# Nanomedicine for ARDS:  A new paradigm to target drugs to multiple cell types within alveolar capillaries

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $405,000

## Abstract

ABSTRACT
 Dozens of drugs have failed in clinical trials for the inflammatory lung disease ARDS (acute
respiratory distress syndrome), largely due to 3 pharmacological challenges particular to ARDS: ARDS
patients have multi-system organ failure, so cannot tolerate off-target drug side effects; the column of
liquid covering alveoli prevents effective inhaled delivery; dozens of signaling pathways underlie ARDS,
so modulating just one will not work. To overcome these 3 challenges, we designed M-LACs, which
are 100-nanometer lipid spheres (liposomes), loaded with multiple drugs, and coated with targeting
tags that cause them to massively accumulate in the capillaries of the alveoli (air sacs of the lungs).
We have previously published on the benefits of M-LACs targeted to alveolar endothelial cells, but have
long seen the need to target the other major alveolar capillary cell type, alveolar marginated
neutrophils. Here we introduce new targeting tags that can massively concentrate M-LACs in alveolar
neutrophils. With the new ability to target LACs to both endothelium and neutrophils, we can now
answer fundamental questions in ARDS biology (Aim 1) and general pharmacology (Aim 2), while
radically improving M-LACs as a therapy for ARDS (Aim 3). Aim 1: In ​ex vivo​ human lungs and ​in vivo
mouse models of ARDS, we quantify the relative number of marginated neutrophils compared to naive
cases, and we will measure how well neutrophils and endothelial take up M-LACs. Aim 2: We will test
the “depot theory” of targeted drug delivery, which says drugs efficiently elute from targeted cells to
their neighbors. We will test whether drugs meant to act in neutrophils (e.g., neutrophil elastase
inhibitors) will ameliorate ARDS-like phenotypes the same or worse if targeted to endothelial cells, and
vice versa. Aim 3: We will identify the principles of combination therapy. We hypothesize that the most
efficacious combinations will be a pair of neutrophil- and endothelial-modulating drugs (e.g., as
opposed to 2 endothelial-modulating drugs). By the end of these studies, we will have uncovered new
ARDS biology and answered fundamental questions in pharmacology. Additionally, we will have
created a highly optimized therapy for ARDS that we will have tested in multiple mouse models of
ARDS and in human lungs.

## Key facts

- **NIH application ID:** 10030992
- **Project number:** 1R01HL153510-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jacob Brenner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030992

## Citation

> US National Institutes of Health, RePORTER application 10030992, Nanomedicine for ARDS:  A new paradigm to target drugs to multiple cell types within alveolar capillaries (1R01HL153510-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10030992. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*