Figure 2. Tissue imaging and PK/PD/Efficacy studies of BETi-BPDs releasing OTX-015.
(a) Representative whole organ fluorescent imaging of Cy7.5-labled B4 in tumor and indicated organs (Cy7.5 IVIS; λex/em = 745/800 nm). (b) Biodistribution of B4 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) Anti-tumor efficacy in 4T1 orthotopic breast carcinoma model (Balb/C mice). B4 was dosed i.v. with equivalents of OTX-015 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 (n=5 pr group) randomized with pre-treatment tumor sizes of 100 mm3 (BPDs contain ~12% wt. of OTX-015; 500 mg/kg dose BPD is 60 mg/kg API equivalent). OTX-015 was dosed twice daily by oral gavage (bid; po). (e) Tumor PK of B4 prodrug. BETi-BPD provides sustained release of API at the tumor site, and the levels of free OTX-015 at 72 h after injection are close to 50% of the peak concentration of the parent drug OTX-015 2 h are an oral dosage of 200 mg/kg bid. (f) No weight loss was observed in any of the B4 regimens, while the maximum tolerated dose of API (100 mg/kg) caused diarrhea and some weight loss. #: The OTX-015 200-mg/kg bid cohort was taken down after eleven days due severe weight loss.