Protamine-carboxymethyl cellulose magnetic nanocapsules for enhanced delivery of anticancer drugs against drug resistant cancers

Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers. From the Clinical Editor: Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells. (C) 2015 Elsevier Inc. All rights reserved

Effects of Withania somnifera and Tinospora cordifolia Extracts on the Side Population Phenotype of Human Epithelial Cancer Cells: Toward Targeting Multidrug Resistance in Cancer

Recent reports suggest the existence of a subpopulation of stem-like cancer cells, termed as cancer stem cells (CSCs), which bear functional and phenotypic resemblance with the adult, tissue-resident stem cells. Side population (SP) assay based on differential efflux of Hoechst 33342 has been effectively used for the isolation of CSCs. The drug resistance properties of SP cells are typically due to the increased expression of ABC transporters leading to drug efflux. Conventionally used chemotherapeutic drugs may often leads to an enrichment of SP, revealing their inability to target the drug-resistant SP and CSCs. Thus, identification of agents that can reduce the SP phenotype is currently in vogue in cancer therapeutics. Withania somnifera (WS) and Tinospora cordifolia (TC) have been used in Ayurveda for treating various diseases, including cancer. In the current study, we have investigated the effects of ethanolic (ET) extracts of WS and TC on the cancer SP phenotype. Interestingly, we found significant decrease in SP on treatment with TC-ET, but not with WS-ET. The SP-inhibitory TC-ET was further fractionated into petroleum ether (TC-PET), dichloromethane (TC-DCM), and n-butyl alcohol (TC-nBT) fractions using bioactivity-guided fractionation. Our data revealed that TC-PET and TC-DCM, but not TC-nBT, significantly inhibited SP in a dose-dependent manner. Furthermore, flow cytometry-based functional assays revealed that TC-PET and TC-DCM significantly inhibited ABC-B1 and ABC-G2 transporters and sensitized cancer cells toward chemotherapeutic drug-mediated cytotoxicity. Thus, the TC-PET and TC-DCM may harbor phytochemicals with the potential to reverse the drug-resistant phenotype, thus improving the efficacy of cancer chemotherapy

A structural approach to investigate halogen substituted MAO-B inhibitors using QSAR modeling, molecular dynamics, and conceptual DFT analysis

Halogenated inhibitors showed robust, reversible, and selective monoamine oxidase-B (MAO-B) inhibitory efficacy in candidates that were derived from them. Our team has previously synthesized and assessed a panel of halogenated chalcones and coumarin for the study on MAO-B inhibition. The aim of this study was to build GA-MLR based QSAR models and predictive 3D Pharmacophore models, as well as to investigate the relationship between halogenated derivatives and MAO-B inhibitory activity. The robust statistical significance in the parameter (R2 = 0.78 and Q2 = 0.69) was demonstrated. Best Hypo1 contains one hydrophobic and two aromatic rings. The lead molecule for quantum mechanics was performed, and it was revealed that it would bind to proteins and provide stability. To determine the stability of the ligand-enzyme complex, a thorough molecular dynamics analysis of the lead compounds was accomplished

Nanomedicine of anastrozole for breast cancer: Physicochemical evaluation, in vitro cytotoxicity on BT-549 and MCF-7 cell lines and preclinical study on rat model

Aim: Formulation and evaluation of anastrozole, an anti-cancer drug loaded in different biodegradable polymeric nanoparticles. Materials and methods: Different carrier systems such as poly(lactide-co-glycolide) (PLGA 50:50), poly(lacticacid) (PLA) and poly(ε-caprolactone) (PCL) are used to prepare nanoparticles by simple emulsion technique. The surfactants polyvinyl alcohol and sodium deoxycholate were studied for their use as stabilizing agents at varying concentrations. The formulations were studied for their particle size, zeta potential, entrapment efficiency and solid state characteristics, and also were tested for their in vitro cytotoxicity and in vivo behavior in rats. Key findings: The entrapment ranged from 35 to 85%, depending on the drug-polymer ratio used. Particle size ranged from 100 to 350 nm with optimal zeta potential. Accordingly, discrete spherical nanoparticles with smooth surface were obtained as evidence from Field Emission Scanning Electron Microscopy (FESEM) study. The solid state characteristics revealed dispersion of drug at the molecular level in the polymeric matrix of nanoparticles. A non-Fickian transport with initial burst release followed by slow release was observed with nanoparticles. The remarkable decrease in cell viability at various time points was observed for PLGA nanoparticles compared to other polymer matrices. The AUC(0 → ∞) of PLGA, PLA and PCL nanoparticles were found to be 4.77, 19.31 and 19.81 fold higher than (p b 0.05) anastrozole in solution, respectively. Also, pharmacokinetics study revealed the long time circulation of anastrozole loaded polymeric nanoparticles. Significance: The results suggest that developed nanoparticles could be used successfully for effective management of breast cancer chemotherapy

Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones

A series of novel 5-alkyl/aryl thiadiazole substituted thiazolidin-4-ones were synthesized by a two-step process. In the first step, 5-alkyl/aryl substituted 2-amino-thiadiazoles were synthesized, which on reaction with substituted aromatic aldehydes and thioglycolic acid in presence of dicyclohexylcarbodiimide afforded thiazolidin-4-ones. All compounds were synthesized in fairly good yields and their structures were confirmed by spectral and physical data. The title compounds were screened for in vitro anti-proliferative activity on human breast adenocarcinoma cells (MCF-7) by the MTT assay. Most derivatives showed an IC50 less than 150 µmol L–1. Among the compounds tested, 2-(2-nitrophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3f), 2-(3-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3b), and 2-(4-chlorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3c) were found to be the most active derivatives with IC50 values of 46.34, 66.84, and 60.71 µmol L–1, respectively. Antioxidant studies of all synthesized compounds were carried out using diphenylpicrylhydrazyl assay. Among the compounds tested, 2-phenyl-3-(5-styryl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3s) elicited superior antioxidant activity with IC50 of 161.93 µmol L–1

In vitro anticancer activity of microbial isolates from diverse habitats

Extracts from natural products, especially microorganisms, have served as a valuable source of diverse molecules in many drug discovery efforts and led to the discovery of several important drugs. Identification of microbial strains having promising biological activities and purifying the bio-molecules responsible for the activities, have led to the discovery of many bioactive molecules. Extracellular, as well as intracellular, extracts of the metabolites of thirty-six bacterial and twenty-four fungal isolates, grown under unusual conditions such as high temperature, high salt and low sugar concentrations, were in vitro tested for their cytotoxic potential on various cancer cell lines. The extracts were screened on HeLa and MCF-7 cell lines to study the cytotoxic potential. Nuclear staining and flow cytometric studies were carried out to assess the potential of the extracts in arresting the cell cycle. The crude ethylacetate extract of isolate F-21 showed promising results by MTT assay with IC50 as low as 20.37±0.36 µg/mL on HeLa, and 44.75±0.81 µg/mL on MCF-7 cells, comparable with Cisplatin. The isolate F-21 was identified as Aspergillus sp. Promising results were also obtained with B-2C and B-4E strains. Morphological studies, biochemical tests and preliminary chemical investigation of the extracts were also carried out.<br>Extratos de produtos naturais, especialmente de microrganismos, constituíram-se em fonte valiosa de diversas moléculas em muitas descobertas de fármacos e levaram à descoberta de fármacos importantes. A identificação de espécies microbianas que apresentam atividade biológica e a purificação de biomoléculas responsáveis pelas atividades levou à descoberta de muitas moléculas bioativas. Extratos extracelulares tanto quanto intracelulares de metabólitos de 36 isolados de bactérias e 24 isolados de fungos, que cresceram sob condições não usuais, como alta temperatura, alta concentração de sal e baixa concentração de açúcar, foram testados in vitro quanto ao seu potencial citotóxico em várias linhagens de câncer. Os extratos foram ensaiados em células HeLa e MCF-7 para o estudo do potencial citotóxico. A coloração nuclear e os estudos de citometria de fluxo foram realizados para avaliar o potencial dos extratos em bloquear o ciclo celular. O extrato bruto em acetato de etila do isolado F-21 mostrou resultados promissores no ensaio de MTT, com IC50 de 20,37±0,36 µg/mL em células HeLa e 44,.75±0,81 µg/mL em células MCF-7, comparativamente à cisplatina. O isolado F-21 foi identificado como Aspergillus sp. Resultados promissores foram obtidos com cepas B-2C e B-4E. Realizaram-se, também, estudos morfológicos, testes bioquímicos e investigação química preliminar dos extratos