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

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 to limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug-resistance barriers. Cationic polymer polylysine (PLL) is capable of nuclear localization and may be used as drug carriers for nuclear drug delivery, but its cationic charges make it toxic and cause problems in vivo applications. Herein, we use PLL to demonstrate a pH-triggered charge-reversal carrier to solve this problem. PLL's primary amines are amidized as acid-labile β-carboxylic amides (PLL/amide). The negatively charged PLL/amide has very low toxicity and low interactions 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 traverse to their nuclei. CPT conjugated to the carrier via intracellular cleavable disulfide bonds shows much improved cytotoxicity.