New Thermal Sensitive Carboplatin Liposome for Cancer

新型热敏卡铂脂质体治疗癌症

• 批准号: 8003888
• 负责人: Robert A. Reed
• 金额: $ 18.29万
• 依托单位: CELSION CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-02 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003888
• 关键词: Address; American Cancer Society; Animal Model; Antineoplastic Agents; Biological Availability; Bladder; Blood; Cancer Patient; Cancer cell line; Carboplatin; Cell Line; Characteristics; Chest wall structure; Cisplatin; Clinical; Clinical Protocols; Clinical Trials; Colorectal; Data; Development; Devices; Dose; Doxorubicin; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug toxicity; Effectiveness; Encapsulated; Engineering; Esophageal; Esophageal Melanoma; Exposure to; Extravasation; Fever; Focused Ultrasound Therapy; Foundations; Future; Goals; Grant; Half-Life; Head and Neck Cancer; Head and neck structure; Heating; Hour; Human; Induced Hyperthermia; Injection of therapeutic agent; Kidney; Lipids; Liposomes; Local Therapy; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of urinary bladder; Marketing; Medical; Membrane; Metastatic Melanoma; Metastatic Neoplasm to the Liver; Modeling; Modest-Temperature Hyperthermia; Ovarian; Pancreas; Parents; Penetration; Performance; Permeability; Pharmaceutical Preparations; Pharmacoeconomic Study; Phase; Platinum; Platinum Compounds; Preclinical Testing; Preparation; Price; Primary carcinoma of the liver cells; Prostate; Protocols documentation; Radiation-Sensitizing Agents; Radiofrequency Interstitial Ablation; Recurrence; Refractory; Renal carcinoma; Research; Safety; Sales; Schedule; Site; Small Business Innovation Research Grant; Solid Neoplasm; Staging; Stream; Technology; Temperature; Testing; Time; Toxic effect; Vascular Permeabilities; Work; Xenograft procedure; base; cell killing; chemotherapeutic agent; clinical efficacy; cold temperature; conventional therapy; design; effective therapy; efficacy evaluation; improved; killings; manufacturing process; meetings; melanoma; microwave electromagnetic radiation; mouse model; nanoparticle; neoplastic cell; oncology; pre-clinical; preclinical study; public health relevance; sarcoma; scale up; soft tissue; targeted delivery; treatment program; tumor; tumor growth

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.

描述（由申请人提供）：SBIR 第一阶段资助的总体目标是完成卡铂负载低温敏感脂质体（LTSL-卡铂）的配方设计，并证明优化产品与 HyperThermia (HT) 相结合的有效性，杀死黑色素瘤靶癌细胞系中的细胞。这项工作的动机是，2009 年预计将有 140 万新发癌症病例，其中超过 50 万例可以接受铂类疗法的治疗。含有阿霉素的热敏脂质体产品（LTSL-Dox 或 ThermoDox(R)）已进入针对复发性胸壁的 I/II 期人体临床试验，以及 III 期人体临床试验（经过 FDA 的特殊方案评估）对于肝细胞癌，我们想引入第二种抗癌药物卡铂，它不仅具有化疗作用，而且还是放射增敏剂。该提案的具体目标是： SA1：制备 LTSL-卡铂批次，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与温度和脂质体成分的函数关系； SA2：在单个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 应用的时间进程，以优化临床方案，并为后续人体临床试验做出明智的选择。这种热激活药物的药用价值预计将改善铂类药物可能解决的多种肿瘤适应症（转移性黑色素瘤、肾、胰腺、卵巢、肺、头颈、膀胱和食管）的局部治疗。 公共健康相关性：该项目提议扩展 Celsion 的热敏脂质体平台技术，该技术目前有一种药物 (ThermoDox(R)) 处于 III 期肝癌临床试验中，包括封装卡铂的热敏脂质体，有可能开发成临床药物治疗转移性黑色素瘤的计划。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征，目标是在给药伴随肿瘤部位热升温时实现靶向药物释放，以及 2) 随后的疗效评估针对主题癌症的异种移植肿瘤小鼠模型。一种新的脂质体封装的卡铂预计将极大地造福于癌症患者，因为封装和靶向递送预计将带来优异的安全性、耐受性和毒性特征。