Department of General Surgery , Peking University First Hospital , Beijing 100034 , China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety , National Center for Nanoscience and Technology , Beijing 100190 , China.
ACS Nano. 2018 Nov 27;12(11):10785-10796. doi: 10.1021/acsnano.8b01573. Epub 2018 Nov 12.
Pancreatic cancer (PCa) is one of the most lethal malignancies, with a 5 year survival rate of less than 8%. Current treatment regiments have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from poly-ADP-ribose polymerase inhibitors (PARPi) due to their biological properties in DNA repair. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to tumor sites at an adequate concentration is challenging. To address this issue, we have engineered an epidermal growth factor receptor (EGFR) targeting (with GE11 peptide) self-assembly amphiphilic peptide nanoparticle (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa. The GENP was relatively stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs in tumor milieu. Gemcitabine and olaparib showed strong synergistic actions in optimized conditions in vitro. The nanoparticle prolonged the half-life of both drugs and resulted in their tumor accumulation at the optimal therapeutic ratio in vivo. The drug-loaded nanoparticles were able to significantly suppress tumor growth in a murine PCa model with minimal side effects. Drug co-delivery of DNA damaging agents and PARP inhibitors via the GENP represents a promising approach for treatment of pancreatic cancers with molecular defects in the DNA repair pathway.
胰腺癌（PCa）是最致命的恶性肿瘤之一，5 年生存率不足 8%。目前的治疗方案对未经选择的患者反应率较低。然而，BRCA 突变的 PCa 患者亚组可能受益于聚 ADP 核糖聚合酶抑制剂（PARPi），因为它们在 DNA 修复方面具有生物学特性。当 PARPi 与其他化疗药物联合使用时，正常组织中经常观察到剂量限制毒性，并且将两种药物以足够的浓度递送到肿瘤部位是具有挑战性的。为了解决这个问题，我们设计了一种表皮生长因子受体（EGFR）靶向（带有 GE11 肽）自组装两亲肽纳米颗粒（GENP），以共同递送吉西他滨和 PARPi 奥拉帕利来治疗 BRCA 突变的 PCa。GENP 相对稳定，具有较高的包封效率，并能在肿瘤微环境中协调释放两种药物。吉西他滨和奥拉帕利在体外优化条件下表现出强烈的协同作用。纳米颗粒延长了两种药物的半衰期，并使其在体内达到最佳治疗比时在肿瘤中积累。载药纳米颗粒能够显著抑制小鼠 PCa 模型中的肿瘤生长，副作用极小。通过 GENP 共递送 DNA 损伤剂和 PARPi 代表了治疗 DNA 修复途径分子缺陷的胰腺癌的一种有前途的方法。
