New Thermal Sensitive Carboplatin Liposome for Cancer

描述（由申请人提供）：该SBIR 1期资助的总体目标是最终确定载卡铂的低温敏感脂质体（LTSL-卡铂）的配方设计，并证明优化产品与高热（HT）结合杀死黑色素瘤靶癌细胞系中细胞的有效性。这项工作的动机是，在2009年预计的140万新的癌症病例中，超过50万例可以用铂基疗法治疗。由于含有阿霉素的热敏脂质体产品（LTSL-Dox或ThermoDox（R））已经在用于复发性胸壁的I/II期人体临床试验和用于肝细胞癌的III期人体临床试验（具有FDA的特殊方案评估）中，我们希望引入第二种抗癌剂卡铂，其不仅是化疗剂，而且还是辐射增敏剂。该提案的具体目的是：SA 1：制备LTSL-卡铂批次，并表征其药物和脂质稳定性、热、载药量、药物泄漏和触发释放曲线（作为温度和脂质体组成的函数）; SA 2：在单肿瘤小鼠模型中比较Paraplatin（R）（卡铂注射液）和LTSL-卡铂。这些研究将为2期SBIR奠定基础，其中将进一步研究药物和HT应用的时间过程，以优化临床方案，并为后续人体临床试验做出明智的选择。这种热活化药物的药用价值预计将改善铂类药物可能解决的许多肿瘤适应症（转移性黑色素瘤、肾脏、胰腺、卵巢、肺、头颈部、膀胱和食管）的局部治疗。 公共卫生相关性：该项目建议扩展Celsion的热敏脂质体平台技术，该技术目前有一种药物（ThermoDox（R））在III期肝癌临床试验中，包括封装卡铂的热敏脂质体，以潜在地开发成治疗转移性黑色素瘤的临床项目。该项目的两个方面包括1）进行制剂设计和优化研究，以设计所需的生物性能特征，目标是在给药伴随肿瘤部位的热升温时实现靶向药物释放，以及2）随后在异种移植瘤小鼠模型中对受试者癌症进行疗效评价。一种新的脂质体包封的卡铂预计将极大地受益于癌症患者，因为包封和靶向递送预计将导致上级安全性、耐受性和毒性特征。

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.