New class of polymers for the delivery of macromolecular therapeutics
New class of polymers for the delivery of macromolecular therapeutics
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DOI：
10.1021/bc990072j
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发表时间：
1999-11-01
影响因子：
4.7
通讯作者：
Davis, ME
中科院分区：
文献类型：
--
作者：
Gonzalez, H;Hwang, SJ;Davis, ME
阳离子聚合物显示出用于大分子治疗剂的体外和体内递送的前景。已知的阳离子聚合物，聚（L）赖氨酸（PLL）和聚乙烯亚胺（PEI）已经以天然和修饰形式用于递送质粒DNA（pDNA），并显示出不同水平的毒性。在这里，我们报告了一类新的阳离子聚合物，专门设计用于提供大分子治疗的准备。通过使双官能化β-CD单体（AA）与其它双官能化共聚单体（BB）共聚以形成AABBAABB产物来合成线性阳离子含β-环糊精（β-CD）的聚合物（CD-聚合物）。β-CD聚合物能够结合类似于5 kbp的pDNA，上述聚合物与DNA（+/-）的电荷比为1.5，在高于5+/-的电荷比下将结合的pDNA压实成大小约100-150 nm的颗粒，并在高于10+/-的电荷比下抑制培养的细胞。用新的β-CD聚合物进行体外转染与我们用PEI和Lipofectamine获得的最佳结果相当。在无血清转染中观察到一些细胞系依赖性毒性;然而，在10%血清中进行的转染中，在高达70+/-的电荷比下没有显示毒性。小鼠单次IV和IP剂量高达200 mg/kg时未显示死亡。
Cationic polymers show promise for the in vitro and in vivo delivery of macromolecular therapeutics. Known cationic polymers, e.g., poly(L)lysine (PLL) and polyethylenimine (PEI), have been employed in native and modified forms for the delivery of plasmid DNA (pDNA) and reveal varying levels of toxicity. Here, we report the preparation of a new class of cationic polymers that are specifically designed to deliver macromolecular therapeutics. Linear, cationic, beta-cyclodextrin (beta-CD)-containing polymers (CD-polymers) are synthesized by copolymerizing difunctionalized beta-CD monomers (AA) with other difunctionalized comonomers (BB) such that an AABBAABB product is formed. The beta-CD polymers are able to bind similar to 5 kbp pDNA above polymer to DNA (+/-) charge ratios of 1.5, compact the bound pDNA into particles of approximately 100-150 nm in size at charge ratios above 5+/-, and transfect cultured cells at charge ratios above 10+/-. In vitro transfections with the new beta-CD-polymers are comparable to the best results obtained in our hands with PEI and Lipofectamine. Some cell line-dependent toxicities are observed for serum-free transfections; however, no toxicity is revealed at charge ratios as high as 70+/- in transfections conducted in 10% serum. Single IV and IP doses as high as 200 mg/kg in mice showed no mortalities.