# Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $661,877

## Abstract

Project Summary/Abstract
The goal of this proposal is to develop a novel approach for tumor cells ablation, while leaving healthy cells
alive. This approach is based on 123I, a radioactive iodine isotope that emits Auger electrons. Auger electrons
have the advantage of dissipating their energy in a very narrow radius, principally confined to only 10
nanometers. Therefore, unlike the more commonly used α- and β-emitters, Auger electron emitters inflict
cellular DNA damage only at their targeted site, while leaving healthy cells in the immediate vicinity unaffected.
We intend to target the DNA of cancer cells by conjugating 123I to inhibitors of the DNA repair enzyme PARP1.
In preliminary experiments, we have shown these agents can efficiently transport ionizing radiation into the
nuclei of cancer cells, and we have demonstrated that they are particularly useful for the delivery of targeted
payloads to brain tumors. This use relies on the expression of PARP1 in brain tumors being far higher than in
the healthy surrounding brain tissue. In addition, Auger emitting PARP1 radiopharmaceuticals are also less
likely to damage kidney and liver than α- or β-emitting radionuclides, because in those organs, the
overwhelming amount of activity should be retained outside of the nucleus, where the toxicity of Auger emitters
is significantly lower.
The Specific Aims of this proposal are to synthesize a library of radioiodinated PARP1 targeted inhibitors, and
to determine which of them will most likely be successful as Auger 123I-labeled radiotherapeutics, based on
their bioavailability, metabolic stability, tissue concentrations and residence times. Parallel SPECT imaging
experiments will be used to study the whole body biodistribution and cellular PARP1 expression before and
after DNA damaging treatment. For the 123I-labeled lead compound, we will determine extensive
pharmacodynamic data, both in vitro as well as in vivo. We will perform a dose escalation study, and measure
the effects on tumor growth and systemic toxicity. Infiltrative mouse models will be used to determine the
potential impact of this novel radiotherapeutic drug. We will further design combination treatment studies with
PARP1 Auger emitters, where sub-therapeutic doses of external beam radiation are used to increase activity
and DNA proximity of PARP1, and therapeutic doses are used to increase overall PARP1 expression, with
both effects increasing the sensitivity of tumor tissue to the radiotherapeutics.
The ultimate goal of this study is to validate PARP1 targeted shuttles for Auger emitters in mouse models of
glioblastoma. For this application, an interdisciplinary team of experts has been brought together to aid in the
development of this technology. The research team will include Dr. Thomas Reiner (Radiochemistry and Probe
Development), Dr. Wolfgang Weber (Nuclear Therapy), Dr. Ronald Blasberg (Neurology) and Dr. John Humm
(Medical Physics). Together, the investigators form an ideal team...

## Key facts

- **NIH application ID:** 9961531
- **Project number:** 5R01CA204441-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Nagavarakishore Pillarsetty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $661,877
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961531

## Citation

> US National Institutes of Health, RePORTER application 9961531, Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy (5R01CA204441-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9961531. Licensed CC0.

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