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: 10259187
• 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/10259187
• 关键词: ABCB1 gene; Affinity; Age; Aging; American; Animal Model; Apoptosis; Azides; Binding; Biodistribution; Bypass; Cancer Etiology; Caring; Cations; Cell Culture System; Cell Line; Cell Survival; Cells; Cessation of life; Charge; Chemistry; Clinical Data; Copper; Cost Measures; Data; Development; Diagnosis; Dimensions; Disease; 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; Glycolates; 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; Modeling; Multi-Drug Resistance; Nature; North America; Operative Surgical Procedures; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmaceutical Solutions; Pharmacodynamics; Pharmacology; Pharmacotherapy; Physiological; Polysaccharides; Pre-Clinical Model; Primary Neoplasm; Prognosis; 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; agent orange; androgen deprivation therapy; base; 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; nanocarrier; nanoparticle; novel; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; pre-clinical; promoter; response; side effect; small molecule; specific biomarkers; targeted delivery; targeted treatment; theranostics; 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）是美国男性和 是北美男性与肺癌相关的癌症相关死亡的第二大原因（1）。在2019年， 大约有174,650名男性被诊断出患有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的总体癌症发生率反映了一般 人口，重要的是要了解美国的老年人口老龄化，并且有发展的风险 上限随着年龄的增长而增加。此外，暴露于除草剂的退伍军人，例如特工橙色 增加帽的风险增加。 CAP的第一道治疗是手术或辐射，患者的存活率 被诊断为早期帽的诊断非常好（〜95％）。但是，被诊断出患有晚期的男性的预后 帽子很差，五年生存率不到30％。晚期帽的主要疗法是雄激素剥夺 治疗（ADT）。当该疾病在ADT之后进展时，一个阶段称为耐cuattration Prostate 随之而来的癌症（CRPC）。开发新药治疗CRPC的努力已受到 组蛋白脱乙酰基酶抑制剂（HDACI）或剂量限制细胞毒性的快速肝代谢（多西他赛和剂量 阿霉素）。为了克服这一点，需要创新的药物解决方案来有效地提供药物 专门针对肿瘤部位，同时最大程度地减少了频繁和高剂量有毒的全身施用 化学疗法。新型药物和基因疗法的增强，有针对性的，细胞内的分娩 由生物相容性和可生物降解的聚（乳酸 - 乙醇）酸（PLGA）组成的纳米载体是一个目标 提议。 PLGA在疏水药物（例如多西他赛）的目标递送方面是安全且高效的 （DOC）到特定的肿瘤，表明在较低剂量下的治疗活性增强了 独自的。与被动靶向相反的主动靶向为肿瘤特异性处理增加了价值。这个目标 策略基于对癌细胞过表达的肿瘤生物标志物的分子识别， 通过特定的载体分子结合到药物载体表面。这些矢量分子决定了 运营商的生物分布及其对所需行动地点的亲和力。我们的长期目标是发展 靶向分层纳米颗粒（用于CAP化学和基因疗法的HNP，可以 克服当前可用药物的全身输送的限制。作为原理证明，我们将使用Doc， 微管组件的启动子和稳定剂，在体外表现出极好的功效，但迅速 在我们的HNP中将肝脏和基因沉默剂一起代谢。我们可以将文档定为目标的理由 专门针对临床前动物模型中的前列腺肿瘤将提供封装其他的动力 具有限制毒性的治疗剂（例如cabazitaxel和paclitaxel）可以改善对药物的反应 疗法，同时减少有毒副作用。我们的具体目的是：目标1：优化PSMA-的合成 靶向PTCS-HNP用于递送IL-8 siRNA和DOC以盖帽细胞，并评估不同PTCS-的IC50 hnps; AIM 2：确定CAP细胞中PTCS-HNP的药代动力学（PK）和药效学（PD） 线；目标3：评估PTCS-HNP对原发性肿瘤生长和转移性传播的影响 盖细胞以异种移植的形式移植物在人体帽的原位临床前模型中生长。在这个项目结束后， 我们将生成一个高效，有针对性的药物和基因治疗NP递送系统，以治疗 高级盖。拟议的研究具有创新性，因为我们独特的化学合成我们独特的， 多功能HNP，化学和基因疗法的两次打击性质及其针对CAP的靶向特异性。这 我们的HNP的可调性将允许其应用于将多种不同疗法传递到广泛的范围内 肿瘤。最后，将成像剂纳入我们的HNP将产生真正的疗法方法 对不同癌症的处理，特别是晚期帽。