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， 布里格姆妇女医院和达纳法伯癌症研究所和生物材料专家在东北 大学已经开发了一种创新的局部化疗和放疗的组合治疗策略 使用INCeRT（用于化学辐射的植入物）形式的改进的近距离放射治疗间隔器平台的LCRT 装载多西他赛（DTX）的治疗）间隔器，可使前列腺局部放射增敏，从而实现协同治疗 使用较低的辐射剂量，从而减少直肠辐射毒性， 化疗的全身副作用。 广泛的结果已经证明了该技术的有效性和安全性：（i）作为单一疗法， 在PC 3肿瘤小鼠中，可以使用肿瘤内INCeRT间隔物递送治疗剂量的DTX，其导致肿瘤细胞的增殖。 在90%的动物中完全抑制肿瘤和无病存活。(ii)载有DTX的INCeRT间隔物显示 持续协同放射增敏作用。(iii)对于联合LCRT，持续释放DTX抑制肿瘤生长， 抑制辐射小鼠。(iv)通过毛重和目视观察评估的毒性非常大， 与静脉注射等量的DTX相比，这些结果表明， 使用INCeRT间隔物的LCRT的有效性和可行性。 第一阶段STTR项目证明了无溶剂热熔挤出工艺的可行性， InCeRT DTX间隔物的制造，从而提供了制造的可再现的放大的原理证明 INCeRT间隔区的。制造的HME间隔物具有所有期望的材料和药物特性， 以及体外释放、PrCa模型功效和毒性特征，实现了项目的所有目标。的 第一阶段项目达到并超过了所有目标。在第二阶段的STTR项目中，Theranano将与 优秀的合作者进行IND使能GLP水平的生产和临床前动物研究 通过以下目的：具体目标1：制造GLP质量InCeRT-DTX近距离放射治疗间隔器 将进行InCeRT-DTX植入物的GLP水平生产。GLP植入物将 充分表征其物理化学性质。具体目标2：非GLP治疗有效性 INCeRT间隔区在临床相关PCa小鼠模型中的表达。在SA 1中制造的植入物垫片将 在PC 3细胞和肿瘤模型中测试其释放和治疗功效，以确保其生物活性。具体 目的3：INCeRT植入物的IND使能GLP药代动力学和毒性评价， 近距离放射治疗在犬模型中的应用将在犬模型中进行GLP水平动物研究， 证明了InCeRT-DTX植入物与I125近距离放射治疗粒子联合使用的安全性。具体 目标4：FDA IND申请的提交将提交FDA IND申请并计划阶段 将启动临床试验。