Ultrasound augments on-demand breast tumor radiosensitization and apoptosis through a tri-responsive combinatorial delivery theranostic platform.

Advanced inoperable triple negative breast cancer (TNBC) are aggressive tumors with modest pathological response to neoadjuvant chemotherapy. Concomitant use of chemoradiotherapy improves pathological response rates, however dose dependent systemic toxicity of clinical radiosensitizers with poor circulation half-life and limited passive bioavailability limits their clinical utility. We address these challenges by rationally designing a stealth and tumor microenvironment responsive nano-conjugate platform for ultrasound mediated on-demand spatio-temporal delivery of plant flavonoid curcumin as a combinatorial regimen with clinically approved paclitaxel for the neoadjuvant chemoradiotherapy of locally advanced triple negative breast cancer (TNBC). Interestingly, focussed application of ultrasound at the orthotopic TNBC xenograft of NOD-SCID mice facilitated immediate infiltration of nano-conjugates at the tumor interstitium and conferred in vivo safety over marketed paclitaxel formulation. In addition, curcumin significantly potentiated the in vivo chemoradiotherapeutic efficacy of paclitaxel upon loading into nano-conjugates which gets further enhanced by the concurrent pulse of ultrasound as confirmed by PET-CT imaging alongwith a significant improvement in the mice survival. Quadrapeutic apoptotic effect by the combination of paclitaxel, curcumin, radiation, and ultrasound along with a reduction in tumor microvessel density and cell proliferation marker confers the broad chemo-radiotherapeutic potential of this regimen for radio-responsive solid tumors as well as metastatic niches.