A Long-Acting Thermoresponsive Injectable Formulation of Tin Protoporphyrin Sustains Antitubercular Efficacy in a Murine Infection Model

Abstract

Tuberculosis is the leading cause of death from a single infectious agent, ranking above the human immunodeficiency virus (HIV). Effective treatment using antibiotics is achievable, but poor patient compliance constitutes a major challenge impeding successful pharmacotherapeutic outcomes. This is often due to the prolonged treatment periods required and contributes significantly to the rising incidence of drug resistance, which is a major cause of tuberculosis mortality. Thus, innovative interventions capable of encouraging compliance and decreasing lengthy and frequent dosing are needed. Previously, aqueous tin protoporphyrin IX (SnPPIX), a heme oxygenase-1 inhibitor, administered as multiple daily intraperitoneal (IP) injections, showed considerable antitubercular efficacy and treatment shortening capabilities as a host-directed therapy in infected mice. Since daily IP injection is a clinically impractical administration approach, this proof-of-concept study aims to develop a novel, sustained action injectable formulation of SnPPIX for safe intramuscular (IM) administration. Herein, a SnPPIX-loaded poloxamer-poly(acrylic acid)-based thermoresponsive injectable formulation (SnPPIX-TIF) is designed for effective IM delivery. Results show SnPPIX-TIF is microparticulate, syringeable, injectable, and exhibits complete in vitro/in vivo gelation. Administered once weekly, SnPPIX-TIF significantly prolonged absorption and antimicrobial efficacy in infected mice. In addition, SnPPIX-TIF is well-tolerated in vivo; results from treated animals show no significant histopathologic alterations and were indistinguishable from the untreated control group, thus supporting its biocompatibility and preclinical safety. Overall, the IM delivery of the thermoresponsive injectable formulation safely sustains antitubercular effect in an infected murine model and decreases the number of injections required, signifying a potentially practical approach for future clinical translation.