Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection

作者：Hoang Ky V; Borteh Hassan M; Rajaram Murugesan V S; Peine Kevin J; Curry Heather; Collier Michael A; Homsy Michael L; Bachelder Eric M; Gunn John S; Schlesinger Larry S; Ainslie Kristy M^*

来源：International Journal of Pharmaceutics, 2014, 477(1-2): 334-343.

DOI：10.1016/j.ijpharm.2014.10.022

• Autophagy
• Salmonella
• Macrophage
• Pathogens
• Microparticles
• Drug resistance

AR-12 has been evaluated in clinical trials as an anti-cancer agent but also has demonstrated host-directed, broad-spectrum clearance of bacteria. We have previously shown that AR-12 has activity in vitro against Salmonella enterica serovar Typhimurium and Francisella species by inducing autophagy and other host immune pathways. AR-12 treatment of S. Typhimurium-infected mice resulted in a 10-fold reduction in bacterial load in the liver and spleen and an increased survival time. However, AR-12 treatment did not protect mice from death, likely due poor formulation. In the current study, AR-12 was encapsulated in a microparticulate carrier formulated from the novel degradable biopolymer acetalated dextran (Ace-DEX) and subsequently evaluated for its activity in human monocyte-derived macrophages (hMDMs). Our results show that hMDMs efficiently internalized Ace-DEX microparticles (MPs), and that encapsulation significantly reduced host cell cytotoxicity compared to unencapsulated AR-12. Efficient macrophage internalization of AR-12 loaded MPs (AR-12/MPs) was further demonstrated by autophagosome formation that was comparable to free AR-12 and resulted in enhanced clearance of intracellular Salmonella. Taken together, these studies provide support that Ace-DEX encapsulated AR-12 may be a promising new therapeutic agent to control intracellular bacterial pathogens of macrophages by targeting delivery and reducing drug toxicity.

• 出版日期2014-12-30