A Multimodal Hierarchical Theranostic Nanoparticle for Castration Resistant Prostate Cancer

用于去势抵抗性前列腺癌的多模式分级治疗诊断纳米颗粒

• 批准号: 10513295
• 负责人: STANLEY A SCHWARTZ
• 金额: --
• 依托单位: VA WESTERN NEW YORK HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513295
• 关键词: ABCB1 gene; Acids; Affinity; Age; Aging; American; Animal Model; Apoptosis; Azides; Binding; Biodistribution; Bypass; Cancer Etiology; Caring; Cell Culture System; Cell Survival; Cessation of life; Charge; Chemistry; Clinical Data; Copper; Cost Measures; Data; Development; Diagnosis; Dimensions; Disease; Disease Progression; Dose; Dose Limiting; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Economic Burden; Electrostatics; Encapsulated; Engineering; Exposure to; FDA approved; FOLH1 gene; Gene Silencing; General Population; Goals; Healthcare Systems; Herbicides; Histone Deacetylase Inhibitor; Human; Hydrophobicity; IL8 gene; In Vitro; Incidence; Knock-out; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Microtubules; Multi-Drug Resistance; Nature; North America; Operative Surgical Procedures; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmaceutical Solutions; Pharmacodynamics; Pharmacotherapy; Physiological; Polysaccharides; Pre-Clinical Model; Primary Neoplasm; Prognosis; Proliferating; Prostate Cancer therapy; Prostatic Neoplasms; Public Health; Radiation; Reaction; Refractory; Research; Risk; Role; Site; Small Interfering RNA; Specificity; Surface; Survival Rate; System; Therapeutic; Therapeutic Index; Time; Toxic effect; Treatment outcome; Tumor Markers; Tumor Volume; Tumor Weights; Veterans; Veterans Health Administration; Work; Xenograft procedure; advanced prostate cancer; agent orange; androgen deprivation therapy; biomaterial compatibility; cancer cell; castration resistant prostate cancer; chemical synthesis; chemotherapeutic agent; chemotherapy; copolymer; cytotoxicity; docetaxel; effective therapy; gene therapy; human model; imaging agent; improved; in vivo; innovation; liver metabolism; male; men; military veteran; molecular recognition; multimodality; nano; nanocarrier; nanoparticle; novel; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer risk; response; side effect; small molecule; specific biomarkers; targeted delivery; targeted treatment; theranostics; therapeutic gene; therapeutically effective; tumor; tumor growth; vector

Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer in American males and is the second leading cause of cancer-related deaths of men in North America after lung cancer (1). In 2019, approximately 174,650 men were diagnosed with CaP and nearly 31,620 men will die from the disease. While the overall cancer incidence among men in the U.S. Veterans Affairs Health Care System mirrored the general population, it is important to understand that the U.S has an aging veteran population, and the risk of developing CaP increases with age. Furthermore, veterans who were exposed to herbicides, such as Agent Orange, are at increased risk of CaP. The first line of therapy for CaP is surgery or radiation, and the survival rate for patients diagnosed with early stage CaP is excellent (~95%). However, the prognosis for men diagnosed with advanced CaP is poor' with a five-year survival less than 30%. The major therapy for advanced CaP is androgen deprivation therapy (ADT). When the disease progresses after ADT, a stage referred to as castration resistant prostate cancer (CRPC) ensues. Efforts to develop new drugs for the treatment of CRPC have been hampered either by rapid hepatic metabolism of histone deacetylase inhibitors (HDACi) or dose limiting cytotoxicity (docetaxel and doxorubicin). To overcome this, innovative pharmaceutical solutions are needed to effectively deliver the drugs specifically to the tumor site while minimizing systemic administration of frequent and high doses of toxic chemotherapy. The enhanced, targeted, intracellular co-delivery of drug and gene therapy with novel nanocarriers composed of biocompatible and biodegradable poly(lactic-co-glycolic) acid (PLGA) is a goal of this proposal. PLGA is safe and highly effective in the targeted delivery of hydrophobic drugs such as docetaxel (Doc) to specific tumors, demonstrating enhanced therapeutic activity at lower doses than when administered alone. Active targeting, as opposed to passive targeting adds value to tumor specific-treatment. This targeting strategy is based on the molecular recognition of tumor biomarkers which are over-expressed on cancer cells, via specific vector molecules conjugated to the surface of the drug carrier. These vector molecules dictate the carrier's biodistribution and its affinity for the desired site of action. Our long-term goal is the development of a targeted hierarchical nanoparticle (HNP for the co-delivery of chemo- and gene therapies for CaP, which can overcome the limitation in systemic delivery of currently available drugs. As proof-of-principle, we will use Doc, a promoter and stabilizer of microtubule assembly, that shows excellent efficacy in vitro but which is rapidly metabolized in the liver plus a gene-silencing agent together in our HNP. Our rationale that Doc can be targeted specifically to prostate tumors in pre-clinical animal models will provide the impetus to encapsulate other therapeutics (such as cabazitaxel and paclitaxel) that have dose-limiting toxicities to improve response to drug therapies while reducing toxic side effects. Our specific aims are: Aim 1: To optimize the synthesis of a PSMA- targeted PTCS-HNP for delivery of IL-8 siRNA and Doc to CaP cells and assess the IC50 of different PTCS- HNPs; Aim 2: Determine the pharmacokinetics (PK) and pharmacodynamics (PD) of PTCS-HNP in CaP cell lines; Aim 3: To assess the effects of PTCS-HNPs on primary tumor growth and metastatic dissemination of CaP cells grown as xenografts in an orthotopic, preclinical model of human CaP. Upon conclusion of this project, we will produce a highly effective, targeted drug and gene therapy NP delivery system for the treatment of advanced CaP. The proposed research is innovative because of the exclusive chemical synthesis of our unique, multifunctional HNP, the two-hit nature of the chemo- and gene therapy and its targeted specificity for CaP. The tunable nature of our HNP will allow its application for the delivery of a host of different therapies to a wide range of tumors. Lastly, the incorporation of imaging agents into our HNP will yield a truly theranostic approach for the treatment of different cancers especially advanced CaP.

前列腺癌 (CaP) 是美国男性中最常诊断出的非皮肤癌 是北美男性癌症相关死亡的第二大原因，仅次于肺癌 (1)。 2019年， 大约 174,650 名男性被诊断患有 Cap，近 31,620 名男性将死于该疾病。尽管 美国退伍军人事务医疗保健系统中男性的总体癌症发病率反映了总体情况 人口，重要的是要了解美国退伍军人人口老龄化，以及发展的风险 CaP 随着年龄的增长而增加。此外，接触过橙剂等除草剂的退伍军人 CaP 风险增加。 CaP 的一线治疗是手术或放疗，患者的生存率 诊断为早期 CaP 效果非常好 (~95%)。然而，诊断为晚期男性的预后 CaP 很差，五年生存率低于 30%。晚期 CaP 的主要治疗方法是雄激素剥夺 治疗（ADT）。当 ADT 后疾病进展时，这个阶段被称为去势抵抗性前列腺 癌症（CRPC）随之而来。开发治疗 CRPC 的新药的努力受到以下因素的阻碍： 组蛋白脱乙酰酶抑制剂 (HDACi) 的快速肝代谢或剂量限制性细胞毒性（多西紫杉醇和 阿霉素）。为了克服这个问题，需要创新的药物解决方案来有效地输送药物 专门针对肿瘤部位，同时最大限度地减少频繁和高剂量有毒物质的全身给药 化疗。药物和基因治疗的增强、靶向、细胞内共同递送 由生物相容性和可生物降解的聚乳酸-乙醇酸（PLGA）组成的纳米载体是该项目的目标 提议。 PLGA 在多西紫杉醇等疏水性药物的靶向递送中安全且高效 （文档）针对特定肿瘤，显示出比给药剂量更低的治疗活性增强 独自的。与被动靶向相反，主动靶向增加了肿瘤特异性治疗的价值。这种定位 该策略基于对癌细胞上过度表达的肿瘤生物标志物的分子识别， 通过与药物载体表面缀合的特定载体分子。这些载体分子决定了 载体的生物分布及其对所需作用位点的亲和力。我们的长期目标是发展 靶向分层纳米颗粒（HNP，用于共同递送 CaP 化疗和基因疗法，可以 克服目前可用药物全身输送的限制。作为原理证明，我们将使用 Doc， 微管组装的促进剂和稳定剂，在体外表现出优异的功效，但快速 在肝脏中代谢，加上我们的 HNP 中的基因沉默剂。我们认为 Doc 可以成为目标的理由 特别是针对临床前动物模型中的前列腺肿瘤，将为封装其他药物提供动力 具有剂量限制性毒性以改善药物反应的治疗药物（例如卡巴他赛和紫杉醇） 治疗的同时减少毒副作用。我们的具体目标是： 目标 1：优化 PSMA-的合成 靶向 PTCS-HNP 将 IL-8 siRNA 和 Doc 递送至 CaP 细胞，并评估不同 PTCS-的 IC50 HNP；目标 2：确定 PTCS-HNP 在 CaP 细胞中的药代动力学 (PK) 和药效学 (PD) 线路；目标 3：评估 PTCS-HNP 对原发性肿瘤生长和转移性扩散的影响 CaP 细胞在人类 CaP 的原位临床前模型中作为异种移植物生长。该项目结束后， 我们将生产高效、靶向药物和基因治疗 NP 递送系统，用于治疗 高级帽。拟议的研究具有创新性，因为我们独特的化学合成， 多功能 HNP、化疗和基因治疗的两次打击性质及其对 CaP 的靶向特异性。这 我们的 HNP 的可调性质将使其能够应用于向广泛的范围提供多种不同的疗法 肿瘤。最后，将显像剂纳入我们的 HNP 将为患者提供真正的治疗诊断方法。 治疗不同的癌症，特别是晚期 CaP。