# In situ cancer cell specific biomineralization to overcome nanoparticle delivery barriers and sensitize pancreatic cancer to radiotherapy

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $612,076

## Abstract

Abstract. Pancreatic ductal adenocarcinoma (pancreatic cancer, PDAC) is the classic example of a recalcitrant
tumor that is extremely challenging to treat. Therapeutic strategies which can bypass the desmoplasia `fortress'
and access hypoxic microenvironments without significantly affecting healthy cells would address the critical
issues presented by PDAC physiology. Localized therapies are a critical component of PDAC treatment and
there is strong interest in innovative ways to intensify radiation therapy (RT). A novel approach to enhancing the
radiation dose delivered to tumors is to increase the radiation-interaction probability of the target tissues by
delivering high atomic number (Z) nanoparticles (e.g., gold or hafnium oxide) to tumor cells. However, due to
the exuberant desmoplasia characteristic of PDAC, the diffusion of even the smallest nanoparticles is limited by
the dense stroma making delivery to cancer cells exceedingly challenging. Furthermore, recent evidence
confirms that depleting the stroma may not be the answer since the stroma restrains and confines cancer cells
to within the pancreas rather than promotes the growth of cancer cells. We contend that the ideal strategy is to
penetrate the stroma without destroying it. Here we address this delivery barrier standing in the way of effective
radiosensitization of PDAC tumors by employing a recently reported process of in situ gold biomineralization by
mammalian cancer cells. This strategy will allow replacement of pre-synthetized radiosensitizing gold
nanoparticles (GNPs) with ionic gold atoms thus achieving the smallest possible size of a therapeutic agent – a
single ionic atom. Our hypothesis is that small gold ions (i) will uniformly distribute throughout the tumor as their
diffusion is not likely to be impeded by the stroma, (ii) will be reduced to GNPs via the process of in situ
biomineralization after specific uptake by cancer cells, and (iii) will radiosensitize the tumor while sparing
adjacent normal tissue. This hypothesis is based on our preliminary data demonstrating a strong
radiosensitization effect in PDAC cells by the intracellularly synthetized GNPs both in vitro and in vivo. In addition,
normal pancreatic cells synthesized significantly fewer GNPs than cancer cells, consistent with recent reports
showing higher efficiency of in situ gold biomineralization in cancer vs. non-cancer cells. Further, a long history
of the clinical use of gold-salt based drugs in treatment of rheumatoid arthritis can provide a clear path towards
clinical translation. In this project we have devised comprehensive mechanistic studies to evaluate and to
optimize in situ biomineralization for efficient radiosensitization of PDAC. To this end we will carry out studies in
three synergistic Aims: (1) to determine the mechanism of and to optimize conditions for intracellular synthesis
of GNPs by PDAC cells; (2) to evaluate the determinants of radiosensitization efficacy in vitro and in vivo; an...

## Key facts

- **NIH application ID:** 10519097
- **Project number:** 1R01CA274415-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Sang Hyun Cho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $612,076
- **Award type:** 1
- **Project period:** 2022-08-02 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519097

## Citation

> US National Institutes of Health, RePORTER application 10519097, In situ cancer cell specific biomineralization to overcome nanoparticle delivery barriers and sensitize pancreatic cancer to radiotherapy (1R01CA274415-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10519097. Licensed CC0.

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