Ultrahigh Drug-Loaded Micelles for the Treatment of Triple-Negative Breast Cancer and Their Bone Metastases

Triple-negative breast cancer (TNBC) is responsible for 15-20% of breast cancers and are unresponsive to therapies targeting estrogen, progesterone and HER2. Conventional chemotherapeutics are front-line for TNBC but resistance to these drugs make it a particularly challenging cancer to treat. Nanomedicine offers an exciting modality to better target, treat and potentially prevent resistance, e.g. by significantly increasing the maximum tolerated doses (MTD) of drug and consequently increasing the overall tumoral drug concentration. This effect is dependent on having a high drug loading capacity (LC), with ‘ultra’high drug loading (LC = 35%) observed to give the highest potential MTDs.<br/><br/>Herein, we have rationally designed through carefully tailoring pi-interacting and hydrogen-bond donating co-monomer ratios a polymeric nanocarrier library capable of loading paclitaxel with an LC in the ‘ultra’high range, and which also possess a tunable, Reactive Oxygen Specie (ROS)-triggered release mechanism. These particles were found to have field-leading MTDs for paclitaxel (150 mg/kg, dosed 2-times per week for 2 weeks). We further investigated the difference between fast or slow drug release formulations in a xenograft mammary fat pad model of TNBC (MDA-MB-231s). Using only a single dose of ultrahigh paclitaxel-loaded micelles at their MTD (150 mg/kg), the Slow-release group displayed a significantly longer median survival than the Fast-release (59.5* v 47.5 days); both were significantly better than conventional paclitaxel treatment, Taxol and the saline control (only 34 and 26.5 days respectively).<br/><br/>With this slow release formulation we further evaluated their ability to treat an aggressive bone metastasis model in mice intratibially inoculated with 4T1-bone-cloned cells. When treated 2x/week over 3 weeks we found significant reduction in bone lesions and tumor burden, and with complete tumor eradication in 2/7 mice when treated at 75 mg/kg paclitaxel or 5/8 when treated at 150 mg/kg.<br/><br/>This study therefore highlights the importance of controlling the release rate from nanomedicines as well as the importance of ultrahigh loading of nanoparticles. Together, these factors maximize the overall drug dose as well as its retention time in the tumor, ultimately improving therapeutic outcomes.