Figure 5. Tissue imaging and PK/PD/Efficacy studies of BETi-BPDs releasing the AZD5153-derivative T-API.

a, Representative whole organ Cy7.5 fluorescent imaging showing favorable accumulation of the T2 prodrug in tumor. b, Biodistribution of the T2 quantified using fluorescence signal (n=5) in homogenized tissue samples normalized by tissue weight; gut and bone marrow labeled in red font to highlight their low biodistribution; error bars represent SE. c,d, Efficacy in 4T1 orthotopic breast carcinoma model in Balb/C mice. T2 was dosed with T-API equivalents at 15 mg/kg, 30 mg/kg, or 60 mg/kg, twice per week for two weeks for a total of 4 doses, or at 60 mg/kg every other day for two weeks for a total of 6 doses to mice randomized with tumor sizes of 100 mm³ (BPDs contain ~12% wt. of T-API; 500 mg/kg dose BPD is 60 mg/kg API equivalent). AZD5153 was dosed qd as a PO bolus. e, Tumor pharmacokinetics of T2 Brush prodrug. Brush provides sustained release of T-API at the tumor site, and the levels of free active drug at 72h after injection are comparable to the peak concentration of tumor AZD5153 (at 2 h post dosing) at the non-tolerated dosage of 20 mg/kg qd. f, No significant weight loss was observed in any of the T2 regimens, while the highest tolerated dose of API at 10 mg/kg caused diarrhea and showed some weight loss. ^#: AZD5153 20-mg/kg cohort was taken down after ten days due severe weight loss.