title: A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration.
abstract: Effective targeting drug delivery system for glioma treatment is still greatly challenged by the existence of the blood-brain barrier (BBB) and the intracranial overspreading of anti-tumor drug. Herein, we presented a dual-functional glioma targeting delivery of doxorubicin based on the PAMAM G5 dendrimer, modified with folic acid (FA) to target tumor cell, also borneol (BO), a well known safe material derived from traditional Chinese medicine, to facilitate the BBB permeability and reduce the toxicity of naked PAMAM. The intracranial transportation and glioma targeting ability were evaluated on the BBB model and C6 glioma cells in vitro. Also, pharmacokinetics and biodistribution were studied on C6 glioma-bearing rats in vivo. It indeed reduced the cytotoxicity of PAMAM against both HBMEC and C6 cells by coupling BO on the surface, while efficiently boosted BBB permeability with the improvement of transportation ratio by 2 folds to the BO-unmodified conjugates. Furthermore, conjugated FA increased total uptake amount by C6 cells leading to strong inhibition with the 3-fold lower IC50 value than FA-unmodified DOX conjugate. In comparison with DOX solution, FA-BO-PAMAM/DOX exhibited significantly prolonged half-life time and increased area under the curve and improved DOX accumulation in brain tumor. The tumor growth inhibition, in vivo, was significantly increased up to 57.4%. The median survival time of xenograft rats after administering FA-BO-PAMAM/DOX (28days) was significantly prolonged compared to free DOX (18days, P<0.05) or other controls. In conclusion, this strategy of novel targeting nanocarrier provides a promising method to increase the drug accumulation in the tumor site for therapy of glioma.
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: xuxiuling@zcmu.edu.cn.
authors.forename: XiuLing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: ljj0704@zcmu.edu.cn.
authors.forename: JingJing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: hansp1991@163.com.
authors.forename: ShunPing
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: 1223077184@qq.com.
authors.forename: ChengHao
authors.initials: C
authors.lastname: Tao
authors.affiliation: Laboratory of Clinical Pharmacy, Zhejiang Cancer Hospital, Hangzhou 310022, China. Electronic address: fangluo@zjcc.org.cn.
authors.forename: Luo
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: sunmoon1004@126.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: 80789694@qq.com.
authors.forename: JiaZhen
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: 1046698407@qq.com.
authors.forename: ZeHua
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: lifanzhu@zcmu.edu.cn.
authors.forename: FanZhu
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy; D001892:Camphanes / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D050091:Dendrimers / Q000009:adverse effects / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D042783:Endothelial Cells / Q000187:drug effects; D005492:Folic Acid / Q000737:chemistry*; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009457:Neuroglia / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D001892:Camphanes; D050091:Dendrimers; C104700:PAMAM Starburst; D004317:Doxorubicin; D005492:Folic Acid; C022871:isoborneol
keywords: BBB penetration; Borneol; Doxorubicin; FA-BO-PAMAM; Glioma; Targeted delivery; Toxicity