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

项目摘要/摘要。乳腺癌是最常被诊断出的癌症之一。它解释了 全球每年近四分之一的癌症诊断病例。转移通常发生在乳房的早期 癌症，它是最重要的死亡原因。目前乳腺癌的治疗和分期是 根据TNM预后标记物：肿瘤大小(T)、有无淋巴结(N)和转移(M)。 越来越多的证据表明，乳腺癌的发展与 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， 结缔组织增生症，导致肿瘤相关的细胞外基质中纤维蛋白线性增加，如 以及矩阵的硬化。这些变化与越来越多的证据表明， 转移的原因。负责ECM重组的一个关键角色是MATRIX 金属蛋白酶(MMPs)，一个依赖锌的蛋白水解酶家族，能分解细胞外基质中的蛋白质。 人们一直在努力通过使用基质金属蛋白酶来对抗这种转移倾向。 作为癌症治疗的一种形式的抑制剂。一种非常有希望的研究药物是Batimastat，一种基质金属蛋白酶 通过I、II和III期临床试验取得进展的抑制剂，后来由于质量不佳而被淘汰 溶解性和有问题的给药途径。巴替马斯特的关键限制因素是分娩。至 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替马斯特的载体。vt.N- (2-羟丙基)甲基丙烯酰胺(HPMA)共聚物是水溶性、无毒、无免疫原性、 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 多肽(CMP)是一种合理设计的与变性胶原结合的类胶原多肽。 与内源性胶原蛋白相同的三螺旋结构。由于胶原蛋白是人体内最丰富的蛋白质 是细胞外基质中最集中的分子，在细胞外基质中存在过多的变性胶原 重塑的肿瘤相关ECM为肿瘤选择性靶向提供了良好的机会。我们 假设通过在HPMA的侧链中引入CMP作为靶向部分 通过使用共聚聚合物，我们可以提高治疗性药物、巴替马斯特以及显像剂的传递能力和疗效。 为了验证这一假设，将追求以下具体目标：1)设计和表征一个 具有与肿瘤相关的ECM结合能力的多功能HPMA-CMP结合物；2)表征 聚合物结合系统调节肿瘤细胞迁移和侵袭的能力，[胶原重塑， 和基质金属蛋白酶活性]；以及3)评估聚合物结合物在肿瘤中蓄积的能力 并影响肿瘤的生长[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].