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：
8197950
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 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197950
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 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 abstracting 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

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.

抽象的前列腺癌是最常见的致命癌症，也是癌症死亡的第二大原因 2007 年，美国癌症协会估计美国约有 218,000 名男性。新病例和约 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、高分子科学和化疗取得的进展，开发出一种新的治疗方法方式，这可能比现有的前列腺治疗药物更有效临床数据表明纳米级（5-20 nm）水溶性聚合物药物的治疗用途。缀合物似乎是一种新颖且成功的癌症治疗策略。结合药物（与低分子量药物相反）是： a) 通过液相胞饮作用主动摄取（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) 增加通过靶向使药物在肿瘤部位主动蓄积，c) 增加药物在肿瘤部位的被动蓄积由于增强的渗透性和滞留效应，d) 肿瘤部位的持久循环血流，e) 降低结合药物的非特异性毒性，f) 降低药物的免疫原性靶向部分，f) 免疫保护和免疫动员活性，g) 设计的潜力双靶向缀合物。拟议研究的主要目的是设计新型水溶性聚合物 ¿抗癌药物结合物在治疗雄激素非依赖性前列腺方面比现有治疗方案更有效我们建议设计和合成包含以下成分的新型双靶向大分子疗法：水溶性 N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 共聚物主链、靶向部分（单克隆抗体或靶向肽，通过组合方法选择）针对前列腺特异性膜抗原 (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。显着改善雄激素非依赖性前列腺癌（AIPC）的治疗指数。靶向 HPMA 共聚物的功效 ¿ 3Cl-AHPC 缀合物基于其双靶向能力，即通过靶向前列腺部分和前列腺固有的线粒体介导靶向癌细胞细胞凋亡诱导剂 (3Cl-AHPC)，由孤儿核受体 Nur77 介导。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 的一线治疗药物）是一种创新的治疗范例，提供其他治疗方法无法达到的肿瘤治愈的潜力。成立的目的是设计一种新的靶向药物输送系统，用于治疗雄激素非依赖性疾病基于体外和体内动物数据的人类前列腺癌。该提案解决了前列腺癌治疗的主要问题之一 ¿缺乏特异性低双靶向大分子治疗药物的概念提供了一种新的治疗方法。设计用于治疗前列腺癌的有效抗癌药物输送系统的新范例。活性剂不仅会导向癌细胞，还会导向特定的亚细胞区室。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis and Characterization of Poly ( e-caprolactone )-block-poly [ N-( 2-hydroxypropyl ) methacrylamide ] Micelles for Drug Delivery

药物输送用聚(ε-己内酯)-嵌段-聚[N-(2-羟丙基)甲基丙烯酰胺]胶束的合成与表征

DOI：
发表时间：
2024-09-14
期刊：
Heat and Mass Transfer
影响因子：
2.2
作者：
S. Krimmer;H. Pan;Jihua Liu;Jiyuan Yang;J. Kopeček
通讯作者：
J. Kopeček

HPMA copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects.

基于 HPMA 共聚物的联合疗法对前列腺癌干/祖细胞和分化细胞具有毒性，可诱导持久的抗肿瘤作用。

DOI：
10.1016/j.jconrel.2013.09.005
发表时间：
2013-12-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Zhou Y;Yang J;Rhim JS;Kopeček J
通讯作者：
Kopeček J

Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells.

HPMA共聚物-环巴明缀合物对前列腺癌干细胞的选择性抑制作用。