Charge-Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery

被引:292
作者
Zhou, Zhuxian [1 ]
Shen, Youqing [1 ,2 ]
Tang, Jianbin [2 ]
Fan, Maohong [1 ]
Van Kirk, Edward A. [3 ]
Murdoch, William J. [3 ]
Radosz, Maciej [1 ]
机构
[1] Univ Wyoming, Dept Chem & Petr Engn, Laramie, WY 82071 USA
[2] Zhejiang Univ, Ctr Bionanoengn, Dept Chem & Biochem Engn, Hangzhou 310027, Zhejiang, Peoples R China
[3] Univ Wyoming, Dept Anim Sci, Laramie, WY USA
基金
美国国家科学基金会;
关键词
BLOCK-COPOLYMER MICELLES; POLY-L-LYSINE; MULTIDRUG-RESISTANCE; NANOPARTICLES; LOCALIZATION; CAMPTOTHECIN; DENDRIMERS; RELEASE; PHARMACOKINETICS; TRANSFECTION;
D O I
10.1002/adfm.200900825
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
DNA-toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane- associated but also many intracellular drug-resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug-resistance barriers. The cationic polymer poly(L-lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in-vivo applications. Herein, PLL is used to demonstrate a pH- triggered charge-reversal carrier to solve this problem. PLL's primary amines are amidized as acid-labile beta-carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid-labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer-cell targeted nuclear-localization polymer-drug conjugate has, thereby, been developed by introducing folic-acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA-PLL/amide-CPT). The conjugate efficiently enters folate-receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular clevable disulfide bonds shows much improved cytotoxicity.
引用
收藏
页码:3580 / 3589
页数:10
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