COMbined Physico-chemical Experimental Therapy to Improve prognosis against Triple negative breast by Immune activation and laser ablation OptimizatioN.

The lack of specific cellular targets makes triple-negative breast cancer (TNBC) hardly treatable and often leads to the worst prognosis. TNBC can moderately respond to chemotherapy, but the systemic administration of drugs often leads to toxicity have many patients must stop the cure. Safe and reliable alternatives are needed. The ablative laser photothermal (PTT) is theoretically very promising, but its clinical translation is still limited due to the potential detrimental effects on the surrounding parenchyma. In the last years the PI is optimizing, in collaboration with the Politecnico of Milano, a new laser able to both improve the anatomical resolution and reduce the intensity of stimulation by the use of gold NP antennas directly injected into the mass of TNBC bearing mice. This project aims to combine the physical effect of gold NPs upon PTT to a chemical activity due to the topical release of Doxorubicin (Dox) incorporated into temperature breakable silver-gold nano-hollow loaded. This strategy is somehow in line with the currently used combined approach with radiotherapy and chemotherapy but with an enormous advancement both as safety profile (the laser-gold stimulation can accurately involve the tumour) and specific (Dox will be confined to the critical area by a single treatment). Nano based therapy will also be applied to induce a prolonged immunosurveillance against the potential cluster of TNBC cells remained after the stimulation. More specifically, we will systemically treat mice with biodegradable poly(d,l-lactic-co-glycolic acid) PLGA incorporating an antibody targeting the Programmed cell death protein 1 (PD-1). Indeed, anti-PD-1 therapy has already demonstrated an excellent efficacy at the preclinical and clinical levels in TNBC. This project firmly fits the call and aims at demonstrating that Nanomedicine is crucial to allow the triple action (thermal ablation, topical chemotherapy, and systemic immunosurveillance) that will be exerted by this treatment.