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Water Soluble Polymers to Target Tumor-Associated Extracellular Matrix for Delivery of MMP Inhibitors

水溶性聚合物靶向肿瘤相关细胞外基质以递送 MMP 抑制剂

基本信息

批准号：
10162529
负责人：
Nithya Subrahmanyam
金额：
$ 3万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162529
关键词：
Adenocarcinoma Cell Affect Amino Acids Animals Basement membrane Batimastat Binding Biochemical Biodistribution Biological Biological Assay Biological Models Biomechanics Blood Circulation Breast Adenocarcinoma Cell Line Cell Survival Cell physiology Cell surface Cells Chelating Agents Chemical Structure Chlorides Clinical Trials Collagen Communication Cues Deposition Development Drug Delivery Systems Environment Extracellular Matrix Extracellular Matrix Degradation Family Fatty acid glycerol esters Growth and Development function Half-Life Harvest Homeostasis Human Hybrids Implant In Vitro Indium Indium-111 Individual Integrins Investigation Investigational Drugs MDA MB 231 Malignant Neoplasms Mammals Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mechanics Mediating Metastatic Neoplasm to Lymph Nodes Neoplasm Metastasis Nude Mice Organ Pathway interactions Peptide Hydrolases Peptides Permeability Pharmaceutical Preparations Phase Polymers Prognostic Marker Proteins Radiolabeled Renal clearance function Role Route Side Signal Pathway Signal Transduction Site Solubility Staging Stimulus Structure Survival Rate System TNM Techniques Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Treatment Efficacy Tumor Cell Migration Tumor Markers Water Work X-Ray Computed Tomography Zinc anti-cancer therapeutic base cancer diagnosis cancer imaging cancer therapy cell growth cell motility combat copolymer design fibrous protein imaging agent improved in vitro activity in vivo malignant breast neoplasm mammary mechanotransduction methacrylamide migration mimetics mortality neoplastic cell novel peptidomimetics polycarbonate scaffold single photon emission computed tomography success triple helix tumor tumor growth tumor progression

项目摘要

Project Summary/Abstract. Breast cancer is among the most frequently diagnosed cancers. It accounts for nearly a quarter of all cancer diagnoses worldwide every year. Metastasis typically occurs early in breast cancer, and it is the most significant cause of mortality. The current treatment and staging for breast cancer are based on the TNM prognostic markers: tumor size (T), presence of lymph nodes (N), and metastasis (M). Increasing evidence indicates that breast cancer development is correlated with significant changes in the extracellular matrix (ECM). An important change is the excess accumulation and deposition of collagen, termed desmoplasia, which results in increased linearity of fibrous protein in the tumor-associated ECM, as well as stiffening of the matrix. These changes are highly correlated with and, based on increasing evidence, causative of metastasis. A key player that is responsible for this restructuring of the ECM is matrix metalloproteinases (MMPs), a zinc-dependent family of proteases which break down proteins in the ECM. There have been efforts to therapeutically combat this propensity for metastasis through the use of MMP inhibitors as a form of cancer therapy. One highly promising investigational drug is Batimastat, an MMP inhibitor which progressed through Phases I, II, and III clinical trials, before being eliminated due to poor solubility and problematic routes of administration. The key limiting factor of Batimastat was in delivery. To improve this, this study proposes to develop a water-soluble polymer as a vehicle for delivery of Batimastat. N- (2-hydroxypropyl)methacrylamide (HPMA) copolymers are water soluble, non-toxic, non-immunogenic, multifunctional polymer platforms, which have been studied extensively for drug delivery. Collagen mimetic peptide (CMP) is collagen-resembling peptide that was rationally designed to bind to denatured collagen in the same hallmark triple helical form as endogenous collagen. As collagen is the most abundant protein in mammals and is the most concentrated molecule in the ECM, the presence of excessive denatured collagen in the remodeling tumor-associated ECM provides an excellent opportunity for tumor-selective targeting. We hypothesize that through the incorporation of CMP as a targeting moiety in the side chains of HPMA copolymers, we can improve the delivery and efficacy of the therapeutic, Batimastat as well as imaging agents. To test this hypothesis the following Specific Aims will be pursued: 1) to design and characterize a multifunctional HPMA-CMP conjugate with the ability to bind to tumor-associated ECM; 2) to characterize the ability of the polymer conjugate systems to modulate tumor cell migration and invasion, [collagen remodeling, and MMP activity] in vitro; and 3) to evaluate the ability of the polymer conjugate to accumulate in tumor regions and affect tumor growth [and metastasis].

项目摘要/摘要。乳腺癌是最常诊断的癌症之一。它占每年全球癌症诊断总数中近四分之一。转移通常发生在乳房早期癌症，它是导致死亡的最重要原因。目前乳腺癌的治疗和分期是基于 TNM 预后标志物：肿瘤大小 (T)、淋巴结存在 (N) 和转移 (M)。越来越多的证据表明乳腺癌的发生与身体结构的显着变化相关。细胞外基质（ECM）。一个重要的变化就是胶原蛋白的过量积累和沉积，称为结缔组织增生，它会导致肿瘤相关 ECM 中纤维蛋白的线性增加，如以及基体的硬化。这些变化与以下因素高度相关，并且基于越来越多的证据，转移的原因。负责 ECM 重组的关键参与者是矩阵金属蛋白酶 (MMP) 是一种锌依赖性蛋白酶家族，可分解 ECM 中的蛋白质。人们已经努力通过使用 MMP 来治疗性地对抗这种转移倾向抑制剂作为癌症治疗的一种形式。 Batimastat 是一种非常有前途的研究药物，它是一种 MMP 该抑制剂已通过 I、II、III 期临床试验，但因性能不佳而被淘汰溶解度和有问题的给药途径。巴马司他的关键限制因素是给药。到为了改善这一点，本研究建议开发一种水溶性聚合物作为巴马司他的递送载体。 N- (2-羟丙基)甲基丙烯酰胺 (HPMA) 共聚物是水溶性、无毒、非免疫原性、多功能聚合物平台，已被广泛研究用于药物输送。胶原蛋白模拟物肽（CMP）是一种类似胶原蛋白的肽，经过合理设计，可与胶原蛋白中的变性胶原蛋白结合与内源性胶原蛋白相同的标志性三螺旋形式。由于胶原蛋白是体内最丰富的蛋白质哺乳动物中，并且是 ECM 中最浓缩的分子，因此存在过量的变性胶原蛋白重塑肿瘤相关的 ECM 为肿瘤选择性靶向提供了绝佳的机会。我们假设通过将 CMP 作为靶向部分掺入 HPMA 的侧链共聚物，我们可以改善治疗剂巴马司他以及显像剂的输送和功效。为了检验这一假设，将追求以下具体目标：1) 设计并表征多功能 HPMA-CMP 缀合物，能够结合肿瘤相关 ECM； 2）表征聚合物缀合物系统调节肿瘤细胞迁移和侵袭的能力，[胶原重塑，和MMP活性]体外； 3)评价聚合物缀合物在肿瘤中积累的能力区域并影响肿瘤生长[和转移]。