Theranostics 2014; 4(6):565-578. doi:10.7150/thno.7581

Research Paper

Anti-Angiogenesis Therapy in the Vx2 Rabbit Cancer Model with a Lipase-cleavable Sn 2 Taxane Phospholipid Prodrug using αvβ3-Targeted Theranostic Nanoparticles

Dipanjan Pan1*, Anne H. Schmieder1*, Kezheng Wang1,2, Xiaoxia Yang1, Angana Senpan1, Grace Cui1, Kendall Killgore3, Benjamin Kim1, John S. Allen1, Huiying Zhang1, Shelton D. Caruthers1, Baozhong Shen2, Samuel A. Wickline1, Gregory M. Lanza1✉

1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
2. Radiology Department and Molecular Imaging Center, 4th Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China.
3. Kereos, Inc., Center for Emerging Technology, St. Louis, MO 63108, USA.
* Equal first author co-contributors.

Abstract

In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of αvβ3-integrin targeted perfluorocarbon (PFC) nanoparticles (αvβ3-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of αvβ3-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of αvβ3-Dxtl-PD NP in endothelial cell culture was as effective as Taxol® or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of αvβ3-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same αvβ3-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane® given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that αvβ3-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit.

Keywords: lipase-labile docetaxel prodrug, perfluorocarbon, nanoparticles

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How to cite this article:
Pan D, Schmieder AH, Wang K, Yang X, Senpan A, Cui G, Killgore K, Kim B, Allen JS, Zhang H, Caruthers SD, Shen B, Wickline SA, Lanza GM. Anti-Angiogenesis Therapy in the Vx2 Rabbit Cancer Model with a Lipase-cleavable Sn 2 Taxane Phospholipid Prodrug using αvβ3-Targeted Theranostic Nanoparticles. Theranostics 2014; 4(6):565-578. doi:10.7150/thno.7581. Available from http://www.thno.org/v04p0565.htm