# Pharmacokinetics and Immunodynamics of Immune stimulating chemotherapeutic  nanoparticles for TB

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $470,531

## Abstract

Project Summary
The risk of developing TB is estimated to be between 26 to 31 times greater in people living with HIV-1. TB
suppresses the macrophage anti-bacterial response by preventing the maturation of phagosomes to
phagolysosomes (Ca2+ dependent) and suppressing the production of intracellular reactive oxygen species and
reactive nitrogen species (ROS/RNS) and pro-inflammatory cytokines. Effective antibacterial drugs against
Mycobacterium tuberculosis exist (e.g., rifampin, isoniazid). However, these drugs have a major challenge with
respect to entering macrophage in order to eradicate the microbe. In addition, the low intracellular drug
concentrations are rapidly cleared from macrophage before the microbe has been completely eradicated. These
issues have clinical implications: 1) TB treatment is lengthy in order to eradicate the microbe within the cells
(minimum 6 month-treatment); and 2) poor cellular drug penetration plays a role in the generation of drug
resistant strains, due to the periods of sub-optimal drug exposure of the microbe, allowing the microbe to mutate
and become resistant. Thus it is necessary to develop targeted macrophage therapies in which the effects of
current TB drugs act synergistically with the actions of the innate immune system to eradicate pathogens. This
strategy may potentially reduce the drug dosage required, shorten the duration of treatment, and reduce the
emergence of drug resistance. We have developed a macrophage targeted nanoparticle drug delivery system that
is combined with immunomodulation using a single ligand, β-glucan. We designed a core-shell nanoparticle
prepared from the biocompatible polymers, poly-lactic-co-glycolic acid (PLGA; core containing TB drug) and
chitosan (CS; shell) with surface adsorbed β-glucan (GLU) (GLU-CS-PLGA). GLU on the nanoparticle's surface
binds to Dectin-1 on macrophage, enhancing cellular uptake. This binding also activates macrophage, enhancing
the production of Ca2+, ROS/RNS and cytokines. We will first determine the in vitro cellular pharmacokinetics
(PK) and pharmacodynamics (PD) of the GLU-CS-PLGA nanoparticles utilizing a novel PK/PD-based
macrophage cell culture system. These data will inform our in vivo mouse studies. We will next determine the
PK and PD of the GLU-CS-PLGA nanoparticles in vivo in a healthy mouse model. These studies will yield the
optimal dose, route of delivery, biodistribution, PK and PD of the nanoparticle. Physiologically based PK (PBPK)
modeling will next be used to integrate the in vitro and in vivo data to provide key insights for future in vivo TB
studies. This research represents a paradigm shift whereby nanocarrier systems may be designed based on first
principles with in silico and in vitro model predictions. This approach will broaden our scientific knowledge of
TB disease therapies and, by combining targeted drug delivery with immune augmentation, create new
approaches that will facilitate reducing individual drug doses, shorten d...

## Key facts

- **NIH application ID:** 9974460
- **Project number:** 5R01AI129649-03
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** JESSICA L REYNOLDS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $470,531
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974460

## Citation

> US National Institutes of Health, RePORTER application 9974460, Pharmacokinetics and Immunodynamics of Immune stimulating chemotherapeutic  nanoparticles for TB (5R01AI129649-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974460. Licensed CC0.

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