DOUBLE-TARGETED MACROMOLECULAR THERAPEUTICS FOR THE TREATMENT OF PROSTATE CANCER

治疗前列腺癌的双靶点大分子疗法

• 批准号: 7759540
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759540
• 关键词: Acids; Address; Alanine; American; American Cancer Society; Androgens; Antibodies; Antigen Targeting; Antineoplastic Agents; Apoptosis; Apoptosis Promoter; Binding; Blood Circulation; Cancer Etiology; Caspase; Cell Survival; Cessation of life; Clinical Data; Cytochromes; DNA Fragmentation; Drug Delivery Systems; Drug Formulations; Evaluation; Glutamate Carboxypeptidase II; Human; In Vitro; Individual; Induction of Apoptosis; J591 Monoclonal Antibody; Lead; Libraries; Liquid substance; Malignant neoplasm of prostate; Mediating; Methods; Mitochondria; Modality; Molecular Biology; Molecular Conformation; Molecular Weight; Monoclonal Antibodies; Non-Essential Amino Acid; Nuclear Orphan Receptor; Peptides; Permeability; Pharmaceutical Preparations; Phase; Pinocytosis; Polymers; Problem Solving; Public Health; Randomized; Regimen; Scanning; Science; Site; Specificity; Structure; Therapeutic; Therapeutic Agents; Therapeutic Index; Therapeutic Uses; Tissues; Toxic effect; Vertebral column; Water; androgen independent prostate cancer; animal data; antigen binding; base; cancer cell; cancer diagnosis; cancer therapy; chemotherapy; cinnamic acid; combinatorial; combinatorial chemistry; copolymer; design; docetaxel; efficacy evaluation; immunogenicity; improved; in vivo; indexing; innovation; interdisciplinary approach; macromolecule; men; methacrylamide; mouse model; nanosized; novel; novel therapeutics; protein expression; receptor; receptor mediated endocytosis; synergism; tumor; uptake

DESCRIPTION (provided by applicant): Prostate cancer is the most common lethal cancer diagnosed and second leading cause of cancer death in American men. In 2007, the American Cancer Society estimates that in the USA there will be about 218,000 new cases and about 27,000 men will die of prostate cancer. The purpose of this project is to draw on the advances made in molecular biology, polymer science, and chemotherapy to develop a novel therapeutic modality, which will be potentially more effective than existing therapeutic agents in the treatment of prostate cancer. Clinical data indicate that the therapeutic use of nanosized (5-20 nm) water-soluble polymer-drug conjugates appears to be a novel and successful strategy for cancer treatment. The advantages of polymer- bound drugs (in contrast to low-molecular weight drugs) are: a) active uptake by fluid-phase pinocytosis (non- targeted polymer-bound drug) or receptor-mediated endocytosis (targeted polymer-bound drug), b) increased active accumulation of the drug at the tumor site by targeting, c) increased passive accumulation of the drug at the tumor site due to the enhanced permeability and retention effect, d) long-lasting circulation in the bloodstream, e) decreased non-specific toxicity of the conjugated drug, f) decreased immunogenicity of the targeting moiety, f) immunoprotecting and immunomobilizing activities, and g) potential for the design of double-targeted conjugates. The main aim of the proposed studies is to design new water-soluble polymer anticancer drug conjugates that are more effective than existing therapeutic regimens in the treatment of androgen-independent prostate cancer. We propose to design and synthesize novel double-targeted macromolecular therapeutics containing a water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone, a targeting moiety (monoclonal antibody or targeting peptide, selected by combinatorial approaches) against prostate-specific membrane antigen (PSMA), and a mitochondrial apoptosis inducer, ((E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]- 3-chlorocinnamic acid (3Cl-AHPC)) as a therapeutic drug. We hypothesize that this conjugate will demonstrate a dramatically improved therapeutic index in androgen-independent prostate cancer (AIPC). The superior efficacy of targeted HPMA copolymer 3Cl-AHPC conjugates is based on their double-targeting capacity, i.e. targeting to prostate cancer cells mediated by the targeting moiety and the inherent mitochondriotropism of the apoptosis inducer (3Cl-AHPC), as mediated by Nur77, an orphan nuclear receptor. In addition, the combination of a targeted HPMA copolymer-bound apoptosis inducer (3Cl-AHPC) with targeted HPMA copolymer-bound docetaxel (the first-line therapeutic agent for metastatic AIPC) is an innovative therapeutic paradigm with the potential to provide tumor cures that cannot be reached by other therapeutic approaches. Criteria will be established for the design of a new, targeted drug delivery system for the treatment of androgen-independent prostate cancer in humans based on the in vitro and in vivo animal data. PUBLIC HEALTH REVELANCE The proposal addresses one of the main problems in prostate cancer treatment the lack of specificity of low molecular weight anticancer drugs. The concept of double-targeted macromolecular therapeutics provides a new paradigm for the design of efficient anticancer drug delivery systems for the treatment of prostate cancer. The active agent will be directed not only to the cancer cell, but into a specific subcellular compartment as well.

描述（由申请人提供）：前列腺癌是美国男性中最常见的致死性癌症，也是癌症死亡的第二大原因。2007年，美国癌症协会估计，在美国将有大约218，000个新病例，大约27，000名男性将死于前列腺癌。该项目的目的是利用分子生物学，聚合物科学和化学疗法的进展来开发一种新的治疗方式，这将可能比现有的治疗药物更有效地治疗前列腺癌。临床数据表明，纳米（5-20 nm）水溶性聚合物-药物缀合物的治疗用途似乎是一种新的和成功的癌症治疗策略。聚合物结合药物的优点（与低分子量药物相比）：a）通过液相胞饮作用的主动摄取（非靶向聚合物结合药物）或受体介导的内吞作用（靶向聚合物结合的药物），B）通过靶向增加药物在肿瘤部位的主动积累，c）由于增强的渗透性和滞留效应增加药物在肿瘤部位的被动积累，d）在血流中的持久循环，e）降低缀合药物的非特异性毒性，f）降低靶向部分的免疫原性，f）免疫保护和免疫动员活性，和g）设计双靶向缀合物的潜力。本研究的主要目的是设计新的水溶性聚合物 在雄激素非依赖性前列腺癌的治疗中比现有治疗方案更有效的抗癌药物缀合物。我们建议设计和合成新型的双靶向大分子治疗剂，（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物骨架，靶向部分（单克隆抗体或靶向肽，通过组合方法选择），和线粒体凋亡诱导剂，（（E）-4-[3-（1-金刚烷基）-4-羟基苯基]-3-氯肉桂酸（3Cl-AHPC））作为治疗药物。我们假设这种偶联物将在雄激素非依赖性前列腺癌（AIPC）中显示出显著改善的治疗指数。靶向HPMA共聚物的上级功效 3Cl-AHPC偶联物基于其双重靶向能力，即靶向由靶向部分介导的前列腺癌细胞和凋亡诱导剂（3Cl-AHPC）的固有亲异性，如由孤儿核受体Nur 77介导的。此外，靶向HPMA共聚物结合的细胞凋亡诱导剂（3Cl-AHPC）与靶向HPMA共聚物结合的多西他赛（转移性AIPC的一线治疗药物）的组合是一种创新的治疗范例，有可能提供其他治疗方法无法达到的肿瘤治愈。基于体外和体内动物数据，将建立用于治疗人类雄激素非依赖性前列腺癌的新型靶向药物递送系统的设计标准。公共卫生报告该提案解决了前列腺癌治疗中的一个主要问题 低分子量抗癌药物缺乏特异性。双靶向大分子治疗的概念为设计有效的前列腺癌治疗药物递送系统提供了新的范例。活性剂将不仅被引导至癌细胞，而且也被引导至特定的亚细胞区室。