Multimodal nanoparticles that provide immunomodulation and intracellular drug delivery for infectious diseases

Abstract

Infectious diseases are a worldwide health concern. For some infections, a common feature is the intracellular residence of the pathogen and evasion of the host immune response. In the case of tuberculosis (TB), Mycobacterium tuberculosis evades clearance within macrophages through suppression of intracellular reactive oxygen and nitrogen species (ROS/RNS) and pro-inflammatory cytokines. We propose new nanoparticle designs for infectious diseases, functionalized with ligands able to modulate the cellular immune response and concurrently deliver drug. We have designed 1,3-beta-glucan functionalized chitosan shell, poly(lactide)co-glycolide core nanoparticles to stimulate ROS/RNS, pro-inflammatory cytokine secretion, and delivery of rifampicin inside human alveolar like macrophages (ALM). Nanoparticles significantly enhanced ALM secretion of IL-12p70 (2.9-fold), TNF-alpha (16-fold) and INF-gamma (23-fold) compared to controls over 24 h, and doubled ROS/RNS generation over 6 h. Nanoparticles could deliver 4-fold greater rifampicin into ALM compared to rifampicin solution. These results provide proof-of-concept of multimodal nanoparticles and support their further development. From the Clinical Editor: In this paper, a new nanoparticle design is proposed to address hard to treat infectious diseases such as TB, through the use of nanoparticles functionalized with ligands that are able to concurrently modulate the cellular immune response and deliver a drug. The authors have designed 1,3-beta-glucan functionalized chitosan shell - poly(lactide) co-glycolide core nanoparticles to stimulate reactive oxygen and nitrogen species production, pro-inflammatory cytokine secretion, and delivery of rifampicin inside human alveolar-like macrophages. (C) 2014 Elsevier Inc. All rights reserved.