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

Abstract 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 β ‐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 cleavable disulfide bonds shows much improved cytotoxicity.