title: Vitamin B6 Tethered Endosomal pH Responsive Lipid Nanoparticles for Triggered Intracellular Release of Doxorubicin.
abstract: This study reports the development of Vitamin B6 (VitB6) modified pH sensitive charge reversal nanoparticles for efficient intracellular delivery of Doxorubicin (DOX). Herein, VitB6 was conjugated to stearic acid, and the nanoparticles of the lipid were formulated by solvent injection method (DOX-B6-SA-NP). Because of the pKa(5.6) of VitB6, DOX-B6-SA-NP showed positive charge and enhanced release of DOX at pH 5. Confocal microscopy illustrated that DOX-B6-SA-NP treatment kept higher DOX accumulation inside the cells than conventional pH insensitive lipid nanoparticles (DOX-SA-NP). The cationic charge of nanoparticles subsequently facilitated the endosomal escape and promoted the nuclear accumulation of DOX. Furthermore, in vitro cytotoxicity, apoptosis, cell cycle arrest, and mitochondrial membrane depolarization studies supported the enhanced efficacy of DOX-B6-SA-NP in comparison to free DOX and DOX-SA-NP. Intravenous pharmacokinetics and biodistribution investigations indicated that pH sensitive nanoparticles can significantly prolong the blood circulation time of DOX in biological system and increase the drug accumulation to tumor site. Consequent to this, DOX-B6-SA-NP also exhibited much enhanced therapeutic efficacy and lower toxicity in tumor-bearing rats compared to free DOX. The reduction in toxicity was confirmed by histological and survival analysis. In conclusion, these results suggest that the VitB6 modified charge reversal nanoparticles can be a novel platform for the successful delivery of anticancer drugs.
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, Delhi 110020, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.forename: Ashwni
authors.initials: A
authors.lastname: Verma
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, Delhi 110020, India.
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singh
authors.forename: B Venkatesh
authors.initials: BV
authors.lastname: Teja
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, Delhi 110020, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Mittapelly
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, Delhi 110020, India.
authors.forename: Gitu
authors.initials: G
authors.lastname: Pandey
authors.forename: Sandeep
authors.initials: S
authors.lastname: Urandur
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Shukla
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, Delhi 110020, India.
authors.forename: Prabhat Ranjan
authors.initials: PR
authors.lastname: Mishra
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006863:Hydrogen-Ion Concentration; D008055:Lipids; D053758:Nanoparticles; D051381:Rats; D014018:Tissue Distribution; D025101:Vitamin B 6
chemical_list: D004337:Drug Carriers; D008055:Lipids; D004317:Doxorubicin; D025101:Vitamin B 6
keywords: LA-7 cells; Vitamin-B6 transporting membrane carrier (VTC); charge reversal; proton sponge effect; pyridoxine; stearic acid