Functional Biodegradable Nitric Oxide Donor-Containing Polycarbonate-Based Micelles for Reduction-Triggered Drug Release and Overcoming Multidrug Resistance

Nitric oxide (NO), as a bioeffector to improve chemosensitivity by reversing multidrug resistance (MDR), is highly attractive for developing combinational delivery systems to deal with MDR tumors, while it is highly challenged by the stability and controlled release of NO during the pathway. Here we design and synthesize a cyclic nitrate trimethylene carbonate monomer (NTC), followed by ring-opening polymerization to prepare amphiphilic biodegradable polycarbonate-based copolymers as polymeric NO donors with tailored contents. The copolymer with desirable molecular weight is readily self-assembled to biodegradable micelles (NO-M) with a uniform size of 130 nm for highly stabilizing NO donors at the physiological conditions, while triggered NO release from micelles is performed at the intracellular reduction conditions. More importantly, NO-M shows superior inhibition of P-gP expression to enhance the chemosensitivity of multidrug-resistant MCF7 cells (MCF7/DOX^R). DOX-loaded NO-M (NO-M@DOX) realizes fast DOX release at the intracellular conditions, resulting in more intracellular DOX accumulation and higher antitumor activity mediated by the reduction-triggered NO/DOX release and NO-induced MDR reversal. Furthermore, the in vivo results show that NO-M@DOX effectively suppresses the MCF7/DOX^R tumor growth by a combination of directly NO-induced therapy and NO-mediated enhanced chemotherapy; meanwhile, the treatment with NO-M systems have much fewer side effects.