Adaptable Polymer Micelles for Tumor Targeting

用于肿瘤靶向的适应性聚合物胶束

• 批准号: 8391233
• 负责人: KINAM PARK
• 金额: $ 28.14万
• 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/8391233
• 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; Homing; 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.

描述（由申请人提供）：聚合物胶束已广泛用于递送水溶性差的药物。尽管它们具有有前途的性质，但它们尚未被完全开发为抗癌剂靶向递送的载体。这主要是由于缺乏对聚合物胶束在静脉给药后的体内行为的了解。物理自组装聚合物胶束在血液中不稳定，但尚未进行系统的研究。本研究的重点是了解聚合物胶束和血液成分之间的相互作用，开发一类新的聚合物胶束靶向输送抗癌药物的临床应用。 这项研究的长期目标是开发适应性强的聚合物胶束，这些胶束在血液中稳定，但在肿瘤部位大量存在的酶作用下发生解离。该项目的假设是，聚合物胶束在血液中的稳定性是成功治疗肿瘤的先决条件。只有稳定的聚合物胶束才有机会靶向肿瘤并以治疗有效水平递送抗肿瘤药物。本项目的具体目标是：（1）开发适应性聚合物胶束;（2）检查胶束在血液中的稳定性;（3）阐明胶束-细胞相互作用;（4）表征胶束的体内命运并研究载药胶束的抗肿瘤活性。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。预期两种药物对的协同作用，导致显著更好的抗肿瘤效果。 可适应的聚合物胶束将通过二硫化物或肽交联胶束的疏水核心来制备，所述二硫化物或肽可被肿瘤部位丰富的凝血酶或基质金属蛋白酶2（MMP 2）降解。将通过相干反斯托克斯拉曼散射（汽车）、荧光反射成像（FRI）和荧光分子断层扫描（FMT）检查自适应聚合物胶束的血液稳定性和肿瘤靶向性质。体外和体内实验的结果将被用来改善适应性聚合物胶束的性能，并且这种反馈循环将被重复以产生最佳的聚合物胶束。 我们提出的研究的意义在于，它将阐明影响聚合物胶束在血液中的稳定性的因素，以及细胞摄取和胶束的体内命运/行为。该项目的成功完成预计将产生可适应的聚合物胶束，有效地将两种药物对靶向递送到肿瘤部位。