Doxorubicin-Loaded Mixed Micelles for the Effective Management of Skin Carcinoma: In Vivo Anti-Tumor Activity and Biodistribution Studies.

Skin cancer is an alarming concern due to increased radiation and chemical exposure. Doxorubicin is a drug prescribed for various cancers by parenteral route. Apart from the pharmaceutical challenge of being a biopharmaceutical classification system (BCS) Class III drug, the side effects of doxorubicin are also a great concern. With an aim to enhance its safety and bioavailability, a phospholipid-based micellar system was developed. The developed nanometric and symmetric carriers not only offered substantial drug loading, but also offered a temporal drug release for longer durations. The pH-dependent drug release assured the spatial delivery at the target site, without loss of drug in the systemic circulation. The cancer cell toxicity studies along with the in vivo anti-tumor studies established the superior efficacy of the developed system. The blood profile studies and the biochemical estimations confirmed the safety of the developed nanocarriers. Lesser amount of drug was available for the microsomal degradation, as inferred by the biodistribution studies. The findings provide a proof of concept for the safer and effective doxorubicin delivery employing simple excipients like phospholipids for the management of skin cancer.

Delivery of Docetaxel to Brain Employing Piperine-Tagged PLGA-Aspartic Acid Polymeric Micelles: Improved Cytotoxic and Pharmacokinetic Profiles.

In this study, poly-(lactic-co-glycolic) acid (PLGA) was conjugated with aspartic acid and was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. Docetaxel-loaded polymeric micelles were prepared, and piperine was tagged. The neuroblastoma cytotoxicity studies revealed a substantially higher cytotoxic potential of the developed system to that of plain docetaxel, which was further corroborated by cellular uptake employing confocal laser scanning microscopy. The hemocompatible system was able to enhance the pharmacokinetic profile in terms of 6.5-fold increment in bioavailability followed by a 3.5 times increase in the retention time in comparison with the plain drug. The single-point brain bioavailability of docetaxel was amplified by 3.3-folds, signifying a better uptake and distribution to brain employing these carriers. The findings are unique as the physically adsorbed piperine was released before the DTX, increasing the propensity of curbing the CYP3A4 enzyme, which plays a vital role in the degradation of docetaxel. Meanwhile, piperine might have compromised the P-gp efflux mechanism, which can be ascribed to the enhanced retention of the drug at the target site. The elevated target site concentrations and extended residence by a biocompatible nanocarrier supplemented with co-delivery of piperine inherit immense promises to deliver this BCS class IV drug more safely and effectively.

Chitosan-Stearic Acid Based Polymeric Micelles for the Effective Delivery of Tamoxifen: Cytotoxic and Pharmacokinetic Evaluation.

Chitosan is a widely employed polysaccharide with positive zeta-potential and better tissue/cell adhesion. Its hydrophilicity, high viscosity, and insolubility at physiological pH are major hurdles in proper utilization of this macromolecule. Therefore, it was conjugated with biocompatible stearic acid and the conjugate was employed to develop polymeric micelles for delivery of tamoxifen to breast cancer cells. The conjugate was characterized by FT-IR and NMR, and the nanocarrier was characterized for micromeritics, surface charge, drug loading, and morphological attributes. The efficacy was evaluated by in vitro MTT studies, safety by erythrocyte compatibility, and biodistribution by in vivo pharmacokinetic studies. Despite better drug loading and sustained drug release, cytotoxicity on MCF-7 breast cancer cells was substantially enhanced and the pharmacokinetic profile was significantly modified. The AUC was enhanced manifolds along with reduced clearance. The findings are unique and provide an alternative to the conventional lipid-based nanocarriers for better dose delivery, tissue adhesion, and desired pharmacokinetic modulation.

Assessing the pharmacokinetics and toxicology of polymeric micelle conjugated therapeutics.

Introduction: Analogous to nanocarriers such as nanoparticles, liposomes, nano lipoidal carriers, niosomes, and ethosomes, polymeric micelles have gained significance in the field of drug delivery. They have attracted scientists worldwide by their nanometric size, wide range of polymers available for building block synthesis, stability and potential to enhance the targeting and safety of drugs. Incorporation of drugs within the interior of polymeric micelles alters the drug pharmacokinetics, which generally results in increased efficiency.Areas covered: This review deals with the pharmacokinetics of various anti-neoplastic drugs loaded into micelles. The structure of polymeric micelles, polymers employed in their development and techniques involved will be discussed. This is followed by discussion on the pharmacokinetics of anti-cancer drugs loaded into polymeric micelles and the toxicity concerns associated.Expert opinion: Polymeric micelles are nanometeric carriers, with higher stability, polymeric flexibility and higher drug loading of poorly water-soluble drugs. These nanosystems help in increasing the bioavailability of drugs by encapsulating them within the hydrophobic core. The proper selection and design of the amphiphilic polymer for micelles is a crucial step as it decides the toxicity and the biocompatibility.

Promises of Lipid-based Drug Delivery Systems in the Management of Breast Cancer.

Breast cancer is one of the leading types among the common non-cutaneous malignancies in women. All the curative methods available for its treatment are minimal due to their toxicity issues and dose-related side effects. Various evolving nanotechnology techniques displayed the opportunity to target breast cancer. One such delivery system is lipid-based drug delivery systems (LDDS). This concept is constrained only for the laboratory scale should be shifted to the industrial level targeting the nanomedicine with clinical benefits. This work tried to portray the advancements in the LDDS along with the lipid-based excipients, advantages, disadvantages and applications. It even helped in highlighting the recently developed lipid-based nanocarriers for breast cancer management.

Enhancement effects of process optimization technique while elucidating the degradation pathways of drugs present in pharmaceutical industry wastewater using Micrococcus yunnanensis.

Pharmaceutical effluents released from industries are accountable to deteriorate the aquatic and soil environment through indirect toxic effects. Microbes are adequately been used to biodegrade pharmaceutical industry wastewater and present study was envisaged to determine biodegradation of pharmaceutical effluent by Micrococcus yunnanensis. The strain showed 42.82% COD (Chemical oxygen demand) reduction before optimization. After applying Taguchi's L8 array as an optimization technique, the biodegradation rate was enhanced by 82.95% at optimum conditions (dextrose- 0.15%, peptone 0.1%, inoculum size 4% (wv-1), rpm 200, pH 8 at 25 °C) within 6 h. The confirmation of pharmaceuticals degradation was done by 1H NMR (Nuclear magnetic resonance) studies followed by elucidation of transformation pathways of probable drugs in the effluent through Q-Tof-MS (Quadrupole Time of Flight- Mass Spectrometry). The cytotoxicity evaluation of treated and untreated wastewater was analyzed on Human Embryonic Kidney (HEK 293) cells using Alamar Blue assay, which showed significant variance.

Aspartic acid tagged carbon nanotubols as a tool to deliver docetaxel to breast cancer cells: Reduced hemotoxicity with improved cytotoxicity.

The present study aimed to explore the potential of hydroxylated carbon nanotubes (CNTnols) conjugated with aspartic acid for the delivery of docetaxel (DTX) to breast cancer cells. The conjugate was well-characterized by FT-IR, NMR, XRD and FE-SEM. The nanoconjugate offered a hydrodynamic diameter of 86.31 ±â€¯1.02 nm, with a PDI of 0.113 and zeta potential of -41.6 ±â€¯0.17 mV. The designed nanosystem offered a controlled & pH dependent release vouching release of drug in the cancerous cytosol, not in blood, assuring delivery of the pay-load to the site of action. The carriers offered substantial hemocompatibility and lower plasma protein binding, ensuring more drug available at the site of action. The in-vitro cell viability studies in MDA MB-231 cells inferred approx. 2.8 times enhancement in the cytotoxicity potential of the conjugate vis-à-vis plain drug. Pharmacokinetic studies also corroborated the superiority of the designed nanoconjugate in terms of enhanced bioavailable fractions, reduced clearance and longer bioresidence to that of plain docetaxel. The present studies, successfully provide a workable nanomedicine, loaded with a BCS class-IV drug, for improved efficacy and safety in breast cancer.

Aspartic acid derivatized hydroxylated fullerenes as drug delivery vehicles for docetaxel: an explorative study.

The objective of the present study was to deliver docetaxel to cancerous cells with enhanced efficacy and safety profile, using aspartic acid linked fullerenols. This aspartic acid derivatized fullerenol conjugate linked with docetaxel was characterized by UV, FT-IR and NMR spectroscopy. Studies for particle size, PDI, zeta potential and FE-SEM were also performed. The conjugate was evaluated for release kinetics, cancer cell cytotoxicity, cellular uptake using confocal laser microscopy and also for pharmacokinetic profile. Cytotoxic studies proved that there was almost 4.3 folds decrease in IC50 with significantly enhanced cellular uptake of the nanometric conjugates. It was observed that the bioavailability was enhanced by 5.8 folds when compared to that of pure DTX. The developed nanoconstructs were erythrocyte compatible and offered decreased protein binding. The findings are encouraging and offer a novel carrier with enhanced efficacy and safety of a drug, belonging to BCS class IV.

Advanced Approaches of Bioactive Peptide Molecules and Protein Drug Delivery Systems.

Despite the fact that protein and peptide therapeutics are widely employed in the treatment of various diseases, their delivery is posing an unembellished challenge to the scientists. It was discovered that delivery of these therapeutic systems through oral route is easy with high patient compliance. However, proteolytic degradation and absorption through the mucosal epithelium are the barriers in this route. These issues can be minimized by the use of enzyme inhibitors, absorption enhancers, different carrier systems or either by direct modification. In the process of investigation, it was found that transdermal route is not posing any challenges of enzymatic degradation, but, still absorption is the limitation as the outer layer of skin acts as a barrier. To suppress the effect of the barrier and increase the rate of the absorption, various advanced technologies were developed, namely, microneedle technology, iontophoresis, electroporation, sonophoresis and biochemical enhancement. Indeed, even these molecules are targeted to the cells with the use of cell-penetrating peptides. In this review, delivery of the peptide and protein therapeutics using oral, transdermal and other routes is discussed in detail.

Dermatokinetics as an Important Tool to Assess the Bioavailability of Drugs by Topical Nanocarriers.

BACKGROUND: Now-a-days, numerous nanocarrier-based drug products for topical applications are present in the market and number of similar products are being researched. To estimate the amount of drug delivery to skin, the scientists have now established techniques for separation of skin layers for the determination of drug concentrations. This forms the basis of pharmacokinetics of drug(s) in skin, i.e., dermatokinetics. However, dermatokinetic modeling of topical products is still a colossal challenge. Assessment of bioavailability helps in determination of safety and efficacy of topical formulations. OBJECTIVE: This article is an attempt to explore the usefulness and methodologies of dermatokinetics for nanocarriermediated topical delivery. It also showcases challenges in methodologies used for determination of dermatokinetic parameters along with advantages. METHOD: All the articles (research and review) used for writing the manuscript were collected from various search engines like Science Direct, Google Scholar, PubMed and Eureka Select using keywords like dermatokinetics, novel drug delivery systems, bioequivalence, bioavailability and topical delivery. CONCLUSION: As the methods used for determination of pharmacokinetics of oral and intravenous formulations are not useful for dermatokinetic assessment, various methods like tape stripping, microdialysis and vasoconstrictor assays are being used for dermatokinetic assessment. These methods are not only useful to determine the drug concentrations in skin layers, but can also be used to correlate the toxic effects of xenobiotics.

Chitosan-palmitic acid based polymeric micelles as promising carrier for circumventing pharmacokinetic and drug delivery concerns of tamoxifen.

Being a BCS class II drug and a good substrate for microsomal enzymes, tamoxifen (TAM) offers a scope for research owing to poor aqueous solubility and compromised bioavailability. The present study designs a novel copolymer derived from palmitic acid and chitosan, and evaluate the derived TAM-loaded micelles for various delivery attributes. The nanometric micellar carriers not only substantially loaded the drug, but also controlled the rate of release of TAM. The designed nanocarrier significantly enhanced the cytotoxicity of TAM on MCF-7 cancer cells. The developed system was designed for intravenous route and was observed to be substantially haemo-compatible with an enhancement of approx. 5 times in AUC vis-a-vis plain drug. The findings employing new polymer-based carrier are promising in nature for the better delivery of similar drugs.

Improved cellular uptake, enhanced efficacy and promising pharmacokinetic profile of docetaxel employing glycine-tethered C60-fullerenes.

Water dispersible fullerenes were synthesized by tethering with glycine. The glycinated fullerenes were conjugated to docetaxel and characterized using FT-IR and NMR. The nanometric drug-loaded carriers were able to release drug at cancer cell pH, but resisted drug release at plasma pH. The cytotoxicity in MDA MB-231 cells was substantially enhanced as well as the system was well tolerated by erythrocytes. The confocal laser scanning microphotographs confirmed the substantial drug delivery to cytosol as well as nuclei of cancer cells. The developed system not only increased the circulation time of drug, but also decreased its protein binding and substantially enhanced AUC. The glycinated fullerenes can serve as promising "cargo vehicles" for delivery of anti-cancer drugs in safe and effective manner.

PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: Cellular uptake, cytotoxic and pharmacokinetic evidences.

Biocompatible and biodegradable polymers like PLGA have revolutionized the drug delivery approaches. However, poor drug loading and substantially high lipophilicity, pave a path for further tailing of this promising agent. In this regard, PLGA was feathered with biocompatible phospholipid and polymeric micelles were developed for delivery of Methotrexate (MTX) to cancer cells. The nanocarriers (114.6nm±5.5nm) enhanced the cytotoxicity of MTX by 2.13 folds on MDA-MB-231 cells. Confocal laser scanning microscopy confirmed the increased intracellular delivery. The carrier decreased the protein binding potential and enhanced the bioavailable fraction of MTX. Pharmacokinetic studies vouched substantial enhancement in AUC and bioresidence time, promising an ideal carrier to effectively deliver the drug to the site of action. The developed nanocarriers offer potential to deliver the drug in the interiors of cancer cells in an effective manner for improved therapeutic action.

Chitosan-modified PLGA polymeric nanocarriers with better delivery potential for tamoxifen.

Breast cancer is believed as the second most common cause of cancer-related deaths in women for which tamoxifen is frequently prescribed. Despite many promises, tamoxifen is associated with various challenges like low hydrophilicity, poor bioavailability and dose-dependent toxicity. Therefore, it was envisioned to develop tamoxifen- loaded chitosan-PLGA micelles for potential safe and better delivery of this promising agent. The chitosan-PLGA copolymer was synthesised and characterised by Fourier Transform-Infrared, Ultraviolet-visible and Nuclear Magnetic Resonance spectroscopic techniques. The drug-loaded nanocarrier was characterised for drug-pay load, micrometrics, surface charge and morphological attributes. The developed system was evaluated for in-vitro drug release, haemolytic profile, cellular-uptake, anticancer activity by cytotoxicity assay and dermatokinetic studies. The developed nano-system was able to substantially load the drug and control the drug release. The in-vitro cytotoxicity offered by the system was significantly enhanced vis-a-vis plain drug, and there was no substantial haemolysis. The IC50 values were significantly decreased and the nanocarriers were uptaken by MCF-7 cells, noticeably. The carrier was able to locate the drug in the interiors of rat skin in considerable amounts to that of the conventional product. This approach is promising as it provides a biocompatible and effective option for better delivery of tamoxifen.

C60-fullerenes for delivery of docetaxel to breast cancer cells: A promising approach for enhanced efficacy and better pharmacokinetic profile.

Docetaxel has always attracted the researchers owing to its promises and challenges. Despite marked efficacy, concerns like poor aqueous solubility, lower bioavailability, poor tissue penetration and dose related side-effects offer further scope of research on docetaxel. The present study aims to explore the potential of C60-fullerenes in the delivery of docetaxel to cancerous cells. C60-fullerenes were carboxylated, acylated and conjugated with the drug. The chemical processes were monitored by UV, FT-IR and NMR spectroscopy. The conjugate was further characterized for drug loading, micromeritics, drug release, morphology and evaluated for in-vitro cytotoxicity, haemolysis and in-vivo pharmacokinetic profile. The developed nanoconstruct was able to enhance the bioavailability of docetaxel by 4.2 times and decrease the drug clearance by 50%. The developed system was able to control the drug release and was found to be compatible with erythrocytes. The cytotoxic potential on studied MCF-7 and MDA-MB231 cell lines was also enhanced by many folds, indicating marked promise in efficacy enhancement and dose reduction. The present findings are encouraging and offer a technique to enhance the delivery and efficacy potential of anticancer agents, especially belonging to BCS class IV.