am9b09485_si_001.pdf (2.67 MB)
New Water-Soluble Oxyamino Chitosans as Biocompatible Vectors for Efficacious Anticancer Therapy via Co-Delivery of Gene and Drug
journal contribution
posted on 2019-10-07, 11:37 authored by Mohini Kamra, Parikshit Moitra, Devasena Ponnalagu, Anjali A. Karande, Santanu BhattacharyaAmong 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.
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gene binding abilitychitosan-pyridine imine vectornonviral gene delivery vectorsCOOHtumorMWoxime ether linkageanticancer drug doxorubicinpyridine-tethered carboxymethyl chitosanDNACSEfficacious Anticancer Therapyvivoformulationdrug delivery vectoroptimizedNew Water-Soluble Oxyamino ChitosanspH sensitivity