Adaptable Polymer Micelles for Tumor Targeting

用于肿瘤靶向的适应性聚合物胶束

• 批准号: 7797889
• 负责人: KINAM PARK
• 金额: $ 30.56万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797889
• 关键词: Abraxane; Acute; Affect; Animal Testing; Antineoplastic Agents; Behavior; Biochemical; Biodistribution; Blood; Buffers; Cell Communication; Cells; Collaborations; Data; Databases; Development; Dissociation; Disulfides; Doctor of Philosophy; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Dyes; Endocytosis; Enzymes; Feedback; Fluorescence; Fluorescence Microscopy; Fluorescence Resonance Energy Transfer; Folate; Gefitinib; Gelatinase A; Goals; Hemolysis; Hydrophobicity; Image; Imaging Techniques; In Vitro; Institutes; International; Korea; Lead; Ligands; Matrix Metalloproteinases; Micelles; Molecular; Monitor; Paclitaxel; Peptides; Phagocytosis; Pharmaceutical Preparations; Physiological; Polymers; Property; Protocols documentation; Research; Role; Science; Site; System; Technology; Testing; Thrombin; Toxic effect; Treatment Efficacy; Tumor Tissue; Universities; Water; base; biomaterial compatibility; cancer therapy; clinical application; copolymer; crosslink; design; fluorescence imaging; improved; in vivo; intravenous administration; intravenous injection; neoplastic cell; non-invasive monitor; polypeptide; public health relevance; research study; targeted delivery; tomography; tumor; tumor specificity; uptake; whole body imaging

DESCRIPTION (provided by applicant): Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Despite their promising properties, they have not been fully developed as a vehicle for target delivery of anticancer agents. This is mainly due to the lack of understanding on the in vivo behavior of polymer micelles upon intravenous administration. Physically self-assembled polymer micelles are not expected to be stable in blood, and yet, no systematic studies have been made. This study is focused on understanding the interactions between polymer micelles and blood components for development of a new class of polymer micelles for targeted delivery of anticancer agents for clinical applications. The long-term goal of this research is to develop adaptable polymer micelles that are stable in blood but undergo dissociation by enzymes abundant at the tumor site. The hypothesis in this project is that the stability of polymer micelles in blood is prerequisite for successful tumor therapy. Only the stable polymer micelles have chances to target tumors and deliver anti-tumoral drugs at the therapeutically effective level. Specific Aims of this project are: (1) to develop adaptable polymer micelles; (2) to examine the micelle stability in blood; (3) to elucidate the micelle-cell interactions; and (4) to characterize the in vivo fate of micelles and to study the anti-tumoral activity of drug-loaded micelles. The two drugs to be used for tumor therapy are paclitaxel and gefitinib, which have similar hydrophobicity. The synergistic effect of the two-drug pair is expected, resulting in substantially better anti-tumoral effect. The adaptable polymer micelles will be prepared by crosslinking the hydrophobic core of the micelles through disulfide or peptides that are degradable by thrombin or matrix metalloproteinase 2 (MMP2) which are abundant at the tumor sites. The blood stability and tumor targeting properties of the adaptable polymer micelles will be examined by coherent anti-Stokes Raman scattering (CARS), fluorescence reflectance imaging (FRI), and fluorescence molecular tomography (FMT). The results of in vitro and in vivo experiments will be used to improve the properties of the adaptable polymer micelles, and such feedback cycle will be repeated to produce the optimal polymer micelles. The significance of our proposed research is that it will elucidate the factors affecting the stability of polymer micelles in blood, as well as cellular uptake, and in vivo fate/behavior of the micelles. Successful completion of this project is expected to produce adaptable polymer micelles that are effective for targeted delivery of a two-drug pair to the tumor sites. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a new type of polymer micelles that are stable in blood but undergo structural changes by enzymes abundant at the tumor site (i.e., adaptable polymer micelles) for targeted delivery of anticancer agents to the tumor site via intravenous injection.

描述（由申请人提供）：聚合物胶束已被广泛用于水溶性不良的药物。尽管具有有希望的特性，但并未完全开发作为抗癌剂目标递送的工具。这主要是由于对静脉内给药后聚合物胶束的体内行为缺乏了解。物理上自组装的聚合物胶束预计在血液中不会稳定，但是尚未进行系统的研究。这项研究的重点是理解聚合物胶束和血液成分之间的相互作用，以开发新的聚合物胶束，以靶向抗癌剂用于临床应用。 这项研究的长期目标是开发适应性的聚合物胶束，这些聚合物胶束在血液中稳定但在肿瘤部位丰富的酶解离。该项目的假设是，血液中聚合物胶束的稳定性是成功肿瘤治疗的先决条件。只有稳定的聚合物胶束有机会靶向肿瘤并在治疗有效水平上输送抗肿瘤药物。该项目的具体目的是：（1）开发适应性的聚合物胶束； （2）检查血液中的胶束稳定性； （3）阐明胶束细胞相互作用； （4）表征胶束的体内命运，并研究药物负载的胶束的抗肿瘤活性。用于肿瘤治疗的两种药物是紫杉醇和吉非替尼，它们具有相似的疏水性。预期两次毒品对的协同作用将产生更好的抗肿瘤作用。 适应性的聚合物胶束将通过通过在肿瘤部位丰富的凝血酶或基质金属蛋白酶2（MMP2）降解的二硫化物或肽通过二硫化物或肽进行交联。适应性聚合物胶束的血液稳定性和肿瘤靶向性能将通过连贯的反stokes拉曼散射（CAR），荧光反射成像（FRI）和荧光分子断层扫描（FMT）来检查。体外和体内实验的结果将用于改善适应性聚合物胶束的特性，并将重复进行此类反馈循环以产生最佳的聚合物胶束。 我们提出的研究的意义在于，它将阐明影响血液中聚合物胶束稳定性，细胞摄取以及胶束的体内命运/行为的因素。预计该项目的成功完成将产生适应性的聚合物胶束，这些聚合物胶束可有效地靶向两次毒品对向肿瘤部位递送。 公共卫生相关性：该项目的目的是开发一种新型的聚合物胶束，在血液中稳定但在肿瘤部位丰富的酶（即适应性聚合物胶束）经历结构变化，以通过静脉内注射将抗癌剂靶向肿瘤部位。