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 (Mn = 1000 or 1500 or 2000)-block-polycaprolactone (Mn = 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 β-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.