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

项目概要/摘要。乳腺癌是最常见的癌症之一。它占 占全球癌症诊断的近四分之一。转移通常发生在乳腺癌的早期 癌症，它是最重要的死亡原因。目前乳腺癌的治疗和分期是 基于TNM预后标记：肿瘤大小（T）、淋巴结存在（N）和转移（M）。 越来越多的证据表明，乳腺癌的发展与乳腺癌发生的显著变化有关。 细胞外基质（ECM）。一个重要的变化是胶原蛋白的过度积累和沉积， 称为结缔组织增生，导致肿瘤相关ECM中纤维蛋白线性增加， 以及基质的硬化。根据越来越多的证据，这些变化与以下因素高度相关， 引起转移的。负责企业内容管理重组的一个关键角色是矩阵 金属蛋白酶（MMPs）是锌依赖性蛋白酶家族，其分解ECM中的蛋白质。 已经努力通过使用MMP在治疗上对抗这种转移倾向 抑制剂作为癌症治疗的一种形式。一种非常有前途的研究药物是巴马司他，一种MMP 抑制剂，通过I期，II期和III期临床试验进展，然后由于不良反应而被淘汰。 溶解性和有问题的给药途径。巴马司他的关键限制因素是分娩。到 为了改进这一点，本研究提出开发一种水溶性聚合物作为递送巴马司他载体。不，不 （2-羟丙基）甲基丙烯酰胺（HPMA）共聚物是水溶性的、无毒的、无免疫原性的， 多功能聚合物平台，其已被广泛研究用于药物递送。胶原模拟 肽（CMP）是胶原蛋白样肽，其被合理地设计以结合到胶原蛋白中的变性胶原蛋白。 与内源性胶原蛋白相同的标志性三螺旋形式。由于胶原蛋白是人体内最丰富的蛋白质， 在哺乳动物中，胶原蛋白是ECM中最集中的分子， 重塑肿瘤相关ECM为肿瘤选择性靶向提供了极好的机会。我们 假设通过在HPMA的侧链中引入CMP作为靶向部分， 通过使用共聚物，我们可以改善治疗剂、巴马司他以及成像剂的递送和功效。 为了检验这一假设，将追求以下具体目标：1）设计和表征 具有结合肿瘤相关ECM的能力的多功能HPMA-CMP缀合物; 2）表征具有肿瘤相关ECM的多功能HPMA-CMP缀合物; 聚合物缀合物系统调节肿瘤细胞迁移和侵袭，[胶原蛋白重塑， 和MMP活性];和3）评价聚合物缀合物在肿瘤中积累的能力 影响肿瘤生长[和转移]。

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].