Biomimetic nanocarriers for boosting chemotherapy by restoring breast cancer immunosurveillance
Worldwide Cancer Research
National Research Council
Triple-negative breast cancer (TNBC) still lacks effective treatment options; thus, innovative targeted therapies are urgently needed to tackle this disease. Emerging evidence suggests that chemotherapeutic drugs, including paclitaxel (PTX), can re-establish immunosurveillance by inducing immunogenic cell death (ICD) at the tumour site. Immune modulators are known to additionally boost ICD; in particular, clinical studies reveal that inhibitors of the indoleamine 2,3-dioxygenase (IDO1) pathway enhance the efficacy of traditional chemotherapeutics. However, poor bioavailability, off-target effects and difficulties in achieving therapeutic drug concentrations at the target tissue still hamper the breakthrough of this combined treatment.  We hypothesise that a specifically-devised biomimetic, bioresponsive and dual-loaded nanosystem will enhance both the antitumor cytotoxicity and the ICD effect of PTX by reversing the immunosuppressive effects of IDO1 overexpression at the breast cancer site. To demonstrate this hypothesis, we designed an innovative and biomimetic nanobinder (NB) constituted by a finely-tuned combination of redox-responsive PTX and IDO1 inhibitor prodrugs, and able to selectively reach the TNBC tissue by its preferential binding with endogenous human serum albumin (HSA). The specific aims of this proposal are: (i) to synthesize NBs containing an effective combination of PTX and IDO1 inhibitor prodrugs; (ii) to characterize their physicochemical properties, plasma stability and HSA selectivity; and (iii) to assess their ability to revert immune-tolerogenic effects and enhance antitumor efficacy in vitro. Our innovative and highly modular NB approach yearns to improve TNBC treatment and patient compliance by exploiting its unique features. This approach might also be applied to other solid tumours, paving the way for new therapeutic strategies in other oncological areas.
5.1 Pharmaceuticals