Abstract LB-190: IT-141 and IT-147, iron stabilized micellar nanoparticles for therapeutic and diagnostic applications
| Autor: | Kevin Sill, Tyler Ellis, Bradford Sullivan, Adam Carie, Suzanne Bakewell, Jyothi Sethuraman, Tara Lee Costich, J. Edward Semple, Taylor Buley, Tomas Vojkovsky |
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| Rok vydání: | 2016 |
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| Zdroj: | Cancer Research. 76:LB-190 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Site-specific delivery of oncology drugs using nanoparticle technology has been a decades-long goal. IT-141 and IT-147 are polymer micelles that encapsulate (i.e. physically entrap without covalent bonds) hydrophobic chemotherapeutics in the core of the micelle. IT-141 incorporates SN-38, the active moiety of irinotecan, in its core with a weight loading (v/v) of 2%. IT-141 shows increased pharmacokinetics in rat plasma, increased maximum tolerated dose (MTD) and improved anti-tumor efficacy in HCT116 and HT-29 xenograft models over irinotecan in all studies. IT-147 incorporates epothilone D, a microtubule-stabilizing anti-metabolite with a weight loading (v/v) of 2%. IT-147 shows increased pharmacokinetics in rat plasma, increased MTD and improved anti-tumor efficacy in HCT116 colorectal, A549 lung and NCI-H460 lung xenograft models over epothilone D free drug treatment. Both micelles are 70-100 nm diameter clusters of surfactant triblock copolymers stabilized by the interaction between iron and multiple polymer chains. The iron-polymer dative bonds are unstable at low pH, providing a mechanism for environment-dependent micelle stability and subsequent drug release. Furthermore, these stabilized micelles in vivo possess relaxivity constants suitable to provide contrast in magnetic resonance imaging (MRI). The spin-lattice relaxivity value (r1) was 7-16 mM-1s-1 and the spin-spin relaxivity values (r2) were 65-80 mM-1s-1. Small molecule complexes of iron do not typically provide sufficient MR contrast. Because contrast is not observed with individual iron complexes, and the MR contrast is directly related to the properties of the iron-stabilized nanoparticle, only intact nanoparticles provide contrast in MRI. When these iron-stabilized micelle formulations are administered to tumor bearing xenograft mice, increased contrast in the tumor is observed, peaking between 24 and 48 hours. MRI was performed with IT-141 in HCT116, HT-29, and A549 subcutaneous tumor models. IT-147 contrast imaging was performed in HCT116 and NCI-H460 subcutaneous, and MCF-7 orthotopic tumor models. Our technology has produced stable micelles that encapsulate chemotherapeutic drugs to include SN-38, daunorubicin, epothilone D, panobinostat, paclitaxel, and aminopterin with improved pharmacokinetics, decreased toxicity and increased efficacy. The MRI imaging results hold potential for use in the clinic where delivery of the chemotherapeutic-loaded nanoparticle can be monitored non-invasively. Citation Format: Kevin Sill, Tara Lee Costich, Adam Carie, Jyothi Sethuraman, Taylor Buley, Tyler Ellis, Tomas Vojkovsky, Bradford Sullivan, J. Edward Semple, Suzanne Bakewell. IT-141 and IT-147, iron stabilized micellar nanoparticles for therapeutic and diagnostic applications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-190. |
| Databáze: | OpenAIRE |
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