Tara Lee Costich, Adam Carie, J. Edward Semple, Brad Sullivan, Tomas Vojkovsky, Tyler Ellis, Taylor Buley, Suzanne Bakewell and Kevin Sill Pages 3 - 15 ( 13 )
Background: Daunorubicin is an anthracycline family chemotherapeutic indicated for the treatment of acute myelogenous and acute lymphoblastic leukemia. Daunorubicin has a narrow therapeutic window.
Objective: To extend circulation time, decrease toxicity and improve the efficacy of daunorubicin, we encapsulated the drug in our nanoparticle drug delivery platform.
Method: IT-143 is a lyophilized formulation of daunorubicin, non-covalently encapsulated in the hydrophobic core of a polymer micelle. Hydroxamic acid-containing triblock polymers (ITP-102) support ferric crosslinking between the polymer chains, increasing stability for improved drug circulation and allowing a tumor targeted pH dependent release of the encapsulated daunorubicin.
Results: Formulation characterization demonstrates a 3.7% weight loading (w/w) of daunorubicin and an average particle diameter of 58 nm. IT-143 has an in vitro cytotoxicity of 60-100 nM, comparable to free drug cytotoxicity of 67-114 nM. We compared daunorubicin pharmacokinetics between free drug and IT-143 in vivo and the maximum serum concentration of daunorubicin from IT-143 was increased 50-fold. At equivalent doses IT-143 eliminated in vivo gross toxicity observed at daunorubicin’s maximum tolerated dose of 7.5 mg/kg, and increased the equitoxic dose to 17.5 mg/kg. Furthermore, IT-143 improved anti-tumor efficacy. Studies in 3 xenograft models (HCT116, HT-1080 and MNNG-HOS) compared intravenous bolus administration of IT-143 at equivalent and equitoxic doses to daunorubicin treatment. IT-143 increased the inhibition of tumor volume growth in all models.
Conclusion: These studies indicate that the encapsulation of daunorubicin by IT-143 widens the therapeutic window of daunorubicin treatment with reduced toxicity and increased antitumor efficacy.
Anthracyclines, hydroxamic acid, in vivo efficacy, pharmacokinetics, polymer micelle, therapeutic window.
Intezyne Technologies, Tampa, FL, USA.