A Mannosylated Polymer with Endosomal Release Properties for Peptide Antigen Delivery

Overview

Journal J Control Release

Specialty Pharmacology

Date 2023 Mar 6

PMID 36878319

Authors

Kefan Song

Dinh Chuong Nguyen

Tran Luu

Omeed Yazdani

Debashish Roy

Patrick S Stayton

Suzie H Pun

Affiliations

Soon will be listed here.

Abstract

Peptide cancer vaccines have had limited clinical success despite their safety, characterization and production advantages. We hypothesize that the poor immunogenicity of peptides can be surmounted by delivery vehicles that overcome the systemic, cellular and intracellular drug delivery barriers faced by peptides. Here, we introduce Man-VIPER, a self-assembling (40-50 nm micelles), pH-sensitive, mannosylated polymeric peptide delivery platform that targets dendritic cells in the lymph nodes, encapsulates peptide antigens at physiological pH, and facilitates endosomal release of antigens at acidic endosomal pH through a conjugated membranolytic peptide melittin. We used d-melittin to improve the safety profile of the formulation without compromising the lytic properties. We evaluated polymers with both releasable (Man-VIPER-R) or non-releasable (Man-VIPER-NR) d-melittin. Both Man-VIPER polymers exhibited superior endosomolysis and antigen cross-presentation compared to non-membranolytic d-melittin-free analogues (Man-AP) in vitro. In vivo, Man-VIPER polymers demonstrated an adjuvanting effect, induced the proliferation of antigen-specific cytotoxic T cells and helper T cells compared to free peptides and Man-AP. Remarkably, antigen delivery with Man-VIPER-NR generated significantly more antigen-specific cytotoxic T cells than Man-VIPER-R in vivo. As our candidate for a therapeutic vaccine, Man-VIPER-NR exerted superior efficacy in a B16F10-OVA tumor model. These results highlight Man-VIPER-NR as a safe and powerful peptide cancer vaccine platform for cancer immunotherapy.

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