Charge-reversal polyamidoamine dendrimer for cascade nuclear drug delivery

Aims: Polyamidoamine (PAMAM) dendrimers with primary amine termini have been extensively explored as drug and gene carriers owing to their unique properties, but their amine-carried cationic charges cause nonspecific cellular uptakes, systemic toxicity and other severe problems in in vivo applications. Method: In this article, we report a charge-reversal approach that latently deactivates PAMAM's primary amines to negatively charged acid-labile amides in order to inhibit its nonspecific interaction with cells, but regenerates the active PAMAM once in acidic environments. Results: A cascade cancer cell nuclear drug delivery was achieved using the latently amidized PAMAM as the carrier conjugated with folic acid as the targeting group and a DNA-toxin drug camptothecin. The conjugate had low nonspecific interactions with cells, but easily entered cancer cells overexpressing folate receptors via receptor-mediated endocytosis. Subsequently, the endocytosed conjugate was transferred to acidic lysosomes, wherein the active PAMAM carrier was regenerated, escaped from the lysosome and then entered the nucleus for drug release. Conclusion: This reversible deactivation/activation makes PAMAM dendrimers useful nanocarriers for in vivo cancer cell nuclear-targeted drug delivery.