# Targeted nanodelivery in T1D

> **NIH NIH R56** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $570,859

## Abstract

With no effective therapy to date, the ongoing Type 1 diabetes (T1D) epidemic continues to be a major health
problem. While immune therapeutics (ITs) hold great promise for the treatment of T1D, their inadequacy,
serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression
approach. This shortcoming has prompted investigators to search for alternative approaches. Targeted
nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of ITs to
treat T1D. This strategy can minimize the undesirable side effects of ITs by delivering them to diseased
tissues, where they can undergo sustained release. In this multidisciplinary project, we aim to develop an
innovative, targeted nanodelivery method for ITs for T1D. Although progress has been made in developing
new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic
administration remains to be developed. The priming and activation of autoreactive T cells occurs in the
pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature
known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by
dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune
diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in
NOD mice. Our biodegradable polymeric NPs are coated with MECA79 IgM antibody by using maleimide-thiol
chemistry (MECA79-MT-NP); MECA79 binds to peripheral node addressin (PNAd), a glycoprotein family
expressed only by endothelial cells of the HEV. Here, we demonstrate for the first time the targeted delivery of
MECA79-MT-NPs to the PLNs and pancreata of NOD mice following intravenous administration. We also
provide human data that supports the clinical applicability of our delivery platform. Active targeted delivery to
these sites has never been achieved in T1D. Moreover, our preliminary data shows that encapsulation of the IT
anti-CD3 antibody inside our MECA79-MT-NPs results in more effective reversal of autoimmune diabetes in
NOD mice than treatment with free anti-CD3. Our main hypothesis is that targeted delivery of anti-CD3 to the
pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing
systemic dosing significantly. In Aim 1, we will examine and optimize the stability, binding efficacy, and
biodistribution of MECA79-conjugated NPs (MECA79-NPs) by utilizing alkyne-azide chemistry to permit the
attachment of the pentameric form of MECA79 to the NP (MECA79-AA-NP). In Aim 2, we will assess the
clinical efficacy of encapsulating anti-CD3 inside the formulation of MECA79-NP with the optimized properties
from Aim 1 in the reversal of autoimmune diabetes in NOD mice as well as elucidate the mechanisms by which
our targeted therapy works. In Aim 3, we plan to te...

## Key facts

- **NIH application ID:** 10202270
- **Project number:** 1R56AI152146-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Reza Abdi
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $570,859
- **Award type:** 1
- **Project period:** 2020-08-06 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202270

## Citation

> US National Institutes of Health, RePORTER application 10202270, Targeted nanodelivery in T1D (1R56AI152146-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10202270. Licensed CC0.

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