Stability in systemic circulation, effective
tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a
drug. Accordingly, novel nanoparticles based on
polysaccharides that simultaneously presented prolonged systemic circulation and mitochondrial-targeted drug release were synthesized. First, the mitochondrial-targeted
polymer, 3,4-dihydroxyphenyl
propionic acid-
chitosan oligosaccharide-dithiodipropionic
acid-
berberine (
DHPA-CDB), was synthesized, which was used to form self-assembled
curcumin (Cur)-encapsulated cationic
micelles (
DHPA-CDB/Cur). Negatively charged oligomeric hyaluronic acid-3-carboxyphenylboronic
acid (oHA-PBA), a
ligand to
sialic acid and CD44, was further added to the surface of the preformed
DHPA-CDB/Cur core to shield the positive charges and to prolong blood persistence. oHA-PBA@
DHPA-CDB/Cur formed a covalent polyplex of oHA-PBA and
DHPA-CDB/Cur via the pH-responsive
borate ester bond between PBA and
DHPA. The mildly acidic
tumor environment led to the degradation of
borate ester bonds, thereby realizing the exposure of the cationic
micelles and causing a charge reversal from -19.47 to +12.01 mV, to promote cell internalization and mitochondrial localization. Compared with
micelles without the oHA-PBA modification, the prepared oHA-PBA@
DHPA-CDB/Cur showed enhanced cytotoxicity to PANC-1 cells and greater cellular uptake via receptor-mediated endocytosis. oHA-PBA@
DHPA-CDB/Cur was effectively targeted to the mitochondria, which triggered mitochondrial membrane depolarization. In mice xenografted with PANC-1 cells, compared with control mice, oHA-PBA@
DHPA-CDB/Cur resulted in more effective
tumor suppression and greater biosafety with preferential accumulation in the
tumor tissue. Thus, the long-circulating oHA-PBA@
DHPA-CDB/Cur, with mitochondrial targeting and
tumor environment charge-reversal capabilities, was shown to be an excellent candidate for subcellular-specific
drug delivery.