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Molecular mechanism of poly(vinyl alcohol) mediated prevention of aggregation and stabilization of insulin in nanoparticles.

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Molecular mechanism of poly(vinyl alcohol) mediated prevention of aggregation and stabilization of insulin in nanoparticles.
 
Creator Rawat, Sanjay
Gupta, Pawan
Kumar, Anil
Garg, Prabha
Suri, C Raman
Sahoo, Debendra K
 
Subject QR Microbiology
 
Description It is a challenge to formulate polymer based nanoparticles of therapeutic proteins as excipients and process conditions affect stability and structural integrity of the protein. Hence, understanding the protein stability and complex aggregation phenomena is an important area of research in therapeutic protein delivery. Herein we investigated the comparative role of three kinds of surfactant systems (Tween 20:Tween 80), small molecular weight poly(vinyl alcohol) (SMW-PVA), and high molecular weight PVA (HMW-PVA) in prevention of aggregation and stabilization of hexameric insulin in poly(lactide-co-glycolide) (PLGA) based nanoparticle formulation. The nanoparticles were prepared using solid-in-oil-in-water (S/O/W) emulsification method with one of the said surfactant system in inner aqueous phase. The thermal unfolding analysis of released insulin using circular dichroism (CD) indicated thermal stability of the hexameric form. Insulin aggregation monitored by differential scanning calorimetry (DSC) suggested the importance of nuclei formation for aggregation and its prevention by HMW-PVA. Additional guanidinium hydrochloride based equilibrium unfolding and in silico (molecular docking) studies suggested maximum stability of released insulin from formulation containing HMW-PVA (F3). Furthermore, in vivo studies of insulin loaded nanoparticle formulation (F3) in diabetic rats showed its bioactivity. In conclusion, our studies highlight the importance of C-terminal residues of insulin in structural integrity and suggest that the released insulin from formulation containing HMW-PVA in inner aqueous phase was conformationally and thermodynamically stable and bioactive in vivo.
 
Publisher ACS Publications
 
Date 2015-04-06
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://crdd.osdd.net/open/1664/1/sahoodk2015.pdf
Rawat, Sanjay and Gupta, Pawan and Kumar, Anil and Garg, Prabha and Suri, C Raman and Sahoo, Debendra K (2015) Molecular mechanism of poly(vinyl alcohol) mediated prevention of aggregation and stabilization of insulin in nanoparticles. Molecular pharmaceutics, 12 (4). pp. 1018-30. ISSN 1543-8392
 
Relation http://pubs.acs.org/doi/abs/10.1021/mp5003653
http://crdd.osdd.net/open/1664/