Synthesis and characterization of a PAMAM-OH derivative containing an acid-labile β-thiopropionate bond for gene delivery.
The present report describes the synthesis of a hydroxyl terminal PAMAM dendrimer (PAMAM-OH) derivative (PAMSPF). The hydroxyls of PAMAM-OH were attached to S-Methyl-l-cysteine (SMLC) via an acid-labile ester bond, named as β-thiopropionate bond, followed by modification with folic acid (FA) through a polyethylene glycol (PEG) linker. The degrees of attachment of SMLC and FA to the PAMAM-OH backbone were 83.9% and 12.8%, respectively. PAMSPF could condense DNA to form spherical nanoparticles with particle sizes of ∼200nm and remain stable in the presence of heparin and nuclease. The β-thiopropionate bond in PAMSPF was hydrolyzed completely and the DNA release rate was 95.8±3.3% after incubation under mildly acidic conditions at 37°C for 3h. PAMSPF/DNA was less cytotoxic to KB and HepG2 cells and exhibited a higher gene transfection efficiency than native PAMAM/DNA. The uptake assays showed that PAMSPF/DNA entered KB cells within 0.5h through folate receptor-mediated endocytosis and escaped from endosomes within 2h. In addition, PAMSPF/DNA displayed long circulation time along with excellent targeting of tumor sites in vivo. These findings demonstrate that PAMSPF is an excellent carrier for safe and effective gene delivery.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Kang
K
Chen
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Qing
Q
Chen
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Kuanglei
K
Wang
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Jia
J
Zhu
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Weinan
W
Li
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Wenpan
W
Li
Department of Pharmaceutics, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, PR China.
Lipeng
L
Qiu
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Guannan
G
Guan
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Mingxi
M
Qiao
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Xiuli
X
Zhao
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China. Electronic address: haiyang_hu@hotmail.com.
Haiyang
H
Hu
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China; Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, No. 199, Renai Road, Suzhou 215123, PR China. Electronic address: chendawei@syphu.edu.cn.
Dawei
D
Chen
D000143:Acids / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry*; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005492:Folic Acid / Q000737:chemistry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D007624:KB Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D014162:Transfection / Q000379:methods
D000143:Acids; D050091:Dendrimers; C104700:PAMAM Starburst; D011092:Polyethylene Glycols; C008366:3-mercaptopyruvic acid; D004247:DNA; D005492:Folic Acid; D003545:Cysteine
Acid-labile polymer; Cytotoxicity; Gene delivery; PAMAM-OH; Transfection; β-thiopropionate