# Multivalent Nano-conjugates for Targeted Penetration of and Delivery to Dense Extracellular Matrices

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $519,975

## Abstract

Although nanoparticles have been found to be effective in delivery to more traditional vascularized organs and
tissues, there are different challenges for nanoparticle transport in tissues that lack a vascular system to assist
in penetration into the tissue. Here we propose a systematic approach to the design of nanomaterials systems
that are capable of deep penetration and delivery of agents into avascular tissues. The proposed work will focus
on establishing sets of materials design concepts to enhance transport into and through these tissues based on
size, charge density and presentation, targeting and dynamic materials chemistries. In the Aim 1, we will develop
two promising families of multivalent drug nanocarriers with modular design, each presenting unique advantages
for tissue penetration. The transport of these nanocarriers will then be examined as a function of size and charge
using ex vivo tissue models to rapidly screen libraries of nanocarriers and identify optimal size/charge
characteristics for tissues of interest. We will examine transport in three unique avascular tissue types: cartilage,
meniscus and cornea to understand similarities or differences in design requirements and optimal transport
characteristics for a range of avascular tissue types. Further translation of this Aim is anticipated to provide
fundamental knowledge regarding how to address other similar barrier tissues in the context of drug delivery.
Treatment of cartilage to address conditions such as osteoarthritis presents a particularly important medical
challenge, and is the disease focus for the later Aims of these studies; however, successful demonstration of
this system in the first Aim will be applicable to other tissues and conditions, including delivery to the cornea and
joint meniscus. To enable a more tissue-responsive delivery approach, both pH responsive and enzyme
degradable linkers will be examined in Aim 2 for the conjugation of therapeutics, with the focus on conjugation
of IGF-1, a growth factor that can facilitate cartilage regeneration in early stage osteoarthritis. Optimized versions
of the nanocarriers will be studied in an established in vivo using an early surgical trauma rat model to evaluate
the efficacy of IGF-1 treatments with the nondegradable, hydrolytic, and protease-activated degradable linkers
and determine in vivo real-time pharmacokinetics versus free IGF-1. Cartilage treatment studies will be carried
out in this model for IGF-1 delivery. Finally, an additional aspect of this study will be the design of nanoconjugates
that release drug selectively to regions of tissue matched to the different nanocarrier transport properties
determined in earlier Aims, including degree of penetration and residence time within the tissue. Combination
treatments for small molecule drugs including dexamethasone and TLR4 inhibitors will be conjugated to carriers
optimal for each drug, in combination with the top IGF-1 formulation. We will evaluate the ...

## Key facts

- **NIH application ID:** 10179375
- **Project number:** 5R01EB026344-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Paula T Hammond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $519,975
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179375

## Citation

> US National Institutes of Health, RePORTER application 10179375, Multivalent Nano-conjugates for Targeted Penetration of and Delivery to Dense Extracellular Matrices (5R01EB026344-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10179375. Licensed CC0.

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