Thermally targeted drug delivery by elastin biopolymers

弹性蛋白生物聚合物的热靶向药物递送

• 批准号: 6775563
• 负责人: Ashutosh Chilkoti
• 金额: $ 30.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775563
• 关键词: Escherichia coli; athymic mouse; autoradiography; chemical conjugate; chemical synthesis; drug delivery systems; elastin; genetic manipulation; hyperthermia; iodine; light scattering; linear energy transfer; neoplasm /cancer radiation therapy; neoplasm /cancer radionuclide therapy; neoplastic growth; nonhuman therapy evaluation; peptides; precipitation; radiation dosage; radionuclides; site directed mutagenesis; spectrometry; temperature; tissue engineering; transfection /expression vector; video microscopy

The objective of the proposed research is to selectively deliver systemically injected radionuclides to solid tumors by a thermal targeting strategy. This objective will be achieved by conjugating radionuclides (131I and 211 At) to thermally sensitive polypeptide carriers, which will be targeted to solid tumors by focused hyperthermia of the tumor. The thermally responsive macromolecular carriers used for thermal targeting are polypeptides derived from mammalian elastin, composed of Val-Pro- Gly-Xaa-Gly (VPGXG) repeats, which undergo an inverse phase transition; below their inverse transition temperature (Tt), ELPs are highly soluble, but when the temperature is raised above their Tt, they undergo a phase transition within a 2-3 degrees Celsius range, leading to desolvation and aggregation of the polypeptide. The underlying hypothesis of the proposed research is that intravenously injected radionuclides, conjugated to a temperature-responsive ELP, can be designed such that they will selectively accumulate in the tumor, maintained at 42 degrees Celsius by local hyperthermia due to aggregation of the ELP in response to its phase transition. In preliminary research, we have demonstrated that thermal targeting provides a 2-3 fold increase in tumor localization versus non-heated controls and a approximately 2 fold enhancement with respect to a thermally insensitive control ELP in heated human tumor xenografts implanted in athymic mice. We propose the following specific aims to achieve the objectives of this proposal: (1) to synthesize ELPs with a Tt of 40 degrees Celsius by recombinant DNA methods; (2) to conjugate radionuclides to the ELPs; (3) to optimize the thermally targeted delivery of ELPs to human tumor xenografts implanted in athymic mice; (4) to carry out systemic radionuclide therapy with 211 At-labeled ELPs using the optimized protocols and external hyperthermia of solid tumors. The development of thermally responsive radionuclide-ELP conjugates that can be targeted to solid tumors by externally-induced local hyperthermia is a new paradigm for targeted delivery which directly targets the tumor microvasculature and circumvents the barriers associated with the interstitium and antibody-tumor cell surface antigen/receptor binding that are intrinsic to affinity targeting approaches for radionuclide therapy.

拟议的研究的目的是通过热靶向策略选择性地将其系统地注入放射性核素到实体瘤。 通过将放射性核素（131i和211 at）结合到热敏感的多肽载体，该目标将实现这一目标，该载体将通过聚焦的肿瘤高温过高将其靶向实体瘤。 用于热靶向的热响应的大分子载体是源自哺乳动物弹性蛋白的多肽，由哺乳动物弹性蛋白衍生而成，由val-pro-xaa-gly（vpgxg）重复序列组成，它们进行了反相变。在其反向过渡温度（TT）以下，ELP是高度溶解的，但是当温度升高到其TT上方时，它们会在2-3摄氏度范围内进行相变，从而导致多肽的脱溶剂和聚集。 拟议的研究的基本假设是，可以设计与温度响应性ELP相结合的静脉注射的放射性核素，以使它们可以在肿瘤中有选择地积聚在肿瘤中，并通过局部高34度因ELP的聚集而在42摄氏度上维持，而ELP响应其相过渡。 在初步研究中，我们已经证明，热靶向可提供2-3倍的肿瘤定位增加，而非加热对照，并且相对于植入无胸膜小鼠的加热的人类肿瘤异种移植物中的热不敏感对照ELP的增强。 我们提出以下特定目的，以实现该提案的目标：（1）通过重组DNA方法以40摄氏度合成ELP； （2）将放射性核素偶联到ELPS； （3）优化将ELP的热靶向递送到植入无胸腺小鼠中的人类肿瘤异种移植物； （4）使用优化的方案和实体瘤的外部热疗进行211个标签的ELP进行全身放射性核素治疗。 The development of thermally responsive radionuclide-ELP conjugates that can be targeted to solid tumors by externally-induced local hyperthermia is a new paradigm for targeted delivery which directly targets the tumor microvasculature and circumvents the barriers associated with the interstitium and antibody-tumor cell surface antigen/receptor binding that are intrinsic to affinity targeting approaches for radionuclide therapy.