Oxaliplatin and Gedatolisib (PKI-587) Co-Loaded Hollow Polydopamine Nano-Shells with Simultaneous Upstream and Downstream Action to Re-Sensitize Drugs-Resistant Hepatocellular Carcinoma to Chemotherapy.

Multidrug resistance (MDR) is a key to the ineffectiveness of hepatocellular carcinoma (HCC) chemotherapy. Oxaliplatin (OXA), as one of the first-line chemotherapeutic drugs for HCC, abnormally activates the PI3K/AKT/mTOR signaling pathway and DNA damage repair pathway (NHEJ and HR), causing drug resistance and consequnet compromised efficacy. Herein, we developed a hollow polydopamine nanoparticle (H-PDA)-based nano-delivery system (O/P-HP) that contained OXA and a dual PI3K/mTOR inhibitor PKI-587 with complementary effects for combating drug resistance in cancer chemotherapy. The hollow structure of H-PDA endowed O/P-HP with high loading efficiencies of OXA and PKI-587-up to 49.6% and 7.0%, respectively. In addition, benefiting from the intracellular delivery of H-PDA as well as the highly concentrated drugs therein, O/P-HP inhibited the proliferation of OXA-resistant HR cells, resulting in a cell viability of only 17.63%. These values were significantly superior to those with OXA single-agent treatment and treatment with free OXA in combination with PKI-587. We examined the intrinsic mechanisms of the combination therapy: O/PHP had excellent anti-cancer effects via the simultaneous upstream and downstream action to re-sensitize HR cells to chemotherapy; OXA induced strong apoptosis via the direct platinum lesions on DNA molecules, while PKI-587 normalized the abnormally activated PI3K/AKT/mTOR signaling pathway and DNA damage repair pathway (NHEJ and HR) that could attenuate the effectiveness of OXA, thus resulting in inhibition of cell proliferation, migration and DNA repair enzyme activity and the augment of apoptotic effects. Such combination therapy, with simultaneous upstream and downstream action, may be a strategy for minimizing resistance for anti-cancer treatments.