A novel biodegradable gene carrier based on polyphosphoester
A novel biodegradable gene carrier based on polyphosphoester
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DOI：
10.1021/ja016062m
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发表时间：
2001-09-26
影响因子：
15
通讯作者：
Leong, KW
中科院分区：
文献类型：
--
作者：
Wang, J;Mao, HQ;Leong, KW
Gene therapy has been progressively developed with the hope that it will be an integral part of medical modalities in the future. 1 Viral vectors, while efficient in gene transfer in vivo, pose a safety concern unlikely to abate soon, rendering synthetic carriers attractive alternatives. Among existing synthetic vectors, cationic liposomes and polycations such as DC-Chol/DOPE and poly-(ethenyleneimine)(PEI) have been extensively studied for gene delivery. However, their toxicity and biocompatibility in vivo still leave much to be desired. 2 Biodegradable polycations are now emerging as a new generation of synthetic carriers. Biodegradable polymers, such as poly [R-(4-aminobutyl)-L-glycolic acid](PAGA) have been reported recently to mediate gene transfection in vitro and in vivo. 3 Here we report a new biodegradable polymeric carrier, namely, poly (2-aminoethyl propylene phosphate)(PPEEA) with a phosphate backbone and a β-aminoethoxy side chain. Synthesized in high molecular weights, this polymer binds DNA effectively, degrades over days under physiological condition, and shows remarkably low cytotoxicity.PPE-EA was synthesized from a precursor polymer 1, poly-(4-methyl-2-oxo-2-chloro-1, 3, 2-dioxaphospholane), which was obtained by ring-opening polymerization of 4-methyl-2-oxo-2-hydro-1, 3, 2-dioxaphospholane in the presence of triisobutylaluminum as initiator, followed by chlorination of PH according to the method described by Penczek et al. 4 The P-Cl bond in polymer 1 is highly reactive to nucleophiles. Reacting 1 with 10% excess of benzyl N-(2-hydroxyethyl) carbamate in chloroform using 4-(dimethylamino)-pyridine (DMAP) as a catalyst yielded intermediate polymer 2. Polymer 2 was purified by reprecipitation in ethyl ether with a recovery yield of 60%. The NMR spectra (1H, 13C, and 31P) indicated that all of the pendant chains were conjugated with the protected ethanolamine. The weight average molecular weight (Mw) of polymer 2 was 8.62× 104 with a polydispersity index of 1.95 as determined by GPC/LS/RI method (an absolute molecular weight measurement method, dn/dc calculated was 0.051 mL/g), 5 which corresponded to a number average degree of polymerization (DPn) of 140.5. Removal of
