New Thermal Sensitive Carboplatin Liposome for Cancer

描述(由申请者提供)：这项SBIR第一阶段拨款的总体目标是敲定卡铂低温敏感脂质体(LTSL-Carplatin)的处方设计，并证明优化产品与热疗(HT)相结合的有效性，以杀灭黑色素瘤目标癌细胞系中的细胞。这项工作的动机是这样一个事实，即在2009年预计的140万新癌症病例中，超过50万例可以用基于铂的疗法进行治疗。随着一种含有阿霉素的热敏脂质体产品(LTSL-Dox，或ThermoDox(R))已经进入治疗复发性胸壁的I/II期人体临床试验，以及针对肝细胞癌的III期人体临床试验(由FDA进行特殊方案评估)，我们想要推出第二种抗癌药物--卡铂，它不仅具有化疗作用，而且还具有辐射增敏作用。这项建议的具体目标是：SA1：制备批次的LTSL-卡铂，并表征其药物和脂质稳定性、热稳定性、载药量、药物泄漏和触发释放曲线随温度和脂质体组成的变化；SA2：在单个肿瘤小鼠模型中比较Paraplatin(R)(卡铂注射剂)和LTSL-Carplatin。这些研究将为第二阶段SBIR奠定基础，届时将进一步研究药物和羟色胺应用的时间进程，以优化临床方案，并为后续的人体临床试验做出明智的选择。这种热激活药物的药用价值预计将是铂类药物可能解决的一些肿瘤学适应症(转移性黑色素瘤、肾脏、胰腺、卵巢、肺、头颈、膀胱和食道)的局部治疗的改善。 与公众健康相关：该项目建议扩展Celsion的热敏脂质体平台技术，将其包括一种包裹卡铂的热敏脂质体，潜在地开发成治疗转移性黑色素瘤的临床计划。Celsion公司目前有一种药物(ThermoDox(R))正在进行第三阶段的肝癌临床试验。该项目的两个方面包括1)进行配方设计和优化研究，以设计所需的生物性能特性，目标是在给药同时肿瘤部位加热的情况下实现定向药物释放，以及2)随后对受试者癌症的异种移植肿瘤小鼠模型进行疗效评估。一种新的脂质体包裹的卡铂有望极大地造福于癌症患者，因为这种包裹和靶向递送有望产生更好的安全性、耐受性和毒性。

DESCRIPTION (provided by applicant): The overall objective of this SBIR Phase 1 grant is to finalize the formulation design for a carboplatin-loaded Low Temperature Sensitive Liposome (LTSL-carboplatin) and demonstrate the effectiveness of the optimized product combined with HyperThermia (HT), to kill cells in a melanoma target cancer cell line. The work is motivated by the fact that of the 1.4 million new cases of cancer expected in 2009, over 0.5 million cases could be treated with platinum based therapies. With a thermal sensitive liposomal product containing doxorubicin, (LTSL-Dox, or ThermoDox(R)) already in Phase I/II human clinical trials for recurrent chest wall, and Phase III human clinical trials (with a special protocol assessment from the FDA) for hepatocellular carcinoma, we want to introduce a second anti-cancer agent, carboplatin, that is not only chemotherapeutic but is also a radiation sensitizer. The specific Aims of the proposal are: SA1: To prepare batches of LTSL-carboplatin and characterize its drug and lipid stability, thermal, drug loading, drug leakage, and triggered release profiles as a function of temperature and liposome composition; SA2: Compare Paraplatin(R) (carboplatin injection) and LTSL-carboplatin in a single tumored mouse model. These studies will lay the foundation for a Phase 2 SBIR in which the time course of drug and HT application will be further investigated to optimize clinical protocols and to allow well-informed choices to be made for subsequent human clinical trials. The medicinal value for this heat activated drug is expected to be an improvement in the local therapy of a number of oncology indications (metastatic melanoma, kidney, pancreatic, ovarian, lung, head & neck, bladder and esophageal) that platinum agents may address. PUBLIC HEALTH RELEVANCE: This project proposes to extend Celsion's heat sensitive liposome platform technology, which currently has a drug (ThermoDox(R)) in Phase III liver cancer clinical trials, to include a thermally sensitive liposome encapsulating carboplatin, for potential development into a clinical program for the treatment of metastatic melanoma. The two aspects of the project include 1) a formulation design and optimization study conducted to engineer desired bio-performance characteristics with the goal of accomplishing targeted drug release when dosing is accompanied by thermal warming of the tumor site, and 2) subsequent efficacy evaluations in a xenograft tumored mice model for the subject cancer. A new liposome encapsulated carboplatin is anticipated to greatly benefit cancer patients as the encapsulation and targeted delivery is expected to result in a superior safety, tolerance, and toxicity profile.