Human Immunodeficiency Virus (HIV) is ranked globally as the deadliest single most infectious agent, with Mycobacterium tuberculosis (TB) following a close second. At least one-third of HIV-positive people are infected with TB and it is a major cause of mortality among this patient population. On the other hand, HIV is a major co- morbidity in patients with TB, with this population 30 times more likely to develop active TB disease than people without HIV. In the absence of vaccines against these diseases, drug therapy approaches remain the only effective treatment options. The foundation of HIV therapy is based on the combination of multiple antiretroviral agents in a single regimen. However, several factors contribute to the continuing development of treatment failure and drug resistance, among them are suboptimal drug efficacy and/or variable pharmacokinetics, inadequate adherence to lifelong therapy, pre-existing drug resistance and acute or chronic drug toxicities. Standard TB management involves combination therapy for 6 to 9 months using 4 first-line drugs. Treatment failure and drug resistance are primarily related to the long duration of treatment, TB drug side effects and toxicity, various socioeconomic constraints, poor adherence to treatment, loss to follow up, human errors in prescribing inadequate regimens, inconsistent dosing and poor quality of drugs. An innovative alternative for both of these diseases would combine the antimicrobial drug effects with an augmented innate immune system to eradicate pathogens and overcome the problems associated with current therapies. We utilize nanoparticle carriers prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan as the shell in a core-shell configuration that allows attachment of the immune stimulatory ligand, ?-glucan, to the surface of the shell and encapsulation of drugs (HIV and/or TB) in the core. These nanoparticles will deliver TB and/or HIV drugs specifically to macrophages while concomitantly inducing the production of cytokines and reactive oxygen molecules within the macrophage, with the goal of intracellular pathogen clearance. This innovative therapy represents a new and practical alternative to study targeted nanoparticle drug delivery combined with immunomodulation using a single ligand, ?-glucan. The study design utilizes an integrated physiologically-based, dynamic, hollow fiber macrophage cell culture system to determine the pharmacokinetics and immune-dynamics of this multi-modal nanoparticle. We will determine the optimal dose and method of delivery and the bio-distribution, pharmacokinetics and immune stimulation in a mouse model. We will then develop a physiological based-pharmacokinetic model that describes nanoparticle distribution based on chemical and biological parameters (in vitro and in vivo data). This approach will broaden our scientific knowledge of HIV and/or TB disease therapies and, by combining targeted drug delivery with immune augmentation, create new approaches that will facilitate reducing individual drug doses, reduce systemic drug toxicity and reduce the development of drug resistance.
The prevention and treatment of HIV and TB are global health concerns that require patients to take complex medications for prolonged periods resulting in poor compliance, unwanted side effects, drug resistance and treatment failure. The goal of this proposal is to use novel nanoparticle formulations that target HIV and TB drugs to specific cells of the immune system called macrophages while also activating these cells. If successful, this combination of multidrug therapy together with immunotherapy will lead to better treatment outcomes compared to either approach alone.