Modular, targeted polymeric-prodrugs for the treatment of infectious diseases

Abstract

Infectious diseases have haunted mankind since time immemorial, from the oldest strains of Mycobacterium through the recent coronavirus pandemic. There is constant need for new and improved therapies in our never-ending arms race against pathogens. Reversible addition-fragmentation chain transfer (RAFT) polymerization is characterized by its broad range of polymerizable monomers, precise control of chain growth, and general ease of use without the need for toxic transition metals. These qualities make RAFT-based polymers a useful platform for drug delivery, where modularity, user-friendliness, reproducibility, and reduced lead time all contribute to a better, more cost-effective therapeutic platform. This work describes RAFT-based polymeric prodrugs which carry fully synthetic, enzyme- cleavable small molecule therapeutics to specific cell populations– a platform termed drugamers. The first portion of this work focuses on a serum stable peptide linker which improves the pharmacokinetic profile of the anti-malarial drug tafenoquine for the treatment of Plasmodium vivax malaria. P. vivax treatments, including tafenoquine, are contraindicated in patients with G6PD-deficiency due to an increased risk of hemolytic anemia. This design showed efficacy in a causal prophylaxis model using Plasmodium berghei-infected mice and reduced hemotoxicity in a humanized mouse model of G6PD-deficiency. The second portion of this work describes an inhalable, alveolar macrophage-targeted drugamer carrying dexamethasone for the treatment of pulmonary infection, particularly hyperinflammatory diseases such as COVID-19. This polymer design improved the pharmacokinetic profile of dexamethasone relative to free drug and reduced inflammation in a lipopolysaccharide-induced lung injury model. These projects highlight the versatility of drugamers as carriers for small molecule therapeutics to treat infectious diseases.