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。聚合物结合的药物的优点（与低分子量药物相比）是：a）a）流体相性皮细胞增多（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）的主动吸收， b）通过靶向，c）由于渗透性增强和保留效应，d）血液中长期循环，e）非持续的循环，e）通过靶向，c）药物在肿瘤部位增加了活跃的积累。 - 共轭药物的特异性毒性，f）靶向部分的免疫原性，f）免疫保护和免疫授予活性，g）设计双靶标偶联物的潜力。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目标大分子疗法，其中含有水溶性N-（2-羟基丙基）甲基丙烯酰胺（HPMA）共聚物骨架，靶向部分（一种单克隆抗体或靶向肽），由组合型替代型替代肽反对特定剂，反对prosinatoration officiacic officiacy officiacic抗体，膜抗原（PSMA）和线粒体细胞凋亡诱导剂，（（E）-4- [3-（1-辅助）-4-羟基苯基] - 3-氯环酸（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共轭物的出色功效是基于其双靶向能力，即靶向靶向部分介导的前列腺癌细胞和凋亡诱导剂（3CL-AHPC）的固有线粒体介导的前列腺癌细胞（3CL-AHPC），如NUR77所述。孤儿核受体。此外，有针对性的HPMA共聚物结合凋亡诱导剂（3Cl-AHPC）与靶向HPMA共聚物结合的多西他赛（转移性AIPC的第一线治疗剂）的组合是一种创新的治疗范式其他治疗方法无法达到。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。