New Water-Soluble Oxyamino Chitosans as Biocampatible Vectors for Efficacious Anticancer Therapy via Co-Delivery of Gene and Drug

Kamra, Mohini and Moitra, Parikshit and Ponnalagu, Devasena and Karande, Anjali A and Bhattacharya, Santanu (2019) New Water-Soluble Oxyamino Chitosans as Biocampatible Vectors for Efficacious Anticancer Therapy via Co-Delivery of Gene and Drug. In: ACS APPLIED MATERIALS & INTERFACES, 11 (41). pp. 37442-37460.

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Abstract

Among the many nonviral gene delivery vectors, chitosan, being a polysaccharide of natural origin, has gained special importance. In this report, chitosan (CS) has been solubilized in water by preparing its O-carboxymethyl derivative, CS(CH2COOH), with an optimum degree of carboxymethylation. This has been further derivatized to get the pyridine-substituted product (py)CS(CH2COOH), where the degree of pyridine substitution (47%) was optimized based on zeta potential measurements. The optimized formulation showed a high gene binding ability, forming nanosized positively charged polyelectrolyte complexes with DNA. These polyplexes were stable to DNase and physiological polyanions such as heparin. They also exhibited minimal toxicity in vitro and showed transfection levels comparable to the commercial standard Lipofectamine 2000 and much higher than polyethylenimine (MW, 25 kDa). Additionally, in this study, a hitherto unknown oxyamine derivative of chitosan has been prepared by phthaloyl protection, tosylation, and Gabriel's phthalimide synthesis. Nearly 40% of the primary alcohols were successfully converted to oxyamino functionality, which was used for forming oxime with the anticancer drug doxorubicin. The pH sensitivity of the oxime ether linkage and stability under biologically relevant conditions were then used to establish the compound as a versatile drug delivery vector. Co-delivery of functional gene (p53) and drug (doxorubicin) was accomplished in vitro and in vivo with the chitosan-pyridine imine vector (py)CS(CH2COOH) and the newly synthesized doxorubicin oxime ether CS(Dox). Complete tumor regression with no tumor recurrence and appreciable survivability point to the in vivo effectiveness and biocompatibility of the designed composite formulation. Overall, the pH sensitivity of the oxime linkage aiding slow and steady drug release, together with the sustained gene expression by pyridine-tethered carboxymethyl chitosan, allows us to generate a nanobiocomposite with significantly high anticancer therapeutic potential.

Item Type:	Journal Article
Publication:	ACS APPLIED MATERIALS & INTERFACES
Publisher:	AMER CHEMICAL SOC
Additional Information:	Copyright of this article belongs to AMER CHEMICAL SOC
Keywords:	antitumor; chitosan; co-delivery; drug delivery; p53; sustained gene expression
Department/Centre:	Division of Biological Sciences > Biochemistry Division of Chemical Sciences > Organic Chemistry
Date Deposited:	23 Jan 2020 06:22
Last Modified:	23 Jan 2020 06:22
URI:	http://eprints.iisc.ac.in/id/eprint/63969

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