterized for mean particle size and zeta potential, in vitro release profile using dialysis technique, hemolytic behavior against human blood, and cytotoxicity against human cancer cell line (A549) using MTT assay. In vivo acute toxicity of PAADC-DP MMs was determined in albino mice at intravenous single dose of 40 mg/kg. RESULTS: PAADC-DP MMs showed mean particle size of 443±9nm. PAADC-DP MMs showed maximum DTX loading (DTX equivalent; 90.5±2.7%) with minimum DSPE-mPEG2000 molecules (1:1 ratio), while to load 77.9±2.2% of plain DTX, more DSPE-mPEG2000 is required(1:10 ratio). The developed PAADC-DP MMs system showed significantly lower CMC (5 ng/mL), sustained release profile (28.6±1.9% after 48 h of study), lower hemolytic behavior (13.7±1.3% of hemolysis ratio at 40 µg/mL concentration and after 1 h incubation), higher in vitro cytotoxicity (IC50 of 0.0064±0.001 nM after 48 h study) and remarkably reduced in vivo toxicity (9.9±2.1% body weight loss) in mice when compared to marketed Taxotere®. CONCLUSION: The obtained results clearly demonstrated that the developed PAADC-DP MMs system is a promising approach for cancer chemotherapy with reduced toxicity.