Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-09-04 , DOI: 10.1007/s13346-022-01226-2 Holly Maulhardt 1 , Shelagh Verco 1 , Michael Baltezor 2 , Alyson Marin 1 , Gere diZerega 1, 3
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This report describes local administration of large surface area microparticle docetaxel (LSAM-DTX: ~ 3.5- to 7.5-µm-sized particles with high relative surface area) in preclinical oncology models and in a clinical trial in urothelial carcinoma. Reductions in tumor volumes were found following intratumoral (IT) injection of LSAM-DTX into human urologic carcinoma cell lines and syngeneic murine renal and breast cancer cell lines. Compared to IT injections of docetaxel solution typically administered intravenously, IT LSAM-DTX results in 40-fold more docetaxel retained within the tumor. The long residence time of LSAM-DTX within the tumor acts as a drug depot, allowing for continuous release of docetaxel, exposing tumor cells to high, therapeutic levels of chemotherapeutic for several weeks. Local LSAM-DTX results in tumoricidal effects at the site of deposition as well as in distant tumors, and IT LSAM-DTX in combination with immune checkpoint inhibitor therapy reduces or eliminates metastatic spread. Tumoricidal effects of local LSAM-DTX are accompanied by immunomodulation including increases in innate and adaptive immune cells in the tumor microenvironment and peripheral blood. Encouraging clinical results indicate that local administration of LSAM-DTX may provide therapeutic benefits for non-muscle invasive bladder cancer and muscle invasive bladder cancer patients; treatments were well-tolerated with few local and systemic adverse events and negligible systemic docetaxel exposure. Results of preclinical and clinical investigations summarized here indicate that local administration of LSAM-DTX may augment tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity.
Graphical abstract
中文翻译：
对实体癌局部施用大表面积微粒多西紫杉醇可诱导直接细胞毒性和免疫介导的杀肿瘤作用：临床前和临床研究
本报告描述了大表面积微粒多西紫杉醇（LSAM-DTX：约 3.5 至 7.5 µm 大小的颗粒，具有高相对表面积）在临床前肿瘤模型和尿路上皮癌临床试验中的局部给药。将 LSAM-DTX 瘤内 (IT) 注射到人泌尿系癌细胞系以及同基因小鼠肾癌细胞系和乳腺癌细胞系中后，发现肿瘤体积减小。与通常静脉注射的多西紫杉醇溶液 IT 注射相比，IT LSAM-DTX 导致肿瘤内保留的多西紫杉醇多了 40 倍。 LSAM-DTX 在肿瘤内的长停留时间充当药物储存库，允许持续释放多西紫杉醇，使肿瘤细胞暴露于高治疗水平的化疗药物数周。局部 LSAM-DTX 在沉积部位以及远处肿瘤中产生杀肿瘤作用，而 IT LSAM-DTX 与免疫检查点抑制剂治疗相结合可减少或消除转移扩散。局部 LSAM-DTX 的杀肿瘤作用伴随着免疫调节，包括肿瘤微环境和外周血中先天性和适应性免疫细胞的增加。令人鼓舞的临床结果表明，局部给药 LSAM-DTX 可能为非肌层浸润性膀胱癌和肌层浸润性膀胱癌患者提供治疗益处；治疗耐受性良好，局部和全身不良事件很少，全身多西紫杉醇暴露可忽略不计。本文总结的临床前和临床研究结果表明，局部给予 LSAM-DTX 可以增强肿瘤对全身化疗、靶向治疗或免疫治疗的反应，而不会导致全身毒性。
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