# Nanomedicine Development for Systemic Lupus Erythematosus

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $376,250

## Abstract

ABSTRACT
 The overall goal of this project is to develop a highly effective and safe nanomedicine for systemic lupus
erythematosus (SLE) or lupus. Among many medications used in clinical management of lupus, glucocorticoid
(GC) is most widely used because of their high anti-inflammatory potency. But their notorious toxicities have
hampered the long-term clinical application. To reduce their side effects, we have conjugated dexamethasone
(Dex, a potent GC) to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and found that the Dex prodrug
is nephrotropic in a mouse model of lupus nephritis (NZB/W F1). Prophylactic and treatment of established
lupus nephritis with a monthly P-Dex injection (i.v.) are much more effective in prevention and reduction of
albuminuria than dose equivalent daily free Dex treatment. The P-Dex treatment did not elicit osteoporosis,
but other GC side effects (e.g. adrenal gland atrophy) remained. To further address this challenge, we recently
designed a novel prodrug nanomedicine by conjugating Dex to polyethylene glycol (PEG). The resulting
amphiphilic PEG-Dex self-assembles into micelles. When tested in the NZB/W F1 mice, it demonstrated
potent therapeutic efficacy, similar to P-Dex, but did not show any classical GC side effects. Based on these
exciting preliminary data, we hypothesize that due to their different structural design, P-Dex and PEG-Dex
have very different pharmacokinetic/biodistribution (PK/BD) profiles and patterns of interaction with the cellular
components of the immune system, leading to distinct subcellular distribution/activation patterns, similar
therapeutic potency, but different safety profiles. We also speculate that the original structural design of our
lead candidate, PEG-Dex micelle may not always work as well in other lupus models due to the heterogeneity
and comorbidities of lupus disease, which would necessitate further structure optimization. To validate these
hypotheses, we propose first to perform a head-to-head comparative PK/BD study of PEG-Dex and P-Dex.
We will also analyze the PK/BD profiles of the free Dex released from the two prodrug nanomedicine. These
studies may partially explain why PEG-Dex micelle has lower toxicity than P-Dex and will illustrate its working
mechanism from the PK/BD aspect. Second, we will perform in vitro and in vivo cellular studies to compare
and analyze the interaction of P-Dex and PEG-Dex with various cellular components of the immune system
and their impact on the biological functions of the prodrug nanomedicine. The results from this study will
further explain why PEG-Dex shows much better safety profile than P-Dex on the cellular and molecular levels.
Third, we will validate PEG-Dex micelle's efficacy and safety in NZM2410, MRL/lpr and CIA mice because of
the heterogeneity and comorbidities of lupus disease recapitulated in these models. Based on the
experimental feedback, the structure of PEG-Dex micelle will be optimized and the resulting final drug...

## Key facts

- **NIH application ID:** 9914083
- **Project number:** 5R01AI119090-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Dong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,250
- **Award type:** 5
- **Project period:** 2016-05-26 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914083

## Citation

> US National Institutes of Health, RePORTER application 9914083, Nanomedicine Development for Systemic Lupus Erythematosus (5R01AI119090-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9914083. Licensed CC0.

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