Drug-eluting Brachytherapy Implants for Chemo-radiation Therapy

用于放化疗的药物洗脱近距离放射治疗植入物

• 批准号: 10017919
• 负责人: SRINIVAS SRIDHAR
• 金额: $ 99.28万
• 依托单位: THERANANO, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017919
• 关键词: Alternative Therapies; American; Animals; Biocompatible Materials; Brachytherapy; Brachytherapy Seeds; Cancer Etiology; Cancer Patient; Canis familiaris; Cells; Cessation of life; Characteristics; Clinic; Clinical; Collaborations; Dana-Farber Cancer Institute; Development; Disease; Disease-Free Survival; Dose; Drug Kinetics; Drug Utilization; Ensure; Evaluation; Fostering; Foundations; Head and Neck Cancer; Hospitals; I125 isotope; Implant; In Vitro; International; Lead; Licensing; Local Therapy; Low Dose Radiation; Malignant Neoplasms; Malignant neoplasm of prostate; Medical center; Modality; Modeling; Mus; Operative Surgical Procedures; PC3 cell line; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Process; Property; Prostate; Prostate Cancer therapy; Radiation; Radiation Toxicity; Radiation therapy; Radiosensitization; Reproducibility; Risk; Safety; Science; Site; Small Business Technology Transfer Research; Solvents; Structure; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Translations; Treatment Efficacy; Tumor Suppression; Universities; Visual; Weight; Woman; base; cancer recurrence; chemoradiation; chemotherapy; clinically relevant; cohort; combinatorial; commercialization; curative treatments; docetaxel; improved; innovation; manufacturing scale-up; melting; men; mouse model; pre-clinical; rectal; response; side effect; success; treatment strategy; tumor

Theranano LLC in collaboration with internationally renowned prostate brachytherapy clinicians at Brigham and Womens Hospital and Dana Farber Cancer Institute and biomaterials experts at Northeastern University have developed an innovative combinatorial treatment strategy of Local ChemoRadiation Therapy (LCRT) using a modified brachytherapy spacer platform in the form of a INCeRT (ImplaNts for ChemoRadiation Therapy) spacer loaded with Docetaxel (DTX) to locally radiosensitize the prostate, enabling a synergistic cure with the use of lower radiation doses, thereby leading to less rectal radiation toxicity and minimal chemotherapeutic systemic side effects. Extensive results have demonstrated the efficacy and safety of the technology: (i) As monotherapy, in PC3 tumored mice, therapeutic doses of DTX can be delivered using intratumoral INCeRT spacers that lead to complete tumor suppression and disease free survival in 90% of animals. (ii) DTX-loaded INCeRT spacers show sustained synergistic radiosensitization. (iii) For combined LCRT, sustained DTX release prolongs the tumor suppression in irradiated mice. (iv) Toxicity as assessed by gross weight, and visual observation, is greatly reduced compared with IV administration of equivalent doses of DTX. These results have demonstrated the validity and feasibility of LCRT using INCeRT spacers. The Phase I STTR project demonstrated the feasibility of a solvent free hot-melt extrusion process of fabrication of InCeRT DTX spacers thus providing proof-of-principle of reproducible scale-up of manufacturing of INCeRT spacers. The HME spacers fabricated possessed all the desired material and drug characteristics, as well as in vitro release, PrCa model efficacy and toxicity profiles, achieving all the aims of the project. The Phase I project met and exceeded all its aims. In this Phase II STTR project Theranano will partner with outstanding collaborators to carry out IND-enabling GLP level manufacture and pre-clinical animal studies through the following aims: Specific Aim 1: Fabricate GLP quality InCeRT-DTX brachytherapy spacer implants GLP level manufacture of InCeRT-DTX implants will be carried out. The GLP implants will be thoroughly characterized for their physico-chemical properties. Specific Aim 2: Non-GLP therapeutic efficacy of INCeRT spacers in clinically relevant PCa mice models. The implant spacers fabricated in SA1 will be tested for release and therapeutic efficacy in PC3 cells and tumor models to ensure their bioactivity. Specific Aim 3: IND-enabling GLP pharmacokinetics and toxicity evaluation of INCeRT implants with brachytherapy in canine models. GLP level animal studies in canine models will be carried out for demonstrating the safety of the InCeRT-DTX implants in conjunction with I125 brachytherapy seeds. Specific Aim 4: Submission of FDA IND application An FDA IND application will be submitted and planning for a Phase I clinical trial will be initiated.

Theranano LLC与国际知名的前列腺近距离放射治疗临床医生合作 Brigham and Womens Hospital以及Dana Farber癌症研究所以及东北部的生物材料专家 大学已经制定了局部化学放疗治疗的创新组合治疗策略 （LCRT）使用INCERT形式的改良近距离放射治疗垫片平台（植入化学放疗的植入物 疗法）带有多西他赛（DTX）的垫片以局部放射敏感性，从而实现协同治疗 使用较低的辐射剂量，从而导致直肠辐射毒性较小，最小 化学治疗性全身副作用。 广泛的结果表明了技术的功效和安全性：（i）作为单一疗法，在 PC3肿瘤的小鼠，可以使用导致的肿瘤内incert垫片进行治疗剂量DTX 在90％的动物中，完全抑制肿瘤和无疾病生存。 （ii）DTX负载的Incert垫片显示 持续的协同放射敏化。 （iii）对于合并的LCRT，持续的DTX释放可延长肿瘤 在辐照小鼠中抑制。 （iv）通过毛重评估和视觉观察所评估的毒性极大地是 与静脉注射剂量剂量DTX相比，降低了。这些结果证明了 使用Incert垫片的LCRT有效性和可行性。 第一阶段的sttr项目证明 Incert DTX垫片的制造，从而提供了制造的可再现规模的原理证明 Incert垫片。制造的HME垫片具有所有所需的材料和药物特征， 除体外释放外，PRCA模型的功效和毒性概况，实现了项目的所有目标。这 第一阶段项目达到并超出了所有目标。在这一阶段，II STTR项目将与 杰出的合作者，进行辅助GLP水平制造和临床前动物研究 通过以下目的：特定目标1：制造GLP质量Incert-DTX近距离放射治疗垫片 植入物GLP水平生产Incert-DTX植入物将进行。 GLP植入物将是 其物理化学特性彻底特征。特定目标2：非GLP治疗功效 临床相关的PCA小鼠模型中的Incert垫片。 SA1制造的植入物垫片将是 测试了PC3细胞和肿瘤模型中的释放和治疗功效，以确保其生物活性。具体的 AIM 3：Incert植入物的GLP药代动力学和毒性评估 犬模型中的近距离疗法。将在犬模型中进行GLP水平的动物研究 证明了Incert-DTX植入物与I125近距离放射治疗种子的安全性。具体的 目标4：提交FDA IND申请将提交FDA IND申请并计划一个阶段 我将开始临床试验。