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


ABSTRACT: 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.

SUBMITTER: Hoang KV 

PROVIDER: S-EPMC4267924 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Hoang Ky V KV   Borteh Hassan M HM   Rajaram Murugesan V S MV   Peine Kevin J KJ   Curry Heather H   Collier Michael A MA   Homsy Michael L ML   Bachelder Eric M EM   Gunn John S JS   Schlesinger Larry S LS   Ainslie Kristy M KM  

International journal of pharmaceutics 20141022 1-2


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  ...[more]

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