Folate-Targeted Cholesterol-Grafted Lipo-Polymeric Nanoparticles for Chemotherapeutic Agent Delivery.

Docetaxel (DTX), an FDA approved chemotherapeutic agent, is used as a first-line treatment for triple-negative breast cancer (TNBC). Its poor aqueous solubility, rapid metabolism, short half-life, and effective targeting to the cancer cells limits its optimal therapeutic use. Herein, we report folate targeted amphiphilic lipopolymer grafted with cholesterol conjugated carbonate and DL-lactide prepared by microwave assisted ring opening polymerization, for the efficient actively targeted delivery of DTX. The DTX-loaded folate-targeted lipopolymeric nanoparticles (F-DTX-LPNs) prepared by the emulsion solvent evaporation method exhibited a smaller size of ∼115.17 nm with a PDI of 0.205 and encapsulation efficiency of >80%. Further, these lipopolymeric nanoparticles (F-DTX-LPNs) showed a good on-bench stability and sustained DTX release for 7 days. Cell-based assays in MDA-MB-231 cells revealed a significant enhancement in the intracellular uptake of folate-targeted lipopolymeric nanoparticles compared to non-targeted nanoparticles. Further, methyl beta-cyclodextrin (Mß-CD) completely inhibited the uptake of these nanoparticles in the cells, indicating a lipid raft-mediated uptake mechanism. The developed F-DTX-LPNs showed improved cytotoxicity, apoptosis, and significant fold-change in expression levels of Bcl-2, BAX and Ki-67 as compared to non-targeted DTX-LPNs and free DTX. Further, F-DTX-LPNs showed an improved in vivo pharmacokinetic profile in Sprague Dawley rats as compared to the free DTX. The bio-imaging of ex vivo tissues demonstrated that the DiR loaded folate targeted LPNs exhibited intense signals after 24 h because of slow release of DiR dye from the nanoparticles.

Scalable Self-Assembling Micellar System for Enhanced Oral Bioavailability and Efficacy of Lisofylline for Treatment of Type-I Diabetes.

The study summarizes the development of an orally active nanoformulation of a potent but one of the least explored molecules, lisofylline (LSF), in type 1 diabetes (T1D). LSF undergoes rapid metabolism, resulting in poor oral bioavailability and short half-life. In this work, to improve its pharmacokinetic (PK) properties, LSF was encapsulated in the form of its ester prodrug [LSF-linoleic acid (LA) prodrug] into biodegradable self-assembling polymeric micelles [LSF-LA PLM, size: 149.3 nm; polydispersity index: 0.209; critical micelle concentration (cmc); 5.95 µg/mL and Nagg: 14.82 at 10 cmc] of methoxypoly(ethylene glycol)-b-poly(carbonate-co-l-lactide) (mPEG-b-P(CB-co-LA)) block copolymer. LSF-LA PLM was found to be equally effective as the LSF-LA prodrug in cell culture studies in insulin-secreting MIN6 cells and showed excellent stability in simulating biological fluids and plasma. PK of LSF-LA PLM (10 mg/kg dose) revealed a significant improvement in oral bioavailability of LSF (74.86%; 3.3-fold increase in comparison to free LSF) and drastic reduction in the drug metabolism. Further, LSF-LA PLM showed a significant reduction in fasting glucose levels and increase in insulin levels by intraperitoneal as well oral routes in a streptozotocin (STZ)-induced T1D rat model. Production of inflammatory cytokines (TNF-α and IFN-γ) and different biochemical markers for liver and kidney functions were much reduced in diabetic animals after treatment with LSF-LA PLM. LSF-LA PLM-treated pancreatic sections showed minimal infiltration of CD4+ and CD8+ T-cells as indicated by hematoxylin/eosin staining and immunohistochemical analysis.