期刊
ACS NANO
卷 12, 期 11, 页码 10785-10796出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b01573
关键词
pancreatic cancer; BRCA2 mutation; synthetic lethality; drug co-delivery; self-assembly peptide nanoparticle
类别
资金
- National Key R&D Program of China [2018YFA0208900]
- Beijing Municipal Science & Technology Commission [Z161100000116035, Z161100000516038]
- Excellent Young Scientists Fund [31722021]
- National Natural Science Foundation of China [51673051, 21877023, 81572339, 81871954, 81672353]
- Beijing Nova Program [Z171100001117010]
- Beijing Natural Science Foundation [7172164]
- Youth Innovation Promotion Association CAS [2017056]
- Innovation Research Group of the National Natural Science Foundation [11621505]
- Key Research Project of Frontier science of the Chinese Academy of Sciences [QYZDJ-SSW-SLH022]
- National High Technology Research and Development Program of China [SS2015AA020405]
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.
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