title: Tumor targeted delivery of octreotide-periplogenin conjugate: Synthesis, in vitro and in vivo evaluation.
abstract: Periplogenin (PPG), a cardiac glycoside prepared from Cortex periplocae, with similar structure to bufalin, has been found to induce apoptosis in many tumor cells. However, lots of cardiac glycosides possessing strong antitumor activity in vitro have still not passed phase I clinical trials, mostly due to poor tumor selectivity and systemic toxicity. To overcome this drawback, we designed octreotide-periplogenin (OCT-PPG) conjugate by coupling PPG-succinate to the amino-terminal end of octreotide. In comparison with free PPG, the conjugate exhibited significantly stronger cytotoxicity on HepG2 cells (SSTRs overexpression) but much less toxicity in L-02 cells. After intravenous injection of OCT-PPG conjugate into H22 tumor-bearing mice, its total accumulation in tumor was 2.3 fold higher than that of free PPG, but was 0.71- and 0.84-fold lower in heart and liver, respectively, suggesting somatostatin-mediated target delivery of PPG into the tumor tissue and reduced distribution in heart and liver. In vivo studies using H22 tumor model in mice confirmed the remarkable therapeutic effect of this conjugate. These results suggested that OCT-PPG conjugate could provide a new approach for clinical application of cardiac glycosides and as a targeting agent for cancer therapy.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Wen-Qian
authors.initials: WQ
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Yuan-Wen
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Omari-Siaw
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Tong
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China; School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China. Electronic address: yjn@ujs.edu.cn.
authors.forename: Jiang-Nan
authors.initials: JN
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, People's Republic of China. Electronic address: xmxu@ujs.edu.cn.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004073:Digitoxigenin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015282:Octreotide / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004073:Digitoxigenin; C008813:periplogenin; D015282:Octreotide
keywords: Cardiac glycosides; Octreotide; Octreotide-periplogenin conjugate; Periplogenin; Target delivery