pH-Sensitive nanodiamond co-delivery of retinal and doxorubicin boosts breast cancer chemotherapy

Herein for the first time we take the advantage of nanodiamonds (NDs) to covalently immobilize all-trans retinal (NPA) by an imine bond, allowing pH-mediated drug release. DOX is then physically adsorbed onto NPA to form an NPA@D co-loaded double drug in the sodium citrate medium, which is also susceptible to pH-triggered DOX dissociation. The cytotoxicity results showed that NPA@D could markedly inhibit the growth of DOX-sensitive MCF-7 cells in a synergetic way compared to the NP@D system of single-loaded DOX, while NPA basically showed no cytotoxicity and weak inhibition of migration. In addition, NPA@D can overcome the drug resistance of MCF-7/ADR cells, indicating that this nanodrug could evade the pumping of DOX by drug-resistant cells, but free DOX is nearly ineffective against these cells. More importantly, the fluorescence imaging of tumor-bearing mice in vivo and ex vivo demonstrated that the NPA@D was mainly accumulated in the tumor site rather than any other organ by intraperitoneal injection after 24 h, in which the fluorescence intensity of NPA@D was 19 times that of the free DOX, suggesting that a far reduced off-target effect and side effects would be expected. Therefore, this work presents a new paradigm for improving chemotherapy and reversing drug resistance using the ND platform for co-delivery of DOX and ATR.