Understanding and Preventing Tumor Disperal with Hydrogel Therapeutics

了解和预防水凝胶疗法的肿瘤扩散

基本信息

批准号：
8048971
负责人：
RICHARD A GEMEINHART
金额：
$ 32.24万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-06 至 2013-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most advanced and invasive form of brain tumor. Various issues reduce long-term survival, the most common being recurrence even after treatment. GBM invasion and metastasis (dispersal) require the degradation of extracellular matrix (ECM) which is mediated, in part, by matrix metalloproteases (MMP). Since MMP inhibition has not been shown to be clinically effective despite MMPs being shown to be greatly overactive particularly in metastatic disease, a more function-related approach is needed to exploit this therapeutic target. We will investigate a novel method of utilizing MMP expression to understand and treat GBM and other invasive brain tumors. The rationale for this study is to target MMP specificity thereby activating chemotherapeutics in a manner similar to traditional prodrugs; however, unlike traditional prodrugs, activation will take place from a polymeric device. MMP-sensitive substrates (peptides) will be incorporated into hydrogels to allow activation of chemotherapeutics and biodegradation in the presence of MMPs. Cleavage of the peptide by MMPs will release and activate the drug from the hydrogel. With this rationale and goals in mind, we have based our novel intervention on the general hypothesis that extracellular proteases can enter a hydrogel matrix and activate pendant chemotherapeutic agents. Five specific aims have been established to investigate this hypothesis: (1) to optimize MMP-sensitivity; (2) to optimize hydrogel parameters; (3) to determine soluble MMP activity within hydrogels; (4) to determine cell association and activity; and (5) to examine glioma cell invasion within the hydrogels. Consistent with the Program Announcement to which this application was submitted (PAS-04- 079), this proposal describes an innovative approach to understanding and treating brain tumor dispersal. This work will develop a therapy targeted to the tumor's dispersive signals, specifically the invasive nature of the disease. The proposed hypothesis and specific aims are specifically designed to 1) address the localization of MMP activity during invasive behavior of brain tumor, 2) to develop a new tool for fighting this disease, and (3) to develop a new tool for examining tumor cell invasion.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是最先进和最具侵袭性的脑肿瘤。各种问题都会降低长期生存率，最常见的是治疗后复发。 GBM 侵袭和转移（分散）需要细胞外基质 (ECM) 的降解，这部分是由基质金属蛋白酶 (MMP) 介导的。尽管 MMP 被证明非常过度活跃，特别是在转移性疾病中，但由于 MMP 抑制尚未被证明在临床上有效，因此需要一种与功能更加相关的方法来开发这一治疗靶点。我们将研究一种利用 MMP 表达来理解和治疗 GBM 和其他侵袭性脑肿瘤的新方法。这项研究的基本原理是针对 MMP 特异性，从而以类似于传统前药的方式激活化疗药物；然而，与传统的前药不同，激活是通过聚合物装置进行的。 MMP 敏感底物（肽）将被纳入水凝胶中，以便在 MMP 存在的情况下激活化疗药物并进行生物降解。 MMP 对肽的裂解将从水凝胶中释放并激活药物。考虑到这一基本原理和目标，我们的新干预措施基于这样的一般假设：细胞外蛋白酶可以进入水凝胶基质并激活悬垂的化疗药物。为了研究这一假设，我们建立了五个具体目标：(1) 优化 MMP 敏感性； (2)优化水凝胶参数； (3)测定水凝胶内可溶性MMP活性； (4)确定细胞关联和活性； (5)检查水凝胶内神经胶质瘤细胞的侵袭。与提交本申请的计划公告 (PAS-04-079) 一致，该提案描述了一种理解和治疗脑肿瘤扩散的创新方法。这项工作将开发一种针对肿瘤分散信号的疗法，特别是针对疾病的侵袭性。所提出的假设和具体目标是专门设计的：1）解决脑肿瘤侵袭行为期间 MMP 活性的定位，2）开发一种对抗这种疾病的新工具，以及（3）开发一种检查肿瘤细胞的新工具入侵。