# Multimodal dendrimer theranostics targeting aggressive subtypes of prostate cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $692,072

## Abstract

PROJECT SUMMARY
Our ultimate goal is to develop a practical, theranostic platform for managing PC. Prostate cancer (PC) is the
second most common cancer and the fifth most frequent cause of cancer death among men. Despite a gradually
improving trend in outcomes, the current death rate remains unacceptably high, with metastases in 20% of
afflicted men. The American Cancer Society estimates approximately 268,490 new cases and 34,500 deaths
from PC in the United States in 2022. Prostate-specific membrane antigen (PSMA) expression has been
associated with aggressive PC, and is present in over 90% of metastatic disease. Those features have led to
employing PSMA for PC detection with radionuclide imaging, and for therapies including antibody-drug
conjugates, targeted radiotherapeutics and immunotherapeutic approaches. Nearly 450 trials involving PSMA in
PC are registered on clinicaltrials.gov. Nevertheless, all of the current therapies show some degree of toxicity
and are not curative. We are well-positioned to develop novel therapies through application of our PSMA-
targeted theranostic agents. We have recently synthesized PSMA-targeted poly(amidoamine) (PAMAM)
dendrimers that may be used for PC-specific concurrent delivery of imaging and therapy. PAMAM dendrimers
serve as versatile delivery vehicles that can be tailored to different sizes and compositions. Here we propose
development of multimodal theranostic agents enabling: (I) highly specific PSMA targeting; (II) application of
quantitative positron emission tomography/computed tomography (PET/CT) ultimately for selecting patients for
therapy; (III) incorporation of a potent antimitotic agent; and, (IV) incorporation of optimized chemical exchange
saturation transfer (CEST) moieties to enable non-invasive monitoring of PC drug delivery by the clinically
ubiquitous imaging modality, magnetic resonance imaging (MRI). As we have shown, CEST is sufficiently
sensitive to enable targeted imaging. When high-frequency salicylate moieties are used there, is a frequency-
specific contrast not encumbered by background signal, allowing determination of targeting efficiency. Direct
imaging of drug biodistribution provides information needed to understand and improve efficacy. The proposed
PSMA-targeted theranostic agents will be synthesized via consecutive conjugation of PAMAM dendrimer with
deferoxamine (DFO, for radiolabeling with 89Zr, enabling PET/CT and evaluation of pharmacokinetics), lysine-
urea-glutamate moieties (KEU, for PSMA targeting), and numerous 4-(3-carboxypropanamido)-2-
hydroxybenzoic acid molecules [salicylic acid (SA) derivatives for CEST contrast]. For therapeutic studies,
proposed theranostic agents will be additionally equipped with maytansine 1 (DM1) and monomethyl auristatin
e (MMAE, both routinely used of formulation of antibody-drug conjugates) via either encapsulation or
conjugation. We will use mice bearing clinically relevant human PC metastatic xenografts for pharmacokinetic
stu...

## Key facts

- **NIH application ID:** 10977964
- **Project number:** 1R01CA285792-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Wojciech Lesniak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $692,072
- **Award type:** 1
- **Project period:** 2024-09-19 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977964

## Citation

> US National Institutes of Health, RePORTER application 10977964, Multimodal dendrimer theranostics targeting aggressive subtypes of prostate cancer (1R01CA285792-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10977964. Licensed CC0.

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