Redox-responsive polyethyleneimine/tetrahedron DNA/doxorubicin nanocomplexes for deep cell/tissue penetration to overcome multidrug resistance

Abstract Deep penetration of nanomedicines to cancer cells and tissues is a main obstacle to conquering multidrug resistant (MDR) cancer. Here, we presented redox-responsive polyethyleneimine (disulfide cross-linked PEI, PSP)/tetrahedral DNA (TDNs)/doxorubicin (DOX) nanocomplexes (NCs), PSP/TDNs@DOX NCs, to accomplish tumor cell/tissue penetration for overcoming MDR. The NCs can respond to glutathione and DNase I to disassociate and release DOX. In vitro study revealed that the NCs (N/P = 30) with positive charge could be associated to cell membranes and “dig holes” on them, evoking the membrane-breaking for enhanced cellular internalization and bypassing endocytosis regardless of drug-resistant mechanism. Transwell and 3D tumor models study established that NCs can efficiently depart from cells through “holes leakage” and “infected” surrounding cells to penetrate into deep tumor tissues. In vivo study showed that the PSP/TDNs@DOX NCs exhibited superior tumor penetration and therapeutic efficiency in xenografted drug-resistant tumor mouse models including human breast (MCF-7/R) and ovarian (SKOV3/R) cancer, which represent MDR with characteristics of DOX efflux and impermeability, respectively.