Epothilones have demonstrated promising potential for oncology applications but suffer from a narrow therapeutic window.\nEpothilone D stabilizes microtubules leading to apoptosis, is active against multidrug-resistant cells, and is efficacious in animal\ntumor models despite lack of stability in rodent plasma. Clinical development was terminated in phase II due to dose limiting\ntoxicities near the efficacious dose. Taken together, this made epothilone D attractive for encapsulation in a stabilized polymer\nmicelle for improved safety and efficacy. We have designed a library of triblock copolymers to develop IT-147, a lead formulation\nof epothilone D that extends plasma circulation for accumulation in the tumor environment, and potentially decrease systemic\nexposure to reduce dose limiting toxicities. The drug loading efficiency for IT-147 exceeds 90%, is 75nm in diameter, and\ndemonstrates pH-dependent release of epothilone D without chemical conjugation or enzymatic activation. Administration of\nIT-147 at 20mg/kg increases exposure of epothilone D to the plasma compartment over 6-fold compared to free drug. At the same\ndose, 20mg/kg epothilone D fromIT-147 is considered the no observed adverse effect level (NOAEL) but is the maximum tolerated\ndose for free drug. Consequently, IT-147 is positioned to be a safer, more effective means to deliver epothilone D.
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