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: 8019008
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 30.29万
• 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/8019008
• 关键词: AHPN; Abbreviations; Acetates; Acids; Address; Alanine; American; American Cancer Society; Androgen Receptor; Androgens; Antibodies; Antigen Targeting; Antineoplastic Agents; Apoptosis; Apoptosis Promoter; BODIPY; Benzoates; Binding; Blood Circulation; Cancer Etiology; Caspase; Cell Survival; Cessation of life; Clathrin; Clinical Data; Cytochromes; DNA Fragmentation; Dicyclohexylcarbodiimide; Dimethyl Sulfoxide; Doxorubicin; Drug Delivery Systems; Drug Formulations; Endocytosis; Esters; Ethylene Glycols; Evaluation; Fluorescein; Fluorescein-5-isothiocyanate; Fluorescence Resonance Energy Transfer; Furans; Glucocorticoid Receptor; Glutamate Carboxypeptidase II; Glycolates; Green Fluorescent Proteins; Guanidinium Chloride; Health; Horseradish Peroxidase; Human; In Vitro; Individual; Induction of Apoptosis; Isothiocyanates; J591 Monoclonal Antibody; Lactic acid; Lead; Libraries; Liquid substance; MAPK8 gene; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mediating; Methods; Mitochondria; Modality; Molecular Biology; Molecular Conformation; Molecular Sieve Chromatography; Molecular Weight; Monoclonal Antibodies; Names; Non-Essential Amino Acid; Nuclear; Nuclear Orphan Receptor; Outer Mitochondrial Membrane; Paclitaxel; Peptide Synthesis; Peptides; Permeability; Pharmaceutical Preparations; Phase; Phosphate Buffer; Pinocytosis; Polymers; Problem Solving; Prostate-Specific Antigen; RXR; Randomized; Regimen; Retinoid X Receptor alpha; Saline; Scanning; Science; Site; Solid; Son of Sevenless Proteins; Specificity; Structure; Temperature; Testing; Tetradecanoylphorbol Acetate; Therapeutic; Therapeutic Agents; Therapeutic Index; Therapeutic Uses; Thin Layer Chromatography; Thiones; Thiophenes; Tissues; Toxic effect; Transferrin; Transferrin Receptor; Tryptophan; Tweens; Vertebral column; Water; analog; androgen independent prostate cancer; animal data; antigen binding; azobis(isobutyronitrile); base; cancer cell; cancer diagnosis; cancer therapy; chemotherapy; cinnamic acid; combinatorial; combinatorial chemistry; copolymer; design; dithiobis(succinimidylpropionate); docetaxel; efficacy evaluation; ethylene glycol; fast protein liquid chromatography; formamide; immunogenicity; improved; in vivo; indexing; innovation; interdisciplinary approach; macromolecule; major outer membrane protein; member; men; methacrylamide; mouse model; nanosized; novel; novel therapeutics; phenylisoserine; protein expression; pyrrolidin-3-yl-methanesulfonic acid; receptor; receptor mediated endocytosis; small heterodimer partner protein; stable plasma protein solution; stress-activated protein kinase 1; synergism; triethylamine; 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(申请人提供)：前列腺癌是美国男性最常见的致命性癌症，也是导致癌症死亡的第二大原因。2007年，美国癌症协会估计，美国将有大约21.8万个新病例，大约2.7万名男性将死于前列腺癌。这个项目的目的是利用分子生物学、聚合物科学和化疗方面的进展来开发一种新的治疗方式，这种治疗方式在前列腺癌的治疗中可能比现有的治疗药物更有效。临床数据表明，纳米(5-20 nm)水溶性聚合物-药物结合物的治疗应用似乎是一种新的和成功的癌症治疗策略。聚合物结合药物(与低分子药物相比)的优点是：a)通过液相吞饮作用(非靶向聚合物结合药物)或受体介导的内吞作用(靶向聚合物结合药物)主动摄取，b)通过靶向增加药物在肿瘤部位的主动积聚，c)由于增强的渗透性和滞留效应而增加药物在肿瘤部位的被动积聚，d)在血液中持续长时间的循环，e)降低结合药物的非特异性毒性，f)降低靶向部分的免疫原性，f)免疫保护和免疫调节活性，和g)设计双靶向偶联物的潜力。这项研究的主要目的是设计新的水溶性聚合物抗癌药物结合物，在雄激素非依赖性前列腺癌的治疗中比现有的治疗方案更有效。我们建议设计并合成一种新型的双靶向大分子治疗药物，它含有水溶性N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物骨架、抗前列腺特异性膜抗原(PSMA)的靶向部分(通过组合方法选择的单抗或靶向多肽)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。我们假设这种结合物将显着改善雄激素非依赖性前列腺癌(AIPC)的治疗指数。靶向HPMA共聚物3CL-AHPC结合物的优越效果是基于其双靶向能力，即通过孤儿核受体Nur77介导的靶向部分和固有的线粒体趋化凋亡诱导剂(3CL-AHPC)来靶向前列腺癌细胞。此外，靶向HPMA共聚物结合的凋亡诱导剂(3CL-AHPC)与靶向HPMA共聚物结合的多西紫杉醇(转移性AIPC的一线治疗药物)的组合是一种创新的治疗范例，具有提供其他治疗方法无法达到的肿瘤治疗的潜力。根据体外和体内动物数据，将建立设计一种新的、靶向给药系统的标准，用于治疗人类雄激素非依赖性前列腺癌。公共卫生评论该提案解决了前列腺癌治疗中的主要问题之一，即低分子抗癌药物缺乏特异性。双靶向大分子疗法的概念为设计治疗前列腺癌的高效抗癌药物输送系统提供了新的范式。活性物质不仅可以直接作用于癌细胞，还可以进入特定的亚细胞室。