Mackeyev, Yuri

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 Radiation therapy (RT) is frequently used in the neoadjuvant setting in borderline resectable and some resectable pancreatic ductal adenocarcinoma (PDAC) and in the definitive setting in locally advanced PDACs which is third leading cause of cancer associated death. Higher doses of RT improve overall treatment outcomes but increasing the dose significantly above 50Gy in standard 2Gy fractions risks profound gastrointestinal (GI) toxicity. Additionally, genotoxic stress such as RT, can induce CXCL12 secretion by cancer associated fibroblast (CAFs) and overexpression of CXC motif chemokine receptor 4 (CXCR4) in cancer cells. CXCL12-CXCR4 downstream signaling results in immune suppression and consequent enhanced tumor growth and metastasis and poor prognosis in PDAC. To overcome these clinical challenges, we have developed multimodal gold nanoparticle constructs (GNPs) by functionalizing the CXCR4 antagonists to (i) bind to CXCR4 and mediate GNP internalization, (ii) abolish the feedback immune inhibitory signals mediated by CXCR4 overexpression, and (iii) enhance therapeutic benefit of radiation. To achieve these multimodal activities, we have covalently attached the CXCR4 antagonist, AMD070, to thiol-terminated polyethylene glycol (PEG) to synthesize AMD-PEG which was then conjugated with GNPs to produce AMD-PEG-GNP. In our experiment AMD-PEG-GNP has successfully inhibited CXCL12-CXCR4 downstream signalling such as reduction of ERK phosphorylation in PDAC cells. To analyze the radiosensitization role of GNP nanoconjugates, PDAC cells were incubated with AMD-PEG, PEG-GNP and AMD-PEG-GNPs for 4 hours and then treated with increasing doses of radiated, from 1-4Gy. AMD-PEG-GNP demonstrated a systematic enhancement on reactive oxygen species (ROS) production and downregulation of a colony formation. Collectively, the results from in vitro study with PDAC cells confirm that the nanoconjugate with AMD070 enhances radio-cytotoxicity and impair CXCL12-CXCR4 downstream signaling. Hence AMD-PEG-GNP has strong merit to enhance radiation dose locally and simultaneously restrict RT induced immunosuppression in PDAC. Citation Format: Tanmay Kulkarni, Shamit Dutta, Hazel Parent, Karington Perry, Yuri Mackeyev, Santanu Bhattacharya. Immune modulatory activity of radio-sensitizing gold nanoparticle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3181.

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l -glutamic acid and l -lysine within an amphiphilic polymer of poly( l -glutamic acid-co- l -lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.

CXC chemokine receptor 4 (CXCR4) is overexpressed on most breast cancer cell surfaces including triple negative breast cancer (TNBC) which lacks traditional receptor overexpression.