Smart immunotherapeutic gold and palladium nanoparticles functionalized with immunomodulatory phytochemicals (mangiferin, resveratrol, piceatanol, naringin, silibilin, and astringin) and their use as radiosensitizers for tumor ablation therapy

Abstract

Global Cancer burden has risen to 18.1 million new cases, 1 in 6 deaths globally were attributed to Cancer and Cancer metastases which is the major cause of increased death accounting for 9.6 million deaths. [1], [2] Approximately 1,762,450 new Cancer cases were projected, predominantly including 174,650 cases of Prostate Cancer in 2019.[2] One in five men worldwide develop Cancer during their lifetime and 1 in 8 men die from the disease. Prostate Cancer is the most commonly diagnosed Cancers in men and one of the most aggressive Cancers to treat. African descendants which include African-Americans, Afro-Caribbeans, Afro-Brazilians, etc. men bear a disproportionately high Prostate Cancer burden with a mortality rate more than two times that of whites, while the incidence and mortality rates for Hispanics are about one third lower than those for non-Hispanic whites. While 80 to 90 % of Prostate Cancer cases initially respond well to treatment such as Androgen Deprivation Therapy (ADT) or surgical castration, the disease ultimately becomes resistant to all treatments currently available. Nearly all patients eventually develop progressive Castrate-Resistant Prostate Cancer (CRPC). Clinical evidence suggests enhanced levels of Tumor-Associated Macrophages (TAM) in CRPC patients, and a direct correlation between TAM levels and Cancer progression, as well as therapeutic resistance because of enhanced angiogenesis, matrix-remodelling, and immunosuppression. Infiltration of TAMs is also associated with reduced disease-free survival following radical prostatectomy. Transcription factor NF-kB is a key player in tumor progression with distinct roles in regulating the functions of macrophages and tumor cells in prostate tumors. We propose to develop novel immunotherapeutics to block macrophages (TAMs) in advanced prostate tumors as an effective means to abrogate the protumorigenic functions of TAMs and ultimately augment the therapeutic efficacy of androgen blockade therapy and other conventional therapies. We will use an innovative immunotherapeutic approach with tumor-cell-targeting phytochemical-functionalized smart gold, palladium and gold/palladium nanoparticles (PTC-AuNPs, PTC-PdNPs, and PTC-Au/PdNPs) that we develop. The PTC includes Mangiferin (MGF), Silibinin (INN), Naringin (NGN), Resveratrol (RES), Piceatannol (PTN) and Astringin (AGN). We reasoned that PTC-NPs (PTC-AuNPs, PTC-PdNPs, and PTC-Au/PdNPs), capable of targeting NF-ºB transcription factors, will trigger macrophage reprogramming in the tumor microenvironment. Insight into such interactions is crucial to elucidate the molecular basis of Prostate Cancer progression and to design novel macrophage-mediated immunotherapeutic strategies. Based on compelling preliminary in vitro and in vivo results from these smart immunotherapeutic nanoparticles, we hypothesize that their high selectivity, prostate-tumor-receptor specificity and TAM-targeting ability will induce pro-apoptotic cascade disassembly of tumor cells, resulting in a highly effective prostate tumor therapy. The specific aims to test this hypothesis are: (1) validate therapeutic capabilities of TAM targeting PTC-NPs in prostate tumor bearing dogs; (2) develop a panel of methylation biomarkers which predict tumor response and resistance for rapid and agile clinical decision-making; and (3) to evaluate the effectiveness of reprogramming of Tumor Associated Macrophages (TAMs) using PTC-NPs in prostate tumor cells from human patients and a canine model. The successful completion of this project will solve a major challenge in oncology and will bring us closer to clinical translation of multiplexed immunotherapeutic PTC-NPs for treating human Prostate Cancer patients while providing adjuvant therapeutic benefits through nanoparticle mediated selective tumor ablation therapy, thereby providing an additional armamentarium for therapy through X-ray or laser induced heat production around PTC-NPs present within tumor cells. (AU)