title: Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy.
abstract: Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG2C18-L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl-l-glutamyl2-histidyl-hexahydrobenzoic acid, HHG2C18) was used to construct a pH-sensitive lipid bilayer (HHG2C18-L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH2). Erlotinib and DOX were separately incorporated into HHG2C18-L and MSN-NH2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG2C18-L(E+D)). We confirmed that M-HHG2C18-L(E+D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH2, erlotinib released faster than DOX during the cellular transport. Additionally, HHG2C18-L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH2, leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E+D)) and simultaneous DRUG coadministration. M-HHG2C18-L(E+D) with sequential staggered drug release and pH-sensitive charge conversional properties showed great synergistic effects in antiproliferation and apoptosis of A549 human cancer cells in vitro. The in vivo study demonstrated that M-HHG2C18-L(E+D) exhibited considerable tumor accumulation and potent suppression of tumor growth in Lewis lung carcinoma tumor bearing mice. It was also demonstrated that M-HHG2C18-L(E+D) showed no systemic toxicity and possessed distinguished effect on extending survival period. These results suggested that M-HHG2C18-L(E+D) had great potential application in cancer treatment.
authors.affiliation: Lab of Nano-biology Technology, School of Physics and Electronics, Central South University, Changsha, Hunan 410083, China.
authors.forename: Yongju
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Su
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Xue
authors.affiliation: Lab of Nano-biology Technology, School of Physics and Electronics, Central South University, Changsha, Hunan 410083, China; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xuhui@csu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhangcan@cpu.edu.cn.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000737:chemistry; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D065546:Drug Liberation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D010713:Phosphatidylcholines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D004337:Drug Carriers; D010713:Phosphatidylcholines; D047428:Protein Kinase Inhibitors; D004317:Doxorubicin; D000069347:Erlotinib Hydrochloride
keywords: Charge conversion; DOX; Erlotinib; MSN; Synergistic therapy; pH-sensitive