title: pH-triggered sustained release of arsenic trioxide by polyacrylic acid capped mesoporous silica nanoparticles for solid tumor treatment in vitro and in vivo.
abstract: Arsenic trioxide (As2O3, ATO), a FDA approved drug for hematologic malignancies, was proved of efficient growth inhibition of cancer cell in vitro or solid tumor in vivo. However, its effect on solid tumor in vivo was hampered by its poor pharmacokinetics and dose-limited toxicity. In this study, a polyacrylic acid capped pH-triggered mesoporous silica nanoparticles was conducted to improve the pharmacokinetics and enhance the antitumor effect of arsenic trioxide. The mesoporous silica nanoparticles loaded with arsenic trioxide was grafted with polyacrylic acid (PAA-ATO-MSN) as a pH-responsive biomaterial on the surface to achieve the release of drug in acidic microenvironment of tumor, instead of burst release action in circulation. The nanoparticles were characterized with uniform grain size (particle sizes of 158.6 ± 1.3 nm and pore sizes of 3.71 nm, respectively), historically comparable drug loading efficiency (11.42 ± 1.75%), pH-responsive and strengthened sustained release features. The cell toxicity of amino groups modified mesoporous silica nanoparticles (NH2-MSN) was significantly reduced by capping of polyacrylic acid. In pharmacokinetic studies, the half time (t1/2β) was prolonged by 1.3 times, and the area under curve) was increased by 2.6 times in PAA-ATO-MSN group compared with free arsenic trioxide group. Subsequently, the antitumor efficacy in vitro (SMMC-7721 cell line) and in vivo (H22 xenografts) was remarkably enhanced indicated that PAA-ATO-MSN improved the antitumor effect of the drug. These results suggest that the polyacrylic acid capped mesoporous silica nanoparticles (PAA-MSN) will be a promising nanocarrier for improving pharmacokinetic features and enhancing the anti-tumor efficacy of arsenic trioxide.
authors.affiliation: Department of Pharmaceutics, Hubei University of Chinese Medicine, Wuhan, China.
authors.forename: Xuecheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Pharmaceutics, Hubei University of Chinese Medicine, Wuhan, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Manman
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Fei
authors.affiliation: Libraries of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Hongyue
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pharmaceutics, Hubei University of Chinese Medicine, Wuhan, China zgh1227@sina.com lifanzhu@zcmu.edu.cn.
authors.forename: Guohua
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Fanzhu
authors.initials: F
authors.lastname: Li
mesh_terms: D065966:Absorption, Physicochemical; D000180:Acrylic Resins / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000138:chemical synthesis; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D058608:Nanopores / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000180:Acrylic Resins; D000970:Antineoplastic Agents; D001152:Arsenicals; D020099:Coated Materials, Biocompatible; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D010087:Oxides; C006903:carbopol 940; D012822:Silicon Dioxide; D000077237:Arsenic Trioxide
keywords: arsenic trioxide; pH-triggered MSN; pharmacokinetics; solid tumor; sustained release