Oncolytic viruses offer many advantages for cancer therapy when administered directly to confined solid tumors. However, the systemic delivery is problematic due to host immune response and interactions with blood components. Efficacy of systemically administered viruses has been improved by masking viral surface proteins with polymeric materials, through modulation of viral pharmacokinetic profile and accumulation in tumors in vivo. Here we describe poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA) co-polymer conjugates of Enadenotucirev (EnAd), a chimeric oncolytic virus, and demonstrate their ability to circumvent neutralisation by antibodies, as a potential means to improve systemic virotherapy. A series of pHPMA-based reactive copolymers was synthesized via post-polymerization modification of three pHPMA homopolymer precursors with N-Boc-4-aminobenzoic acid. Removal of the Boc groups yielded six polymers with different molar masses and aminobenzoate content. Polymers were activated with TFA/NaNO2 to form the corresponding polydiazonium which were used to coat EnAd. Polymer coating efficiency was found to correlate with increased molar mass and aminobenzoate content as determined by ELISA. Polymer coating decreased viral transgene expression compared to uncoated control in vitro (HT-29 cells) and in vivo (Balb/C mice). However, polymer coated virus could maintain some in vivo activity in the presence of neutralizing antibodies. Changes in viral infectivity resulting from polymer coating were not a consequence of reduced cell entry. Instead, a delayed onset of viral action in target cells indicated that polymer coating did not cause permanent inactivation of the virus. These data suggest that virus activity may be modulated by appropriate design of coating polymers while retaining protection against neutralizing antibodies.

In vitro and in vivo transfection activity of polymer conjugates of oncolytic adenovirus Enadenotucirev

256th National Meeting (2018)

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