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

基本信息

批准号：
9982236
负责人：
WADIH ARAP
金额：
$ 64.28万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
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/9982236
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

项目摘要

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.

抽象的被诊断为前列腺癌的患者中有8％的患者发展为致命转移性疾病。发展对雄激素剥夺疗法的抗性，最终对最后一线化学治疗疗法（例如恩扎拉胺（ENZ），导致致命的转移性前列腺癌。虽然很有趣，可以识别特异性肿瘤分子特征称为精密医学，正在受到人们的青睐，需要识别生理上可访问的目标。通过将分子肿瘤靶标的功能转移到常规抗癌症药物，肿瘤生长速率预计将降低；但是，这没有考虑到获得的耐药性机制取决于全身药物稳定性，可溶性或毒性。稳定固体和/或剧毒剧毒药物以及潜在克服抗药性的一种方法是将药物封装在纳米颗粒（NP）中，以防止其降解并加强其循环时间。此外，可以通过添加肿瘤特异性靶向来改善肿瘤部位的负载NP的积累影响NP内吞作用的部分，从而改善了治疗指数，同时最大程度地减少了抵押品前列腺肿瘤特异性生物标志物，78 kDa葡萄糖调节蛋白（GRP78），由Pasqualini和ARAP团队鉴定，通过筛查前列腺癌患者血清的抗体。 GRP78是疾病进展的生物标志物，对于我们提出的研究至关重要，我们最近确定人体重组抗GRP78抗体具有最佳的体内肿瘤靶向。在这一建议中，我们的目标是针对耐ENZ的前列腺癌产生以GRP78为目标的NP。我们将采用小说模块化 Brinker团队开发的“ Protocell”平台。协议由多孔二氧化硅芯组成，可以是经过安装多种多样和组合的cargos，封装在受支持的脂质双层中保护和保留货物，并提供一个生物相容性的表面，用于靶向和/或贩运配体。边界团队表现出针对性的第一代协议的出色稳定性在体内具有特异性结合和货物递送到单个循环白血病细胞的体内。而不是交付在蛋白质水平上起作用的化学治疗药物，我们建议提供小的干扰RNA（siRNA）针对长的非编码RNA PCA3。我们表明，干扰PCA3会抑制人类前列腺饰面。在Cristini团队进行的预测建模的指导下，我们的模块化将grp78靶向的协议设计为包装PCA3 SiRNA，以选择性地绑定到GRP78表达前列腺癌细胞，细胞内递送PCA3 siRNA以抑制肿瘤生长。我们的项目是第一个实地研究激发了我们当前的联合专业知识和技术。双重前列腺肿瘤“中心” 这些下一代NP原型平台的特征提高了它们的特异性和效率，并克服了常规护理药物的局限性，特别是在获得耐药性的情况下。