THERMALLY SENSITIVE DRUG DELIVERY SYSTEM FOR TUMORS

肿瘤热敏药物输送系统

• 批准号: 6189366
• 负责人: DAVID NEEDHAM
• 金额: $ 33.58万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6189366
• 关键词: apoptosis; athymic mouse; calorimetry; cell line; dextrans; doxorubicin; electron microscopy; fluorescence microscopy; fluorescence spectrometry; lipid bilayer membrane; liposomes; membrane permeability; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; skin neoplasms; surfactant; temperature

The overall objective of this research proposal is to determine mechanisms of drug release and mechanisms of drug action for a new thermal-sensitive liposomal delivery system that has already shown very positive local control in animal experiments. It is proposed to continue basic in vitro studies concerning temperature-triggered drug release from the new liposomes and the use of other lipids and surfactants to provide greater understanding and control over the process. These in vitro studies will be coupled with in vivo studies that will determine drug delivery, drug distributions, drug action and efficacy, all enhanced by the application of mild, clinically attainable hyperthermia. These goals will be accomplished by carrying out the following specific aims. SA1. To more fully characterize the mechanism of thermally-induced lipid membrane permeability to a range of solutes. SA2. To test other bilayer compatible compounds. SA3. To investigate mechanisms of tumor growth delay induced by the new doxorubicin formulation. SA4. To optimize liposomal doxorubicin delivery in solid tumors. SA5. To test preclinically the antitumor effect of two different liposomal drug formulations in tumor growth delay models. Methods in SAs 1, and 2 will include spectrophotometric and calorimetric analysis for drug release, electron microscopy for bilayer structure, and differential scanning calorimetry for characterizing the thermal properties of the liposomes. In the in vivo studies Homozygous NCr athymic nude mice (20 q 3g) will be used to grow four tumor lines: FaDu, a human squamous carcinoma, SKOV3, a human ovarian carcinoma, LNCaP, a human prostate carcinoma, and MCF7, a human mammary carcinoma. Experimental methods for SAs 3, 4 and 5, include, skin flap window chamber with fluorescence microscopy and subcutaneous tumors for drug deposition, distribution and tumor growth delay; tissue extraction and HPLC for drug analysis; and histological staining for apoptosis of endothelial cells. This new low temperature sensitive liposome provides an opportunity for a complete paradigm shift with regard to the use of hyperthermia clinically. It works effectively at less than or equal to 42 C, and so applications of this technology can now be considered for potentially curable deep-seated tumors, such as ovarian and prostate cancer. The studies are necessary in order to optimize the new system to achieve local control for a range of solid tumors in clinical trials of the new liposomal doxorubicin in a Program Project at Duke University. The results of the study will be critical to the burgeoning health-related field of drug delivery, and to cancer treatment in particular.

该研究建议的总体目标是确定新的热敏感脂质体递送系统的药物释放机制和药物作用机制，该系统在动物实验中已经显示出非常积极的局部控制。 建议继续基础有关温度触发的药物从新脂质体释放的基础体外研究，以及使用其他脂质和表面活性剂的使用，以提供对该过程的更多了解和控制。 这些体外研究将与体内研究相结合，这些研究将确定药物递送，药物分布，药物作用和功效，这一切都通过应用轻度，临床上可达到的高热性增强。 这些目标将通过执行以下特定目标来实现。 SA1。更充分地表征了热诱导的脂质膜渗透性的机理，以范围为一系列溶质。 SA2。测试其他双层兼容化合物。 SA3。研究新的阿霉素制剂引起的肿瘤生长延迟机制。 SA4。优化实体瘤中的脂质体阿霉素递送。 SA5。在肿瘤生长延迟模型中，临床上测试两种不同的脂质体药物制剂的抗肿瘤作用。 SAS 1和2中的方法包括用于释放药物的分光光度法和量热分析，用于双层结构的电子显微镜以及用于表征脂质体热性能的差异扫描量热法。 在体内研究中，纯合子NCR无胸腺裸鼠（20 Q 3G）将用于种植四种肿瘤线：FADU，人类鳞状癌，Skov3，人类卵巢癌，LNCAP，LNCAP，人类前列腺癌和人类前列腺癌和MCF7，人类乳腺癌。 SAS 3、4和5的实验方法包括带有荧光显微镜和皮下肿瘤的皮肤瓣窗室，用于药物沉积，分布和肿瘤生长延迟；组织提取和HPLC用于药物分析；和内皮细胞凋亡的组织学染色。 这种新的低温敏感脂质体为在临床上使用高温提供了完全范式转移的机会。 它在小于或等于42 C的情况下有效地工作，因此现在可以考虑使用该技术的应用，以用于潜在可治愈的深座肿瘤，例如卵巢癌和前列腺癌。 为了优化新系统以在新脂质体阿霉素的临床试验中，在杜克大学的计划项目中，这是必要的研究。 这项研究的结果对于迅速发展的与健康相关的药物输送领域，尤其是癌症治疗至关重要。