Therapeutic Targeting Agents for Ovarian Cancer

卵巢癌的治疗靶向药物

• 批准号: 9477423
• 负责人: KIT S LAM
• 金额: $ 34.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9477423
• 关键词: Acids; Adopted; Affinity; Antineoplastic Agents; Binding; Biochemical; Biodistribution; Chemicals; Cholic Acids; Clinic; Clinical; Cyclic Peptides; Development; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; Fatty Acids; Generations; Grant; Hybrids; Hydrophobicity; In Vitro; Integrin alpha3beta1; Integrins; Label; Laboratories; Lead; Legal patent; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Modeling; Mus; Nude Mice; Paclitaxel; Peptide Nucleic Acids; Peptides; Pharmaceutical Preparations; Property; Publications; SN-38; Series; Specificity; Surface; Therapeutic; Time; Transgenic Organisms; Treatment Efficacy; Xenograft Model; Xenograft procedure; amphiphilicity; arm; base; biophysical techniques; cancer cell; cancer therapy; cellular targeting; chemical property; combinatorial chemistry; hydrophilicity; improved; in vivo; intraperitoneal; molecular modeling; monomer; nanocarrier; nanoparticle; nanoparticle drug; neoplastic cell; next generation; novel; novel strategies; public health relevance; subcutaneous; targeted delivery; targeted treatment; tumor; uptake

 DESCRIPTION (provided by applicant): This is a competitive renewal proposal of the R01 CA115483 grant after 9 years. In our last competitive renewal 4 years ago, we proposed to develop a novel oligocholic acid/PEG based nanoplatform to load paclitaxel (PTX) and SN-38 for targeted delivery via i.v. and i.p. for OvCa therapy. We also proposed to use [14C]-labeled paclitaxel to determine the in vivo biodistribution and OvCa targeting properties of PTX-loaded nanocarriers, in both subcutaneous and intraperitoneal OvCa xenograft models. This last 4 year grant support resulted in 24 publications and 3 patent applications. In this second competitive renewal, we propose to further develop our oligocholic acid/PEG based nanoplatform by (i) incorporating novel strategies for efficient display of targeting ligands, and (ii) chemical tuningof the cholic acid core of the amphiphilic telodendrimer (monomer unit) for high capacity loading of a wide range of anti-cancer drugs. These novel concepts will be systematically applied to the basic nanoplatform one at a time and the resulting nanoparticles will be fully characterized for their physicochemical properties and their in vivo tumor targeting properties. Those superior features will then be combined and adopted to the development of a novel third generation targeting nanocarrier that is highly versatile, multifunctional, easy to formulate in the clinics, nd can function as an efficacious drug delivery system for cancer therapy. We will continue to use OvCa xenograft, subcutaneous and intraperitoneal models, to evaluate these novel nanoconstructs. We have previously demonstrated that therapeutic efficacy of telodendrimer-based micellar nanoparticles developed in our laboratory can be enhanced by (i) introducing inter- telodendrimer covalent but reversible crosslinkages to improve the in vivo stability of the nanocarrier, and (ii) by decorating the surface of the nanocarrier with tumor targeting ligands such as OA02 (a cyclic peptide) against 31 integrin. The next generation telodendrimer- based micellar nanoparticle will (i) enable improvement of targeting ligand display, and (ii) increase the range of therapeutic pay-loads suitable for the nanoplatform. We believe these improvements will greatly enhance the versatility and in vivo efficacy of these nanoparticle drugs, not only in xenograft or transgenic murine tumor models, but also in clinical OvCa. In this Competitive Renewal Proposal, we plan to pursue the following specific aims: 1. To improve the ligand display on our micellar nanocarrier 2. To develop new hybrid telodendrimers that can nanoformulate drugs that otherwise cannot be nanoformulated with our existing telodendrimers. 3. Promising nanocarriers from aim 1 and 2 will be selected and evaluated in subcutaneous and intraperitoneal OvCa xenograft models in nude mice for biodistribution and therapeutic efficacies.

 描述（由申请人提供）：这是9年后R 01 CA 115483补助金的竞争性更新提案。在我们4年前的最后一次竞争性更新中，我们提出开发一种新型的基于寡胆酸/PEG的纳米平台，以负载紫杉醇（PTX）和SN-38，用于通过静脉内和腹腔内靶向递送OvCa治疗。我们还提出使用[14 C]标记的紫杉醇来确定在皮下和腹膜内OvCa异种移植模型中的PTX负载的纳米载体的体内生物分布和OvCa靶向特性。在过去4年的资助下，发表了24篇论文，申请了3项专利。在第二次竞争性更新中，我们建议通过以下方式进一步开发我们的基于低聚胆酸/PEG的纳米平台：（i）纳入有效展示靶向配体的新策略，以及（ii）对两亲性末端树枝状聚合物的胆酸核心进行化学调节（单体单元）用于高容量装载多种抗癌药物。这些新的概念将被系统地应用于基本的纳米平台，一次一个，所得的纳米粒子将充分表征其物理化学性质和体内肿瘤靶向性质。这些上级特征将被结合并用于开发一种新型的第三代靶向纳米载体，该载体具有高度通用性、多功能性、易于临床配制，并且可以作为有效的药物递送系统用于癌症治疗。我们将继续使用OvCa异种移植、皮下和腹膜内模型来评估这些新型纳米结构。我们先前已经证明，在我们的实验室中开发的基于末端树枝状聚合物的胶束纳米颗粒的治疗功效可以通过以下方式增强：（i）引入末端树枝状聚合物间共价但可逆的交联以改善纳米载体的体内稳定性，和（ii）通过用肿瘤靶向配体如针对α 3 β 1整联蛋白的0A 02（一种环肽）装饰纳米载体的表面。下一代基于末端树枝状聚合物的胶束纳米颗粒将（i）能够改善靶向配体展示，和（ii）增加适用于纳米平台的治疗有效载荷的范围。我们相信这些改进将大大提高这些纳米颗粒药物的多功能性和体内功效，不仅在异种移植或转基因小鼠肿瘤模型中，而且在临床OvCa中。在此竞争性续约建议中，我们计划追求以下具体目标：1.为了改善配体在我们的胶束纳米载体2上的展示。开发新的混合末端树枝状聚合物，可以纳米配制药物，否则不能用我们现有的末端树枝状聚合物纳米配制。 3.将选择目标1和目标2中有前途的纳米载体，并在裸小鼠皮下和腹腔内OvCa异种移植模型中评估其生物分布和治疗功效。