(548e) Charge-Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery

Many anticancer drugs are DNA-toxins targeting the 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 the nuclear localization of drugs. Thus, delivering such drugs directly to the nucleus would bypass these drug-resistance barriers. Cationic polymers such as polylysine (PLL) are capable of nuclear localization and may be used as drug carriers for nuclear drug delivery, but their cationic charges make them toxic and cause problems in vivo applications. Herein, we use PLL to demonstrate a pH-triggered charge-reversal concept to solve this problem. PLL's primary amines are amidized as acid-labile â-carboxylic amides (PLL/amide). The resulting 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 to the primary amines. The regenerated cationic 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 the charge-reversal PLL/amide (FA-PLL/amide-CPT). The conjugate is found to efficiently enter folate-receptor overexpressing cancer cells, and subsequently localize in the cell nuclei. CPT conjugated to the carrier via intracellular cleavable disulfide bonds shows much improved cytotoxicity.