A Targeted Nanomedicine Prototype Against Enzalutamide-resistant Prostate Cancer

针对恩杂鲁胺耐药性前列腺癌的靶向纳米药物原型

• 批准号: 10202502
• 负责人: WADIH ARAP
• 金额: $ 64.24万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202502
• 关键词: 3-Dimensional; Affect; Antibodies; Antineoplastic Agents; Area; Binding; Biodistribution; Biological Markers; Blood Circulation; Cancer Patient; Cells; Chelating Agents; Chemistry; Clinical Trials; Complex; Confocal Microscopy; Data Analyses; Development; Diagnosis; Diffusion; Disease; Disease Progression; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Drug Stability; Drug resistance; Encapsulated; Endocytosis; Engineering; Environment; Equation; Fluorescent Dyes; Formulation; Generations; Growth; Histology; Human; Hybrids; Image; Immunohistochemistry; In Vitro; Individual; LNCaP; Label; Ligands; Lipid Bilayers; Liposomes; Malignant neoplasm of prostate; Mammary Neoplasms; Mathematics; Metastatic Prostate Cancer; Methods; Modeling; Modification; Molecular; Molecular Profiling; Nucleic Acids; Paper; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Polyethylene Glycols; Property; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Publishing; Radio; Reaction; Recombinants; Research; Resistance; Resistance development; Resolution; Safety; Shapes; Silicon Dioxide; Site; Small Interfering RNA; Solid Neoplasm; Solubility; Specificity; Structure; Structure-Activity Relationship; Surface; Technology; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Translations; Transmission Electron Microscopy; Treatment Efficacy; Treatment Protocols; Treatment outcome; Treatment-related toxicity; Tumor Markers; Tumor Suppressor Proteins; Untranslated RNA; Validation; Variant; Work; Xenograft procedure; acquired drug resistance; androgen deprivation therapy; base; biomaterial compatibility; cancer therapy; circulating leukemia cell; clinical application; cytotoxic; design; field study; glucose-regulated proteins; improved; in vivo; insight; interest; lead candidate; light scattering; mathematical model; multi-scale modeling; nano; nanocarrier; nanomedicine; nanoparticle; nanoparticle delivery; nanoparticle drug; nanotechnology platform; neoplastic cell; next generation; novel; overexpression; particle; precision medicine; predictive modeling; prevent; prostate cancer cell; prototype; real-time images; resistance mechanism; screening; single photon emission computed tomography; standard of care; targeted delivery; targeted treatment; therapeutic nanoparticles; therapy outcome; trafficking; tumor; tumor growth; tumor xenograft

ABSTRACT Eight percent of patients diagnosed with prostate cancer progress to lethal metastatic disease. Development of resistance to androgen-deprivation therapy and eventually, to last line chemotherapeutics such as enzalutamide (ENZ), contribute to lethal, metastatic prostate cancer. While interest to identify tumor-specific molecular signatures, termed precision medicine, is gaining popular favor, it requires identification of physiologically accessible targets. By diverting the function of a molecular tumor target by conventional anti- cancer drugs, rates of tumor growth are expected to decrease; however, this does not take into account acquired drug resistance mechanisms which are dependent on systemic drug stability, solubility or toxicity. One method to stabilize poorly soluble and/or highly toxic drugs, and potentially overcome resistance, is to encapsulate drugs in nanoparticles (NPs) to prevent their degradation and enhance their circulation time. Moreover, accumulation of loaded NPs at the tumor site can be improved by adding tumor-specific targeting moieties that induce NP endocytosis, thereby improving the therapeutic index while minimizing collateral damage to healthy cells. A prostate tumor-specific biomarker, the 78 kDa glucose-regulated protein (GRP78), was identified by the Pasqualini and Arap team by screening antibodies from prostate cancer patient sera. GRP78 is a biomarker of disease progression and, crucial to our proposed research, we recently identified human recombinant anti-GRP78 antibodies with optimal in vivo tumor targeting. In this proposal, our objective is to generate GRP78-targeted NPs against ENZ-resistant prostate cancer. We will employ the novel, modular “protocell” platform developed by the Brinker team. Protocells consist of a porous silica core, which can be engineered to accommodate varied and combination cargos, encapsulated within a supported lipid bilayer that protects and retains the cargo, and provides a biocompatible surface for conjugation to targeting and/or trafficking ligands. The Brinker team demonstrated exceptional stability of targeted, first-generation protocells in vivo with specific binding and cargo delivery to individual circulating leukemia cells. Instead of delivering chemotherapeutic drugs that work at the protein level, we propose to deliver small interfering RNAs (siRNAs) directed against the long non-coding RNA, PCA3. We showed that interfering with PCA3 inhibits growth of human prostate xenografts. Guided by predictive modeling conducted by the Cristini team, our modular GRP78-targeted protocells will be designed to package PCA3 siRNAs to selectively bind to GRP78-expressing prostate cancer cells, and deliver PCA3 siRNAs intracellularly to inhibit tumor growth. Our project is a first-in- field study that galvanizes our current combined expertise and technology. The dual prostate tumor “centric” feature of these next generation NP prototype platforms increases their specificity and efficacy, and overcomes the limitation of conventional standard-of-care drugs, particularly in the case of acquired drug resistance.

摘要 8%被诊断为前列腺癌的患者进展为致命的转移性疾病。发展中的 对雄激素剥夺疗法的抵抗，最终对最后一线化疗药物的抵抗，如 苯扎鲁胺(ENZ)会导致致命的转移性前列腺癌。虽然有兴趣识别肿瘤特异性 分子签名，被称为精确医学，正在受到人们的青睐，它需要识别 生理上可以达到的目标。通过常规的抗肿瘤药物转移分子肿瘤靶点的功能 抗癌药物方面，肿瘤的生长速度预计会下降；然而，这还没有考虑到 获得性耐药机制取决于全身药物的稳定性、溶解性或毒性。 稳定难溶和/或剧毒药物并有可能克服耐药性的一种方法是 将药物包裹在纳米颗粒(NPs)中，以防止其降解并延长其循环时间。 此外，通过增加肿瘤特异性靶向可以改善加载在肿瘤部位的NPs的堆积 诱导NP内吞的部分，从而提高治疗指数，同时最大限度地减少侧支 对健康细胞的损害。前列腺癌特异性生物标志物78 kDa葡萄糖调节蛋白(GRP78)， 是由Pasquini和Arap团队通过筛选前列腺癌患者血清中的抗体而鉴定出来的。 GRP78是疾病进展的生物标记物，对我们拟议的研究至关重要，我们最近发现 具有最佳体内肿瘤靶向性的人重组抗GRP78抗体。在这项提案中，我们的目标是 是产生靶向GRP78的NPs来对抗ENZ耐药的前列腺癌。我们将采用新颖、模块化的 Brinker团队开发的“Protocell”平台。原细胞由一个多孔的二氧化硅核心组成，它可以 设计以容纳不同的和组合的货物，封装在支撑的脂质双层中， 保护和保留货物，并提供生物相容表面以结合靶向和/或 贩卖配体。Brinker团队展示了靶向的第一代原细胞的非凡稳定性 在体内通过与单个循环白血病细胞的特异性结合和货物输送。而不是交付 在蛋白质水平起作用的化疗药物，我们建议传递小干扰RNA(SiRNAs) 针对长的非编码RNA，PCA3。我们发现干扰PCA3可以抑制肿瘤细胞的生长 人前列腺异种移植。在Cristini团队进行的预测建模的指导下，我们的模块 靶向GRP78的原细胞将被设计成包装PCA3 siRNAs，以选择性地结合到GRP78表达 并在细胞内传递PCA3 siRNA以抑制肿瘤生长。我们的项目是第一个- 实地调查，激发了我们目前的专业知识和技术。双前列腺肿瘤的“中心性” 这些下一代NP原型平台的特点增加了它们的特异性和有效性，并克服了 常规护理标准药物的限制，特别是在获得性耐药的情况下。