title: LHD-Modified Mechanism-Based Liposome Coencapsulation of Mitoxantrone and Prednisolone Using Novel Lipid Bilayer Fusion for Tissue-Specific Colocalization and Synergistic Antitumor Effects.
abstract: Coencapsulation liposomes are of interest to researchers because they maximize the synergistic effect of loaded drugs. A combination regimen of mitoxantrone (MTO) and prednisolone (PLP) has been ideal for tumor therapy. MTO and PLP offer synergistic antitumor effects confirmed by several experiments in this research. The deduced synergistic mechanism is regulation of Akt signaling pathway including the targets of p-Akt, p-GSK-3β, p-s6 ribosomal protein, and p-AMPK by MTO reactivating PLP-induced apoptosis. The liposome fusion method is adopted to create coencapsulation liposomes (PLP-MTO-YM). Low molecular weight heparin-sodium deoxycholate conjugate (LHD) then is used as a targeting ligand to prove target binding and inhibition of angiogenesis. LHD-modified liposomes (PLP-MTO-HM) have a high entrapment efficiency around 95% for both MTO and PLP. DSC results indicate that both drugs interacted with liposomes to prevent drug leak during liposome fusion. DiD-C6-HM dyes colocalize well to tumor tissue, and coadministration of DiD-HM and C6-CM did not achieve dye colocalization until 24 h after administration. In both CT26 and B16F10 mouse model, PLP-MTO-HM shows a significantly higher tumor inhibition rate relative to the coadministration of MTO-HM and PLP-CM (p < 0.05 or p < 0.01). Thus, the coencapsulation system (PLP-MTO-HM) offers ideal antitumor effects relative to coadministration therapy due to enhanced synergistic effect, and this suggests a promising future for the tumor targeting vectors.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Zunyi Medical University , 201#, Dalian Road, Zunyi, Guizhou 563000, People's Republic of China.
authors.forename: Chengli
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Gynecology, West China Second University Hospital, Sichuan University , Chengdu 610041, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Gu
authors.initials: G
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Song
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Changyang
authors.initials: C
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Laboratory of Pharmaceutics, School of Medicine, Tsinghua University , 30#, Shuangqing Road, Haidian Dist, Beijing 100084, People's Republic of China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shihezi University , No. 221, North Fourth Road, Shihezi, Xinjiang 832000, People's Republic of China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008942:Mitoxantrone / Q000737:chemistry / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011239:Prednisolone / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008051:Lipid Bilayers; D008081:Liposomes; D011239:Prednisolone; D008942:Mitoxantrone
keywords: coencapsulation liposome; mitoxantrone; prednisolone sodium phosphate; synergistic antitumor effect; tissue-specific colocalization