Muhammad Farhan Sohail

Folate grafted thiolated chitosan enveloped nanoliposomes with enhanced oral bioavailability and anticancer activity of docetaxel

Folate grafted and thiolated chitosan was synthesized and wrapped on the surface of mixed phosphatidylcholine based nanoliposomes (NLs) to improve the oral absorption and targeted pharmacological activity of anti-cancer drugs against breast cancer. In this study, a chitosan derived thiomer, having intrinsic properties of P-glycoprotein (P-gp) efflux pump inhibition, mucoadhesion and controlled drug release at a target site, was exploited to improve the performance of docetaxel (DTX) loaded NLs for better oral pharmacokinetics, targeted anti-cancer activity, liposomal stability and the physical characteristics of NLs. Thiomer enveloped nanoliposomes (ENLs) and bare nanoliposomes (NLs) were synthesized with the ingredient ratio pre-determined via Response Surface Methodology (RSM) plots by Design Expert® software. ENLs and NLs were thoroughly characterized for their surface chemistry, particle size, zeta potential, PDI, encapsulation efficiency, stability and release profile. ENLs were spherical in shape with a particle size of 328.5 ± 30 nm, a positive zeta potential of 18.81 ± 2.45 and a high encapsulation efficiency of 83% for DTX. Controlled release of DTX from formulations was observed for over 72 h for each formulation. The presence of thiol groups at the surface of the ENLs resulted in higher swelling and in situ gelling properties compared to the corresponding NLs. Furthermore, ENL/mucin mixtures showed a time dependent increase in viscosity for up to 12 h, leading to a 19.07-fold increased viscosity. Ex vivo permeation and P-glycoprotein inhibiting properties, studied in rats small intestine, showed a 9.6-fold higher permeation and 13-fold enhancement of DTX in the presence of ENLs. In vitro cytotoxicity studies indicated that the ENLs can efficiently kill MD-MB-231 breast cancer cells with 200 fold lower IC50 values than DTX alone as a positive control. The pharmacokinetic study revealed that the ENLs significantly improved the oral bioavailability of DTX i.e. up to 13.6 fold as compared to an aqueous dispersion of DTX. Therefore, these enveloped hybrid nanoliposomes (ENLs) have the potential to be developed as useful nanocarriers for efficient oral delivery and breast cancer management using DTX.

Polymeric nanocapsules embedded with ultra-small silver nanoclusters for synergistic pharmacology and improved oral delivery of Docetaxel

Despite of the remarkable cytotoxic and imaging potential of ultra-small metal nanoclusters, their toxicity-free and targeted delivery to cancerous cells remains a substantial challenge that hinders their clinical applications. In this study, a polymeric scaffold was first synthesized by grafting folic acid and thiol groups to chitosan (CS) for cancer cell targeting and improved gastric permeation. Furthermore, silver nanocluster (Ag NCs) were synthesized in situ, within CS scaffold by microwave irradiation and core-shell nanocapsules (NCPs) were prepared with hydrophobic docetaxel (DTX) in the core and Ag NCs embedded CS in the shell. A significant cytotoxicity synergism (~300 folds) was observed for DTX with co-delivery of Ag NCs against breast cancer MDA-MB-231 cells. Following oral administration, the DTX-Ag-NCPs increased bioavailability due to enhanced drug transport across gut (9 times), circulation half-life (~6.8 times) and mean residence time (~6.7 times), as compared to the control DTX suspension. Moreover, 14 days acute oral toxicity of the DTX-Ag-NCPs was performed in mice and evaluated for changes in blood biochemistry parameters, organ to body weight index and histopathology of liver and kidney tissues that revealed no significant evidence of toxicity suggesting the safety and efficiency of the DTX-Ag-NCPs as hybrid nanocarrier for biocompatible delivery of metal nanoclusters.

Advancements in the oral delivery of Docetaxel: challenges, current state-of-the-art and future trends

The oral delivery of cancer chemotherapeutic drugs is challenging due to low bioavailability, gastrointestinal side effects, first-pass metabolism and P-glycoprotein efflux pumps. Thus, chemotherapeutic drugs, including Docetaxel, are administered via an intravenous route, which poses many disadvantages of its own. Recent advances in pharmaceutical research have focused on designing new and efficient drug delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics. A decent number of studies have been reported for the safe and effective oral delivery of Docetaxel. These nanocarriers, including liposomes, polymeric nanoparticles, metallic nanoparticles, hybrid nanoparticles, dendrimers and so on, have shown promising results in research papers and clinical trials. The present article comprehensively reviews the research efforts made so far in designing various advancements in the oral delivery of Docetaxel. Different strategies to improve oral bioavailability, prevent first-pass metabolism and inhibition of efflux pumping leading to improved pharmacokinetics and anticancer activity are discussed. The final portion of this review article presents key issues such as safety of nanomaterials, regulatory approval and future trends in nanomedicine research.

Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis

Abstract The aim of this study was to evaluate mannose-anchored thiolated chitosan (MTC) based nanocarriers (NCs) for enhanced permeability, improved oral bioavailability and anti-parasitic potential of amphotericin B (AmB). Transgenic Leishmania donovani parasites expressing red fluorescent protein DsRed2 and imaging-flow cytometry was used to investigate parasitic burdens inside bone marrow-derived macrophages ex vivo. Cytokine estimation revealed that MTC nanocarriers activated the macrophages to impart an explicit immune response by higher production of TNF-α and IL-12 as compared to control. Cells treated with MTC NCs showed a significantly higher magnitude of nitrite and propidium iodide (PI) fluorescence intensity in contrast to cells treated with AmB. Concerning to apparent permeability coefficient (Papp) results, the MTC NCs formulation displayed more specific permeation across the Caco-2 cell monolayer as compared to AmB. The half-life of MTC NCs was about 3.3-fold persistent than oral AmB used as positive control. Also, t oral bioavailability of AmB was increased to 6.4-fold for MTC NCs compared to AmB for positive control. Acute oral evaluation indicated that MTC NCs were significantly less toxic compared to the AmB. Based on these findings, MTC NCs seems to be promising for significant oral absorption and improved oral bioavailability of AmB in leishmaniasis chemotherapy. Graphical Abstract

Mannosylated thiolated polyethylenimine nanoparticles for the enhanced efficacy of antimonial drug against Leishmaniasis

AIM Our aim was to inhibit trypanothione reductase (TR) and P-gp efflux pump of Leishmania by the use of thiolated polymers. Thus, increasing the intracellular accumulation and therapeutic effectiveness of antimonial compounds. METHODS Mannosylated thiolated chitosan and mannosylated thiolated chitosan-polyethyleneimine graft were synthesized and characterized. Meglumine antimoniate-loaded nanoparticles were prepared and evaluated for TR and P-gp efflux pump inhibition, biocompatibility, macrophage uptake and antileishmanial potential. RESULTS Thiomers inhibited TR with Ki 2.021. The macrophage uptake was 33.7- and 18.9-fold higher with mannosylated thiolated chitosan-polyethyleneimine graft and mannosylated thiolated chitosan nanoparticles, respectively, as compared with the glucantime. Moreover, the in vitro antileishmanial activity showed 14.41- and 7.4-fold improved IC50 for M-TCS-g-PEI and M-TCS, respectively as compared with glucantime. CONCLUSION These results encouraged the concept that TR and P-gp inhibition by the use of thiomers improves the therapeutic efficacy of antimonial drugs.

Fabrication of Poly (Butadiene-Block-Ethylene Oxide) Based Amphiphilic Polymersomes: An Approach for Improved Oral Pharmacokinetics of Sorafenib

&NA; Sorafenib (SFN), a hydrophobic anticancer drug, has several limitations predominantly poor aqueous solubility and hepatic first‐pass effect, limiting its oral delivery that results into several other complications. Present study aims to develop Sorafenib loaded polymersomes using poly butadiene block poly ethylene oxide (PB‐b‐PEO), an amphiphilic co‐block polymer. Prior to drug loading, critical aggregate concentration (CAC) of polymer was calculated for stable formulation synthesis. The developed SFN loaded PB‐b‐PEO polymersomes (SFN‐PB‐b‐PEO, test formulation) characterized by DLS and cryo‐TEM showed particle size 282 nm, polydispersity (PDI) of less than 0.29 and membrane thickness of about 20 nm. SFN‐PB‐b‐PEO polymersomes demonstrated encapsulation efficiency of 71% and showed sustained drug release up to 144 h. Formulation remained stable for 3 months in suspension form. In vitro cytotoxicity against HepG2 cells showed 1.7 folds improved toxicity compared to SFN suspension. In addition, oral administration of SFN‐PB‐b‐PEO polymersomes in BALB/c mice showed increased Cmax and AUC0–96 by 1.7 and 2.77‐fold respectively (p < 0.05) compared to those of SFN suspension (reference formulation). Findings suggest that the SFN‐PB‐b‐PEO polymersomes can be a potential candidate for oral delivery of SFN.