Linear polyethyleneimine-based charge-reversal nanoparticles for nuclear-targeted drug delivery

Cationic polymer polyethyleneimine (PEI) can carry DNA across the cell membrane and enter the nucleus, and thus can be a very useful carrier for nuclear drug delivery; however, its highly positive charges make it toxic and not applicable for systemic drug delivery. Here, well-defined linear PEI (M-n = 1000 or 1500 or 2000)-block-polycaprolactone (M-n 2000) (LPEI-PCL) was synthesized and used to fabricate a pH-triggered charge-reversal nanoparticle to solve this problem. LPEI's secondary amines are amidized as acid-labile beta-carboxylic amides (LPEI/amide-PCL). LPEI/amide-PCL formed negatively charged nanoparticles with very low toxicity and low interaction with cells. Once in an acidic environment, the amides hydrolyze to regenerate the amine groups, producing LPEI-PCL nanoparticles carrying cationic charges. The LPEI-PCL escapes from the lysosomes and traverses into the nucleus. Folic-acid targeting groups are introduced to render the nanoparticles cancer-cell targeting capability. The nanoparticles efficiently enter folate-receptor overexpressing cancer cells and traverse to their nuclei. The DOX loaded in the carrier shows much improved cytotoxicity to cancer cells.