Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States of America.
Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States of America.
J Control Release. 2023 Nov;363:682-691. doi: 10.1016/j.jconrel.2023.09.048. Epub 2023 Oct 17.
While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant radiotherapy and systemic chemotherapy provide minimal local control or survival benefit and are dose-limited due to off-target side effects. We describe an implantable, biodegradable poly(1,2-glycerol carbonate) and poly(caprolactone) film with entrapped and covalently-bound paclitaxel enabling safe, controlled, and extended local delivery of paclitaxel achieving concentrations 10,000× tissue levels compared to systemic administration. Films containing entrapped and covalently-bound paclitaxel implanted in the tumor bed, immediately after resection of human cell line-derived chondrosarcoma and patient-derived xenograft liposarcoma and leiomyosarcoma in mice, improve median 90- or 200-day recurrence-free and overall survival compared to control mice. Furthermore, mice in the experimental film arm show no film-related morbidity. Continuous, extended, high-dose paclitaxel delivery via this unique polymer platform safely improves outcomes in three different sarcoma models and provides a rationale for future incorporation into human trials.
虽然手术是大多数实体器官癌症的主要治疗方法，但对于肉瘤等癌症，局部复发是临床上的一个问题，因为辅助放疗和全身化疗对这些癌症的局部控制或生存获益很小，并且由于脱靶副作用而受到剂量限制。我们描述了一种可植入的、可生物降解的聚（1,2-甘油碳酸酯）和聚己内酯薄膜，其中含有并通过共价键结合了紫杉醇，能够安全、可控和延长局部递送紫杉醇，实现浓度达到组织水平的 10,000 倍，而全身给药时则达不到这一水平。在切除人细胞系衍生的软骨肉瘤和患者来源的异种移植物脂肪肉瘤和平滑肌肉瘤后，立即将含有结合和共价结合紫杉醇的薄膜植入肿瘤床，可改善中位 90 天或 200 天无复发生存和总体生存，与对照组相比。此外，实验用薄膜组的小鼠没有出现与薄膜相关的发病率。通过这种独特的聚合物平台持续、延长、高剂量地输送紫杉醇可安全地改善三种不同肉瘤模型的结果，并为未来纳入人类试验提供了依据。
