The combination
therapy of
cisplatin (CDDP) and
metformin (MET) is a clinical strategy to enhance therapeutic outcomes in
lung cancer. However, the efficacy of this combination is limited due to the asynchronous pharmacokinetic behavior of CDDP and MET, used as free drugs. Therefore, in this work,
hyaluronic acid-
cisplatin/
polystyrene-polymetformin (HA-CDDP/PMet) dual-
prodrug co-assembled nanoparticles were developed, with precise ratiometric co-delivery of CDDP and MET for chemo-
immunotherapy against
lung cancer. The HA-CDDP/PMet NPs showed a spherical morphology with an average particle size of 166.5 nm and a zeta potential of -17.4 mV at an HA-CDDP and PMet mass ratio of 1/1. The content of CDDP and MET in HA-CDDP/PMet NPs was 3.7% and 15.2%, respectively. In vitro antitumor effects of CDDP and MET resulted in an improved synergistic action on proliferation inhibition and apoptosis induction on Lewis
lung cancer cells. Moreover, in vivo by co-delivered HA-CDDP/PMet NPs into
tumor cells, with an excellent intracellular CDDP and MET cleavage. These nanoparticles exhibited significantly increased
tumor accumulation and
tumor growth inhibition and prolonged animal overall survival in Lewis
lung cancer bearing mice without nephrotoxicity, excess of free drugs and homo-
prodrugs. The synergistic effect of MET and CDDP in HA-CDDP/PMet NPs resulted in up-regulation of the cleaved
poly(ADP)-ribose polymerase (PARP)
protein to induce
tumor cell apoptosis, and down-regulation of the excision repair cross-complementation group 1 (ERCC1)
protein level to decrease the resistance to CDDP. The synergistic effect of MET and CDDP in HA-CDDP/PMet NPs also resulted in induction of the
adenosine monophosphate (
AMP)-activated protein kinase-α (AMPK-α) pathway and inhibition of the
mammalian target of rapamycin (mTOR), finally exerting a chemotherapeutic effect and modulating a potent immunotherapeutic function with an increase in CD4+ and CD8+ T cells, a concomitant decrease in regulatory T (Treg) cells, and an increased expression of the
cytokines IFN-γ and TNF-α. Therefore, the immunochemotherapy using CDDP and MET mediated by this dual
prodrug co-assembled nano-platform might provide a promising treatment strategy against
lung cancer.