Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer with Breast Cancer 2 (BRCA2) Mutation
Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer with Breast Cancer 2 (BRCA2) Mutation
复制标题
表皮生长因子受体靶向肽纳米颗粒同时递送吉西他滨和奥拉帕尼治疗伴有乳腺癌 2 (BRCA2) 突变的胰腺癌
DOI：
10.1021/acsnano.8b01573
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发表时间：
2018-11-01
期刊：
影响因子：
17.1
通讯作者：
Yang, Yinmo
中科院分区：
文献类型：
--
作者：
Du, Chong;Qi, Yingqiu;Yang, Yinmo
胰腺癌（Pancreatic cancer，PCa）是最致命的恶性肿瘤之一，其5年生存率低于8%。目前的治疗方案对COPD患者的应答率较低。然而，具有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修复中具有生物学特性。当PARPi与其他化学疗法组合时，经常观察到正常组织中的剂量限制性毒性，并且以足够的浓度将两种药物共同递送至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（与GE 11肽）自组装两亲性肽纳米颗粒（GENP），以共同递送吉西他滨和PARPi奥拉帕尼来治疗BRCA突变型PCa。GENP相对稳定，包封率高，在肿瘤环境中可协同释放两种药物。在优化的体外实验条件下，吉西他滨和奥拉帕尼表现出较强的协同作用。纳米颗粒延长了两种药物的半衰期，并导致它们在体内以最佳治疗比例在肿瘤中蓄积。载药纳米颗粒能够显著抑制小鼠PCa模型中的肿瘤生长，副作用最小。通过GENP共同递送DNA损伤剂和PARP抑制剂的药物代表了治疗DNA修复途径中存在分子缺陷的胰腺癌的一种有前途的方法。
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.