BIOTHERAPY OF BRAIN TUMORS BY RADIOIODINATED SAPC-DOPS NANOVESICLES

迫切需要用于治疗脑肿瘤的更有效的药物递送剂，脑肿瘤是最具侵袭性和难治性的癌症之一。SapC-DOPS，由saposin C组成的纳米囊泡 与二油酰磷脂酰丝氨酸（DOPS）偶联的SapC（SapC）已被证明具有肿瘤靶向特性，其包括穿过血脑肿瘤屏障和结合脂质肿瘤标志物细胞外磷脂酰丝氨酸 （PS）。它还在临床前胶质母细胞瘤（GBM）模型中表现出抗肿瘤活性。我们假设，赋予SapC-DOPS纳米囊泡放射性标记的亲脂性报告分子将创造一种新的药物， GBM的靶向放射性核素治疗（TRT）具有上级疗效。GBM的治疗选择非常有限，放射和/或化学疗法的标准疗法仅提供适度的生存益处 潜在的有害影响。为了解决这些问题，我们建议创建一种新的癌症选择性，靶向放射性标记的SapC-DOPS用于GBM的TRT。MTTI方法的一个独特优势在于新型化合物的前馈治疗机制：已知辐射暴露会增加肿瘤细胞中的PS外化，从而导致PS靶向的SapC-DOPS增强抗癌作用 纳米囊泡该提案得到了广泛的、已发表和未发表的初步数据、FDA孤儿药指定SapC-DOPS以及正在进行的I期临床试验的支持。

There is an urgent need for more effective drug delivery agents for treatment of brain tumors, which are among the most aggressive and intractable cancers. SapC-DOPS, a nanovesicle composed of saposin C (SapC) coupled to dioleoylphosphatidylserine (DOPS), has proven tumor targeting properties, which include crossing the blood-brain tumor barrier and binding the lipid tumor marker, extracellular phosphatidylserine (PS). It also exhibits antitumor activities in preclinical glioblastoma (GBM) models. We hypothesize that endowing SapC-DOPS nanovesicles with a radiolabeled lipophilic reporter will create a novel agent with superior efficacy for targeted radionuclide therapy (TRT) of GBMs. Treatment options for GBMs are very limited, and standard therapies with radiation and/or chemotherapy provide only modest survival benefits with potential deleterious effects. To address these issues, we propose to create a novel cancer-selective, targeted radiolabeled SapC-DOPS for TRT of GBMs. A unique advantage of MTTI's approach lies in the feedforward therapeutic mechanism of the novel compound: radiation exposure is known to increase PS externalization in tumor cells, thus leading to enhanced anticancer effects by PS-targeted SapC-DOPS nanovesicles. This proposal is backed by extensive, published and unpublished, preliminary data, the FDA Orphan Drug designation of SapC-DOPS, and an ongoing clinical phase I trial.