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

基本信息

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
项目类别：
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

项目摘要

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）：前列腺癌是最常见的致命癌症，也是美国男性癌症死亡的第二大原因。 2007年，美国癌症协会估计，美国将有约218,000个新病例，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、聚合物科学和化疗领域的进展来开发一种新的治疗方式，这种方式在治疗前列腺癌方面可能比现有的治疗药物更有效。临床数据表明，纳米级（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颖且成功的癌症治疗策略。聚合物结合药物（与低分子量药物相比）的优点是：a)通过液相胞饮作用（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累，c) 由于渗透性和保留效应增强，增加药物在肿瘤部位的被动积累，d) 血流中的持久循环，e) 减少非- 特定毒性缀合药物，f）降低靶向部分的免疫原性，f）免疫保护和免疫动员活性，g）设计双靶向缀合物的潜力。拟议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，其在治疗雄激素非依赖性前列腺癌方面比现有治疗方案更有效。我们建议设计和合成新型双靶向大分子治疗药物，其中包含水溶性 N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 共聚物主链、针对前列腺特异性的靶向部分（单克隆抗体或靶向肽，通过组合方法选择）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 缀合物的卓越功效基于其双重靶向能力，即靶向部分介导的前列腺癌细胞和 Nur77 介导的凋亡诱导剂 (3Cl-AHPC) 固有的线粒体趋向性，孤儿核受体。此外，靶向 HPMA 共聚物结合的细胞凋亡诱导剂 (3Cl-AHPC) 与靶向 HPMA 共聚物结合的多西紫杉醇（转移性 AIPC 的一线治疗剂）的组合是一种创新的治疗范例，有可能提供肿瘤治愈方法，其他治疗方法无法达到。将根据体外和体内动物数据，制定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。公众健康启示该提案解决了前列腺癌治疗中的主要问题之一，即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用于治疗前列腺癌的高效抗癌药物递送系统提供了新的范例。活性剂不仅会导向癌细胞，还会导向特定的亚细胞区室。