Adaptable Polymer Micelles for Tumor Targeting

用于肿瘤靶向的适应性聚合物胶束

• 批准号: 8585830
• 负责人: KINAM PARK
• 金额: $ 28.99万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585830
• 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; 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 molecular tomography; improved; in vivo; intravenous administration; intravenous injection; neoplastic cell; non-invasive imaging; polypeptide; public health relevance; research study; targeted delivery; 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难溶性药物。尽管它们具有前景广阔的特性，但它们尚未完全开发为抗癌药物靶向递送的载体。这主要是由于对静脉注射后聚合物胶束的体内行为缺乏了解。物理自组装聚合物胶束预计在血液中不稳定，但尚未进行系统研究。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，以开发一类新型聚合物胶束，用于临床应用的靶向递送抗癌药物。 这项研究的长期目标是开发适应性强的聚合物胶束，其在血液中稳定，但会被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提供治疗有效水平的抗肿瘤药物。该项目的具体目标是：（1）开发适应性强的聚合物胶束； (2)检测血液中胶束的稳定性； (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。预计两种药物对的协同作用将产生更好的抗肿瘤效果。 适应性聚合物胶束将通过二硫化物或可被肿瘤部位丰富的凝血酶或基质金属蛋白酶2 (MMP2)降解的肽交联胶束的疏水核心来制备。适应性聚合物胶束的血液稳定性和肿瘤靶向特性将通过相干反斯托克斯拉曼散射（CARS）、荧光反射成像（FRI）和荧光分子断层扫描（FMT）进行检查。体外和体内实验的结果将用于改善适应性聚合物胶束的性能，并且重复这样的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、细胞摄取以及胶束体内命运/行为的因素。该项目的成功完成预计将产生适应性强的聚合物胶束，可有效将两种药物对靶向递送至肿瘤部位。

项目成果

FRET imaging reveals different cellular entry routes of self-assembled and disulfide bonded polymeric micelles.

FRET 成像揭示了自组装和二硫键聚合物胶束的不同细胞进入途径。

• DOI: 10.1021/mp4003333
• 发表时间: 2013-09-03
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Lee SY;Tyler JY;Kim S;Park K;Cheng JX
• 通讯作者: Cheng JX

Drug Delivery Research: The Invention Cycle.

药物输送研究：发明周期。

• 发表时间: 2016-07-05
• 影响因子: 4.9
• 作者: Park; Kinam
• 通讯作者: Kinam

Drug delivery of the future: Chasing the invisible gorilla.

未来的药物输送：追逐看不见的大猩猩。

• DOI: 10.1016/j.jconrel.2015.10.048
• 发表时间: 2016-10-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Park K

Controlled drug delivery systems: past forward and future back.

受控药物输送系统：过去的前进和未来的回溯。

• DOI: 10.1016/j.jconrel.2014.03.054
• 发表时间: 2014-09-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Park K

Simulation of complex transport of nanoparticles around a tumor using tumor-microenvironment-on-chip.

使用芯片上的肿瘤微环境模拟肿瘤周围纳米颗粒的复杂运输。

• DOI: 10.1016/j.jconrel.2014.08.027
• 发表时间: 2014-11-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Kwak B;Ozcelikkale A;Shin CS;Park K;Han B
• 通讯作者: Han B