title: Design and evaluation of a phospholipase D based drug delivery strategy of novel phosphatidyl-prodrug.
abstract: A strategy is proposed to design a safe and simple amphiphilic prodrug delivery system, based on the elevated expression of phospholipase D (PLD) in cancer cells. The method utilizes the transphosphatidylation ability of bacterial PLD on alcohol groups and the hydrolysis activity of overexpressed PLD on phospholipids in cancer cells. Doxorubicin (DOX) was selected as a test drug, and the phosphatidyl-doxorubicin (PX) was synthesized by bacterial PLD. The PX prodrug could be readily self-assembled to nanoparticles with uniform size and was stable during storage and circulation. The pharmacokinetics and biodistribution investigations indicated DOX could be selectively released from PX in cancer cells triggered by the local overexpressed PLD, and PX could significantly prolong the half-life of DOX in the tumors and decrease the distribution in heart and kidney. Moreover, the PX prodrug enhanced cellular uptake in MCF-7/ADR cells, demonstrating it could reverse the multi-drug resistance. Consequently, the prodrug displayed favorable anticancer efficacy in the MCF-7/ADR xenograft model without the cardiotoxicity and nephrotoxicity of DOX. The results demonstrated that phosphatidyl modification method can be used as an efficient strategy to develop a promising nanoscale drug delivery system for some drugs.
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Nenghui
authors.initials: N
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Xuni
authors.initials: X
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China. Electronic address: dzhwei@ecust.edu.cn.
authors.forename: Dongzhi
authors.initials: D
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, China. Electronic address: fqwang@ecust.edu.cn.
authors.forename: Feng-Qing
authors.initials: FQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006868:Hydrolysis; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010739:Phospholipase D / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013302:Streptomyces / Q000201:enzymology; D014018:Tissue Distribution
chemical_list: D011355:Prodrugs; D004317:Doxorubicin; D010739:Phospholipase D
keywords: Doxorubicin; Phosphatidyl-prodrug; Phospholipase D; Reverse multidrug resistance; Triggered release