title: Dual sensitive and temporally controlled camptothecin prodrug liposomes codelivery of siRNA for high efficiency tumor therapy.
abstract: The combination of chemotherapeutic drug camptothecin (CPT) and siPlk1 could prohibit cancer development with combined effects. To ensure the two drugs could be simultaneously delivered to tumor region with high loading content, and the modulator siPlk1 could be released in advance to down-regulate the Plk1 expression to improve the sensitivity of CPT to cancer cells, dual sensitive and temporally controlled CPT prodrug based cationic liposomes with siPlk1 codelivery system was constructed. The pH-sensitive zwitterionic polymer poly(carboxybetaine) (PCB) was conjugated with CPT through pH and esterase-sensitive ester bond to enhance the stability and loading content of CPT. CPT-based cationic liposomes consisted of CPT-PCB prodrug and cationic lipid DDAB were then constructed for siRNA codelivery for combination therapy. The dual sensitive CPT-PCB/siPlk1 lipoplexes simultaneously delivered the two drugs to tumor cells and enabled a temporally controlled release of two drugs, that the siRNA was quickly released after 4 h incubation due to the protonation of PCB in endosomes/lysosomes, and CPT was released in a sustained manner in response to pH and esterase and highly accumulated in nucleus after 12 h incubation. The CPT-PCB/siPlk1 lipoplexes induced significant cell apoptosis and cytotoxicity in vitro with a synergistic effect. Furthermore, the dual sensitive CPT-PCB lipoplexes enhanced the tumor accumulation of the two payloads and exhibited a synergistic tumor suppression effect in tumor-bearing mice in vivo, which proved to be a promising delivery system for codelivery of CPT and siPlk1 for cancer therapy.
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China.
authors.forename: Ruiyuan
authors.initials: R
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China. Electronic address: zhangzz08@126.com.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: xzhang@home.ipe.ac.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D000097869:Polo-Like Kinase 1
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D018797:Cell Cycle Proteins; D008081:Liposomes; D011355:Prodrugs; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1
keywords: Camptothecin prodrug; Combination therapy; Dual sensitive; Poly(carboxybetaine); Temporally controlled release