Poly (amino acid) as an Integrin Targeted Drug Carrier

聚（氨基酸）作为整合素靶向药物载体

• 批准号: 6899032
• 负责人: XIAOLING LI
• 金额: $ 17.44万
• 依托单位: UNIVERSITY OF THE PACIFIC-STOCKTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-13 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899032
• 关键词: aspartate; chemical conjugate; copolymer; cytotoxicity; doxorubicin; drug delivery systems; drug design /synthesis /production; extracellular matrix; integrins; laboratory mouse; leucine; melanoma; neoplastic growth; nuclear magnetic resonance spectroscopy; tissue /cell culture; valine

DESCRIPTION (provided by applicant): Integrins are found to play an important role in the adhesion of cancer cells to the extracellular matrix during cancer metastasis. This adhesion occurs via interactions or binding between small peptide sequences located in the extracellular matrix and specific binding sites on integrins. It is hypothesized that this interaction or specific binding can be utilized to design drug carriers for the treatment of cancer. Melanoma cells possess an over-expression of the alpha4beta1 integrin on the cell surface. It is reported that the recognition of the tripeptide sequence, leucine-aspartic acid-valine, (LDV) is limited only to the a4a1 integrin. In this proposal, a random polymer of LDV and a polymer with ordered LDV sequence are designed to serve as a drug carrier by which anticancer agents can be conjugated to the carrier via a labile covalent linkage. Due to the binding specificity between melanoma cells and the LDV sequence in the copolymer, the anticancer agent will be targeted to the melanoma cells. The anticancer agent will be released and exert pharmacological effects after the poly (LDV)-drug conjugate is internalized by melanoma cells. Random copolymers of LDV were chosen in the design of this integrin targeted drug carrier because of achievable high molecular weight with less ordered structure (to avoid immunogenicity of the carrier) at low costs. The goal of this proposal is to design, synthesize, characterize, and test random copolymers of LDV for alpha4beta1 integrin specific targeted drug delivery. This goal will be achieved by conducting a series of studies with the following specific aims: 1) to synthesize novel random terpolymers containing leucine, aspartic acid, and valine and covalently link doxorubicin to this integrin targeted drug carrier, 2) to verify the target specificity of the carrier to malignant melanoma cells, and 3) to test if the conjugation of doxorubicin to poly (LDV) could improve its efficacy by targeting to malignant melanoma cells both in vitro and in vivo. The study of this targeting drug carrier will explore the integrins as targeting site for drug delivery and design the integrin targeted drug carriers to deliver anticancer agents. These novel polymers of LDV would not only serve as a drug carrier but also could potentially act as an inhibitor of cancer metastasis, thus providing a synergetic effect in cancer therapy. Therefore, the polymers of LDV may be a promising target specific carrier to cancers that express the alpha4beta1 integrin. Additionally, when the objective of the proposed study is achieved, specific carriers can also be developed to target other integrins and deliver drugs to cancer cells that express a specific type of integrin. The proposed studies in this AREA grant proposal will provide a solid training to a graduate student in the area of drug delivery and strengthen the research environment at the Univ. of the Pacific, a primarily baccalaureate training institution.

描述(由申请人提供)： 整合素被发现在肿瘤转移过程中癌细胞与细胞外基质的黏附中发挥重要作用。这种黏附通过位于细胞外基质中的小肽序列与整合素上的特定结合部位之间的相互作用或结合而发生。假设这种相互作用或特异性结合可用于设计治疗癌症的药物载体。黑色素瘤细胞表面有α4beta1整合素的过度表达。据报道，对亮氨酸-天冬氨酸-缬氨酸(LDV)三肽序列的识别仅限于a4a1整合素。在该方案中，设计了LDV的随机聚合物和具有LDV序列的聚合物作为药物载体，通过不稳定的共价键将抗癌药物连接到载体上。由于黑色素瘤细胞与共聚物中LDV序列的结合特异性，抗癌剂将靶向黑色素瘤细胞。当聚(LDV)-药物结合物被黑色素瘤细胞内化后，抗癌剂将被释放并发挥药理作用。在整合素靶向药物载体的设计中，选择了LDV的无规共聚物，因为它可以以较低的成本获得较高的相对分子质量和较少的有序结构(避免载体的免疫原性)。 这项建议的目标是设计、合成、表征和测试用于α4beta1整合素特异性靶向给药的LDV随机共聚物。这一目标将通过开展一系列具体目标的研究来实现：1)合成含有亮氨酸、天冬氨酸和缬氨酸的新型随机三元聚合物，并将阿霉素共价连接到这种整合素靶向药物载体上；2)验证载体对恶性黑色素瘤细胞的靶向性；以及3)测试阿霉素与聚(LDV)的偶联是否可以通过体外和体内靶向恶性黑色素瘤细胞来提高其疗效。 这种靶向药物载体的研究将探索整合素作为药物传递的靶点，并设计整合素靶向药物载体来传递抗癌药物。这些新型的LDV聚合物不仅可以作为药物载体，还可以潜在地作为癌症转移的抑制剂，从而在癌症治疗中提供协同效应。因此，LDV的聚合物可能成为表达α4β1整合素的肿瘤的靶向特异性载体。此外，当拟议研究的目标达到时，还可以开发特定的载体来靶向其他整合素，并将药物输送到表达特定类型整合素的癌细胞。 拟议的这一领域的研究将为研究生在药物输送领域提供坚实的培训，并加强大学的研究环境。太平洋大学，一所主要拥有学士学位的培训机构。