# Pulmonary Delivery of Antibiotics Co-crystalized with Cyclodextrin-based Metal Organic Frameworks to Treat Non-Tuberculous Mycobacterial (NTM) Infections

> **NIH NIH R43** · SCIENTIFIC HORIZONS CONSULTING LLC · 2024 · $298,530

## Abstract

Project Summary
Non-tuberculous mycobacterial (NTM) lung disease represents a major public health challenge. The long
treatment period and high-dose systemic administration of antibiotics often leads to adverse effects, resistance
development, and suboptimal therapeutic accumulation at the infection site. Identifying new drugs and routes of
administration as well as shorter and better-tolerated treatment regimes are highly desired for treating NTM lung
infections, including those caused by MAC and M. abscessus, among other species.
Here, we propose a novel antibiotic delivery system, cyclodextrin-based metal-organic frameworks (CD-MOFs),
to form antibiotic/CD-MOF cocrystals administered through an inhalation route via a dry powder inhaler (DPI) to
tackle the challenges in NTM infection treatments. Highlighted innovations include (1) High loading ratios and
deep lung delivery with minimized systemic exposures and adverse effects; (2) Cyclodextrin-improved
bioavailability and permeability for the boosted antimicrobial activity; (3) Synergistic anti-mycobacterial efficacy
via multiple antibiotic integration; (4) Controlled release of antibiotics towards optimized PK/PD performance; (5)
MOF-induced intracellular internalization by alveolar macrophages favorable in treating NTM and other
intracellular infections; and (6) Significantly lowered production cost with complete avoidance of toxic solvents.
Because of the unique value of CD-MOF cocrystals provided, our proposal will offer multiple benefits to the field
of pulmonary antibiotic delivery for the improved efficacy and safety in treating NTM lung infections.
In Aim 1, we plan to demonstrate the pulmonary anti-mycobacterial feasibility of antibiotics/CD-MOF cocrystals.
The investigation starts by synthesizing cocrystals with high loading ratio (>10wt%) and appropriate aerodynamic
performance (MMAD: 1-5µm) suitable for deep lung pulmonary delivery. Then, we will evaluate the in vitro anti-
mycobacterial efficacy using standard broth microdilution method (M. abscessus, 30±2°C; CAMHB) to determine
MIC, providing quantitative insights into the therapeutic potential of the proposed antibiotics/CD-MOF cocrystals.
In Aim 2, we will incorporate mycobacterial intracellular infection by introducing Mycobacterium avium (MAC,
ATCC 700898) in monocyte-derived macrophages (MDMs), co-cultured with a rationally designed 3D alveolar
ALI microtissue (MOI=10), to model the NTM infection in lung. The infected microtissue will be treated in apical
surface with (1) air (negative control), (2) standalone antibiotics (positive control), and (3) antibiotic/CD-MOF
cocrystals (treatment). Multiple endpoints will be evaluated including anti-mycobacterial killing efficacy (CFU
enumeration and log reduction), toxicity (cell viability, pro-inflammatory cytokine expressions, ALI barrier integrity,
gene expression of type I/II pneumocytes), cellular internalization, and antibiotic release and absorption profiles.
In future SBIR p...

## Key facts

- **NIH application ID:** 11006740
- **Project number:** 1R43AI186765-01
- **Recipient organization:** SCIENTIFIC HORIZONS CONSULTING LLC
- **Principal Investigator:** Xiang Gao
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $298,530
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006740

## Citation

> US National Institutes of Health, RePORTER application 11006740, Pulmonary Delivery of Antibiotics Co-crystalized with Cyclodextrin-based Metal Organic Frameworks to Treat Non-Tuberculous Mycobacterial (NTM) Infections (1R43AI186765-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11006740. Licensed CC0.

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