Thermally Targeted Delivery of a c-Myc Inhibitory Polypeptide Inhibits Tumor Progression and Extends Survival in a Rat Glioma Model

Treatment of glioblastoma is complicated by the tumors’ high resistance to chemotherapy, poor penetration of drugs across the blood brain barrier, and damaging effects of chemotherapy and radiation to normal neural tissue. To overcome these limitations, a thermally responsive polypeptide was developed for targeted delivery of therapeutic peptides to brain tumors using focused hyperthermia. The peptide carrier is based on elastin-like polypeptide (ELP), which is a thermally responsive biopolymer that forms aggregates above a characteristic transition temperature. ELP was modified with cell penetrating peptides (CPPs) to enhance delivery to brain tumors and mediate uptake across the tumor cells’ plasma membranes and with a peptide inhibitor of c-Myc (H1). In rats with intracerebral gliomas, brain tumor targeting of ELP following systemic administration was enhanced up to 5-fold by the use of CPPs. When the lead CPP-ELP-fused c-Myc inhibitor was combined with focused hyperthermia of the tumors, an additional 3 fold increase in tumor polypeptide levels was observed, and 80% reduction in tumor volume, delayed onset of tumor-associated neurological deficits, and at least doubled median survival time including complete regression in 80% of animals was achieved. This work demonstrates that a c-Myc inhibitory peptide can be effectively delivered to brain tumors.

胶质母细胞瘤（glioblastoma）的治疗面临诸多挑战：肿瘤对化疗具有高度耐药性、药物难以穿透血脑屏障（blood brain barrier），且化疗与放疗会对正常神经组织造成损伤。为克服上述局限，本研究开发了一种热响应多肽（thermally responsive polypeptide），可通过聚焦热疗（focused hyperthermia）实现治疗肽向脑肿瘤的靶向递送。该肽载体以弹性蛋白样多肽（ELP）为基础，ELP是一种热响应性生物聚合物，在高于特征转变温度时会形成聚集体。研究人员通过接入细胞穿透肽（CPPs）以增强ELP向脑肿瘤的递送效率、介导肿瘤细胞跨细胞膜摄取，同时接入c-Myc肽抑制剂（H1）对ELP进行修饰。在患有脑内胶质细胞瘤（intracerebral gliomas）的大鼠模型中，经全身给药（systemic administration）后，借助细胞穿透肽（CPPs）可使ELP在脑肿瘤中的靶向富集水平提升最高达5倍。当将先导CPP-ELP融合型c-Myc抑制剂与肿瘤聚焦热疗联用时，可观察到肿瘤内多肽水平进一步提升3倍，同时实现肿瘤体积缩小80%、肿瘤相关神经功能缺损的发作延迟，中位生存期（median survival time）至少延长一倍，且80%的受试动物达到肿瘤完全缓解（complete regression）。本研究证实，c-Myc抑制肽可被有效递送至脑肿瘤部位。