# Spatiotemporal delivery of synergistic drug combinations to kidney cancer

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $378,235

## Abstract

Metastatic renal cell carcinoma (RCC) is a devastating disease often refractory to radiation, chemo, and
cytokine therapy. Agents targeting the VEGF and mTOR pathways remain the foundation of RCC treatment.
Despite marginal improvement in survival with targeted therapy, major limitations exist mainly because of the
inter and intra-tumor heterogeneity and redundant pathway activation. While some patients with RCC are
inherently refractory to therapy, others who initially respond to single or sequential targeted therapy eventually
progress. Efforts to extend the clinical benefit of these agents with combination therapy have resulted in
prohibitive toxicity, often with no overall benefit. Targeted multimodality nanoparticles hold great promise in
this scenario; however, such modalities for RCC treatment are not currently available. Our goal is to engineer
a targeted nanoparticle with clinically validated biomaterials and rationally modified drugs, which will self
assemble into a nano-carrier system and provide exquisite spatiotemporal control over drug release to
enhance the therapeutic efficacy and reduce off-target toxicity. Our specific aims are the following: Aim 1:
Engineer and characterize dual drug-loaded targeted high-efficiency nanoparticles for RCC. Because
of the small size and high hydrophobicity, targeted drugs for PI3K and VEGF often exhibit suboptimal
pharmacokinetics with a large volume of distribution, and tend to accumulate in healthy tissues causing off
target toxicity. Further, traditional pharmaceutical approaches for nano-formulation have been challenge with
these molecules because of their incompatible physicochemical properties. We hypothesize that this can be
addressed by rationally re-engineering the active agents into pro-drug amphiphiles that facilitate
supramolecular nano-assembly into stable high efficiency nanoparticles. We will decorate the SNPs with a
targeting ligand for better homing and improved potency. Further, we will optimize conjugation chemistry and
ligand density on the SNPs. Aim 2: Pharmacokinetic, bio-distribution and toxicity evaluation of the
targeted high-efficiency nanoparticles. In this aim, we will test our hypothesis that targeted SNPs are safe
and will preferentially accumulate in tumor tissues yielding high therapeutic index. Aim 3: A mechanistic
ananlysis of in vivo efficacy of the high-efficiency nanoparticles in RCC. We hypothesize that
mechanistically inspired and surface functionalized nanoparticles that deliver payloads directly to tumor cells
and inhibits PI3K-mTORC1/2 and MET/VEGFR2/Tie-2 signaling will regress RCC, evade tumor resistance,
and thus improve antitumor outcome with reduced adverse effects. We will test this hypothesis on an array
of RCC cell lines and biologically relevant experimental mouse models. We will also perform a head-to-head
comparison of targeted vs. untargeted SNPs for their therapeutic efficacy and toxicity. We will dissect the
performance of SNPs at the animal ...

## Key facts

- **NIH application ID:** 9996545
- **Project number:** 5R01CA229772-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Venkata Sabbisetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,235
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996545

## Citation

> US National Institutes of Health, RePORTER application 9996545, Spatiotemporal delivery of synergistic drug combinations to kidney cancer (5R01CA229772-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9996545. Licensed CC0.

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