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）是美国男性中最常诊断的非皮肤癌， 是北美男性癌症相关死亡的第二大原因，仅次于肺癌（1）。在2019年， 大约174，650名男性被诊断患有CaP，并且将近31，620名男性将死于该疾病。而 美国退伍军人事务部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，重要的是要明白，美国有一个老龄化的退伍军人人口，发展的风险， CaP随着年龄的增长而增加。此外，暴露于除草剂（如橙子剂）的退伍军人在 CaP的风险增加。CaP的一线治疗是手术或放疗， 诊断为早期CaP的患者非常好（约95%）。然而，诊断为晚期乳腺癌的男性的预后 CaP很差，五年生存率不到30%。晚期前列腺癌的主要治疗方法是雄激素剥夺 治疗（ADT）当ADT后疾病进展时，称为去势抵抗性前列腺增生的阶段 癌症（CRPC）增强。开发用于治疗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（多西他赛和 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 同时最大限度地减少频繁和高剂量的毒性药物的全身给药 化疗本发明提供了一种新的靶向细胞内药物和基因治疗的增强的靶向细胞内共递送， 由生物相容性和可生物降解的聚（乳酸-共-乙醇酸）（PLGA）组成的纳米载体是本发明的目标 提议PLGA在多西他赛等疏水性药物的靶向给药中安全、高效 (Doc)对特定的肿瘤，证明在较低剂量下比给药时增强的治疗活性 一个人与被动靶向相反，主动靶向增加了肿瘤特异性治疗的价值。该靶向 该策略基于对癌细胞上过表达的肿瘤生物标志物的分子识别， 通过与药物载体表面偶联的特异性载体分子。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一个 靶向分级纳米颗粒（HNP），用于共同递送针对CaP的化疗和基因疗法，其可以 克服了目前可用药物的全身递送的局限性。作为原理证明，我们将使用Doc， 一种微管组装的促进剂和稳定剂，其在体外显示出优异的功效，但其快速 在我们的HNP中，肝脏中代谢的药物加上基因沉默剂。我们的理由是多克可以成为 在临床前动物模型中特异性地应用于前列腺肿瘤将为包封其他肿瘤提供动力。 具有剂量限制性毒性的治疗剂（如卡巴他赛和紫杉醇），以改善对药物的反应 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用于递送IL-8 siRNA和Doc至CaP细胞，并评估不同PTCS-HNP的IC 50。 目的2：确定PTCS-HNP在CaP细胞中的药代动力学（PK）和药效学（PD） 目的3：评估PTCS-HNP对原发性肿瘤生长和转移性播散的影响。 在人CaP的原位临床前模型中作为异种移植物生长的CaP细胞。在这个项目结束后， 我们将生产一种高效的，靶向药物和基因治疗NP输送系统，用于治疗 先进的CaP拟议的研究是创新的，因为我们独特的独家化学合成， 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。的 我们的HNP的可调性质将允许其应用于广泛的不同疗法的主机交付 肿瘤。最后，将显像剂纳入我们的HNP将产生一个真正的治疗诊断方法， 治疗不同的癌症，特别是晚期癌症。