IT-143, A Polymer Micelle Nanoparticle, Widens Therapeutic Window of Daunorubicin

Title:IT-143, A Polymer Micelle Nanoparticle, Widens Therapeutic Window of Daunorubicin

Volume: 4 Issue: 1

Author(s): Tara Lee Costich, Adam Carie, J. Edward Semple, Brad Sullivan, Tomas Vojkovsky, Tyler Ellis, Taylor Buley, Suzanne Bakewell and Kevin Sill

Affiliation:

Keywords: Anthracyclines, hydroxamic acid, in vivo efficacy, pharmacokinetics, polymer micelle, therapeutic window.

Abstract: 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.

Cite this article as:

Lee Costich Tara, Carie Adam, Semple J. Edward, Sullivan Brad, Vojkovsky Tomas, Ellis Tyler, Buley Taylor, Bakewell Suzanne and Sill Kevin, IT-143, A Polymer Micelle Nanoparticle, Widens Therapeutic Window of Daunorubicin, Pharmaceutical Nanotechnology 2016; 4 (1) . https://dx.doi.org/10.2174/2211738504666160310002348