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诊断出的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例新病例，约有27,000名男性将死于前列腺癌。该项目的目的是借鉴分子生物学，聚合物科学和化学疗法的进步，以开发一种新型的治疗方法，这将比现有的治疗剂在治疗前列腺癌中更有效。临床数据表明，使用纳米化（5-20​​ nm）水溶性聚合物 - 药物 - 药物结合物的治疗使用似乎是一种新颖而成功的癌症治疗策略。 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渗透性和保留效果，d）血液中的持久循环，e）降低了共轭药物的非特异性毒性，f）靶向部分的免疫原性降低，f）免疫保护和免疫机构的活性以及g）对双重靶向共轭物设计的潜力。拟议的研究的主要目的是设计新的水溶性聚合物抗癌药物缀合物，这些抗癌物比现有的治疗方案在治疗雄激素独立的前列腺癌方面更有效。我们建议设计和合成新型的双重靶向大分子治疗剂，其中含有水溶性N-（2-羟基丙基）甲基丙烯酰胺（HPMA）（HPMA）共聚物骨架，靶向部分（一种单克隆抗体或靶向肽），由组合型养蜂会和Prostrane-spececiac-speceiciic antific anticiac-speciciic offrostrane oftrane offrostrane oftrantairal offrostrane trosteciic andiciic trosteciica线粒体细胞凋亡诱导剂，（（E）-4- [3-（1-辅助）-4-羟基苯基] - 3-氯环毒素（3Cl-AHPC））作为治疗药物。我们假设这种结合物将在雄激素非依赖性前列腺癌（AIPC）中表现出极大改善的治疗指数。靶向HPMA共聚物3Cl-AHPC共轭物的卓越功效是基于其双重目标的能力，即靶向靶向部分介导的前列腺癌细胞和凋亡诱导剂（3CL-AHPC）的固有线粒体机体（3CL-AHPC）的靶向，如Nur77介导的Orphan Muitoror所介导的。此外，有针对性的HPMA共聚合物结合凋亡诱导剂（3Cl-AHPC）与靶向的HPMA共聚物结合的Docetaxel（转移性AIPC的第一线治疗剂）是一种具有创新的治疗范式，具有创新的治疗范式，该范式具有可为肿瘤提供的潜力，无法提供其他疗法，而这些范式无法与其他属于其他方法。将根据体外和体内动物数据设计一种新的，有针对性的药物递送系统的设计标准，用于治疗人类中雄激素独立的前列腺癌。公共卫生启示该提案解决了前列腺癌治疗中缺乏低分子量抗癌药物的特异性的主要问题之一。双重靶向大分子疗法的概念为设计有效的抗癌药物递送系统的设计提供了一种新的范式，用于治疗前列腺癌。活性剂不仅将针对癌细胞，还针对特定的亚细胞室。