DOUBLE-TARGETED MACROMOLECULAR THERAPEUTICS FOR THE TREATMENT OF PROSTATE CANCER

摘要 前列腺癌是#年确诊的最常见的致命性癌症，也是癌症死亡的第二大原因。 美国男人。2007年，美国癌症协会估计，在美国，大约有21.8万人 新增病例和大约27,000名男性将死于前列腺癌。这个项目的目的是利用 在分子生物学、聚合物科学和化疗方面取得的进展，以开发新的治疗方法 在治疗前列腺癌方面，这种方法可能比现有的治疗药物更有效 癌症。临床资料表明，纳米(5-20 nm)水溶性聚合物药物在治疗中的应用 结合物似乎是一种新的、成功的癌症治疗策略。聚合物的优势-- 结合药物(与低分子药物不同)是：a)液相吞饮作用主动摄取(非 靶向聚合物结合药物)或受体介导的内吞作用(靶向聚合物结合药物)，b)增加 通过靶向在肿瘤部位主动积聚药物，c)增加药物在 肿瘤部位由于渗透性和滞留作用的增强，d)在 血流，e)降低结合药物的非特异性毒性，f)降低免疫原性 靶向部分，f)免疫保护和免疫促进活性，以及g)设计的潜力 双靶向偶联物。 这项研究的主要目的是设计新型的水溶性聚合物抗癌药物结合物。 在治疗雄激素非依赖性前列腺癌方面比现有的治疗方案更有效 癌症。我们建议设计和合成新型的双靶向大分子药物，包括 水溶性N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物主链，靶向基团 (通过组合方法选择的抗前列腺特异性的单抗或靶向多肽) 膜抗原(PSMA)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。我们假设这一共轭关系将证明 显著改善雄激素非依赖性前列腺癌(AIPC)的治疗指数。《上级》 靶向HPMA共聚物3CL-AHPC结合物的有效性是基于它们的双靶向能力，即 靶向部分和固有的线粒体亲和性介导的前列腺癌靶向 凋亡诱导剂(3CL-AHPC)，由孤儿核受体Nur77介导。此外，这一组合 靶向HPMA共聚物结合的细胞凋亡诱导剂(3CL-AHPC)的研究 多西紫杉醇(治疗转移性AIPC的一线药物)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方法。标准将是 为设计一种新的靶向给药系统而建立，用于雄激素非依赖性治疗 根据体外和体内动物数据，前列腺癌在人类中的作用。叙事 该提案解决了前列腺癌治疗中的主要问题之一--低密度脂蛋白缺乏特异性 分子量抗癌药物。双靶向大分子疗法的概念提供了一种 用于前列腺癌治疗的高效抗癌药物输送系统设计的新范例。 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。

ABSTRACT 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. NARRATIVE 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.