title: Efficient Delivery of DOX to Nuclei of Hepatic Carcinoma Cells in the Subcutaneous Tumor Model Using pH-Sensitive Pullulan-DOX Conjugates.
abstract: A series of pullulan-doxorubicin conjugates (Pu-DOXs) were investigated for effectively delivering DOX to nuclei of hepatic carcinoma cells in subcutaneous tumor model. These Pu-DOXs were prepared by conjugating DOX onto pullulan molecule via pH-responsive hydrazone bond using spacers with different alkane chain length. The highest drug loading content of Pu-DOXs went up to nearly 50%, and the diameter of Pu-DOX nanoparticles ranged from 50 to 170 nm, as measured by DLS and TEM. These Pu-DOX nanoparticles could rapidly release DOX in the acidic environment at pH = 5.0 while being kept relatively stable in neural conditions. The in vitro cell coculture experiments revealed that these Pu-DOX nanoparticles were selectively internalized by hepatic carcinoma cells through receptor-mediated endocytosis via asialoglycoprotein receptor on the hepatic carcinoma cell surface. DOX was rapidly released from Pu-DOX nanoparticles in acidic endosome/lysosome, diffused into cell nuclei due to its strong affinity to nucleic acid, inhibited the cell proliferation, and accelerated the cell apoptosis. In the nude mice subcutaneous hepatic carcinoma model, Pu-DOX nanoparticles efficiently accumulated in the tumor site through the enhanced permeation and retention effect. Then DOX was specifically internalized by hepatic carcinoma cells and rapidly diffused into the nuclei of cells. Compared with the control group in in vivo experiments, these Pu-DOX nanoparticles effectively inhibited solid tumor growth, prolonging the lifetime of the experimental animal. These pH sensitive nanoparticles might provide an important clinical implication for targeted hepatic carcinoma therapy with high efficiency and low systematic toxicity.
authors.affiliation: ‡College of Biomedical Engineering, Chongqing Medical University, Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
authors.forename: Huanan
authors.initials: H
authors.lastname: Li
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Cui
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Sui
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Shaoquan
authors.initials: S
authors.lastname: Bian
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Yujiang
authors.initials: Y
authors.lastname: Fan
authors.affiliation: †National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
authors.forename: Xingdong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry* / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D005936:Glucans / Q000737:chemistry*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D005936:Glucans; D053769:Nanocapsules; D004317:Doxorubicin; C009109:pullulan
keywords: doxorubicin; hepatic carcinoma; nanoparticles; pH-sensitive; pullulan