Papineni, Rao V.

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

Abstract The goal of this project is to develop a unique pancreatic cancer treatment platform where, X-ray excited Targeted-Gold nanoparticles (T-GNPs) trigger and enhance drug action (I-RaGAZ, Integrated radiation combined with T-GNP and 2-Azido-2-deoxy-D-glucose (2-AZ-2-DG)). Herein, we plan to utilize a novel three stage nanotechnology-chemoradiation combinatorial approach for enhancing catastrophic cell death in pancreatic tumors and reducing normal tissue toxicity. T-GNP has cytotoxic effect at tumor site and can specifically sensitize tumor tissue for radiation. In this work, we used our GNP-based pancreatic ductal adenocarcinoma (PDAC) -specific drug delivery platform using a plectin-1-targeting peptide (PTP) (patent: US2018/0333432 A1) to demonstrate the cytotoxicity of the nanocomplex in vitro. In PANC-1 cancer cell model, using traditional gold-standard clonogenic assay, we show 2-AZ-2-DG has radiation-mediated cytotoxicity which is further augmented by T-GNP. These results align with our hypothesis and the electron spin resonance (ESR) spectroscopy electron-induced aminyl radical production data presented here. This radiation-produced auger electrons from T-GNP likely increased formation of RNH• which result in enhanced cell kill. This via H-atom abstraction reactions that might cause DNA-strand breaks and/or crosslink formation leading to lesions that could induce apoptosis of cancer cells. This nanotool paraphrased as I-RaGAZ, Integrated radiation induced T-GNP - 2-AZ-2-DG anti-tumor action, will be very useful for treating deep-seated tumors with minimum collateral damage. This approach, integrated radiation-mediated azido tumor cure (I-RaGAZ), has vast global cancer treatment potential considering the dual mode of damaging the tumor tissues and protecting the normal tissues/organs. Citation Format: Rao V. Papineni, Amitava Adhikary, Santanu Bhattacharya. Towards targeted-gold nanoparticle enhanced chemoradiation therapy of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 219.

Abstract A defined spatial and temporal control of induction of toxicity in response to external ionizing radiation such as X-rays has unique clinical benefits over conventional systems such as passive drug delivery or its activation. Here, we have combined X-rays with well characterized nanoscintilators emitting light that activates paired photosensitizers in photodynamic therapy (PDT) that improves the prowess of PDT to deep seated tumor treatment. Yttrium oxide nanoparticle construct doped with Europium (YOE) and coated with a silica layer entrapping methylene blue (MB) as the photosensitizer was fabricated. The nanoconstruct (YSM, for YOE, silica, MB) was decorated with polyethylene glycol (PEG) to make it biocompatible and characterized extensively for physicochemically parameters. Transmission electron microscopy (TEM) revealed a resultant average nanoparticle diameter of 24.1 ± 5.7 nm, and dynamic light scattering (DLS) a hydrodynamic diameter of 135.3 ± 17.9 nm. This nanoconstruct was evaluated for its ability to generate singlet oxygen reactive oxygen species upon irradiation using singlet oxygen sensor green (SOSG) fluorescence assay. Further, demonstrated that this nanoconstruct was taken up by cancer cells in vitro and by tumors in vivo. The uptake of YSM particles by Panc02 murine pancreatic cancer cells was tested by inductively coupled plasma – mass spectrometry. This demonstrated robust uptake in cells after 24hr incubation. No noticeable cell death occurred with doses of 0 Gy and 4 Gy, cell viability decreased significantly after a dose of 8 Gy irradiation in cells cultured with YSM when compared to controls. Since 8 Gy is within the range of a clinically applicable dose used routinely in stereotactic radiotherapy regimens, these results verified the potential of YSM to be used as scintillator-photosensitizer complexes for x-ray activated photodynamic therapy. Finally the biodistribution of YSM nanoconstructs in vivo in C57BL6 mice harboring subcutaneous Panc02 tumors show YSM accumulation in tumors. A versatile, biocompatible Yttrium oxide scintillator-photosensitizer complex (YSM) that can generate x-ray induced cytotoxic reactive oxygen species is fabricated. This is capable of facilitating x-ray activated photodynamic therapy (XPDT (external beam) and/or iXPDT (internal x-ray source)). It shows promise in maximizing the efficacy of the combinatory treatment and enhanced improvement of the quality of life and overall survival of cancer patients. Citation Format: Rao V. Papineni, Sunil Krishnan, Ajayan Pulickel, Onur Sahin. Development of radiation-triggered phosphor platform for localized activation in combinatory cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3057.