A dual-sensitive poly(amino acid)/hollow mesoporous silica nanoparticle-based anticancer drug delivery system with a rapid charge-reversal property

Abstract The negative-to-positive surface charge-reversal capability introduced can reduce the nonspecific cellular uptake of the nanosized anticancer drug delivery systems (DDSs) and enhance the endocytosis capability by cancer cells. In this article, a novel dual-sensitive anticancer DDS with a rapid charge-reversal property was reported. Hollow mesoporous silica nanoparticle (HMSN) with a high drug loading capacity was applied as the “nanocontainer” to package the drug doxorubicin hydrochloride (DOX), then was coated by poly(aspartic acid)-graft-1-(3-aminopropyl) imidazole (PASP-g-API) through the redox-sensitive disulfide bond to obtain the DDS DOX@HMSN–SS–PASP-API. The imidazole group was not ionized at pH 7.4, resulting in a negatively charged surface of the DDS. But in the slightly acidic tumor microenvironment, the ionization of the imidazole group rapidly reversed the surface charge of the carriers for better uptake by cancer cells. After the endocytosis, the disulfide bond linking PASP-g-API and HMSN could be interrupted in the reducing environment intercellular, leading to the DOX release. The rapid charge-reversal property of the carriers was demonstrated by the in vitro studies, and the cell experiments proved that the carriers could enter the cancer cells much easier in the weakly acidic environment. Drug release studies indicated that DOX@HMSN–SS–PASP-API could release ~97% loaded DOX within 5 days with the glutathione concentration of 10 mM, demonstrating its sensitivity to redox. Also, DOX@HMSN–SS–PASP-API at pH 6.5 showed the best therapeutic effect among all the DDS groups. This dual-sensitive system with a rapid charge-reversal property should be a good complement to the researches of anticancer DDSs.