Anti-angiogenesis therapy in the Vx2 rabbit cancer model with a lipase-cleavable Sn 2 taxane phospholipid prodrug using α(v)β₃-targeted theranostic nanoparticles.

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 α(v)β₃-integrin targeted perfluorocarbon (PFC) nanoparticles (α(v)β₃-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of α(v)β₃-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 α(v)β₃-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 α(v)β₃-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same α(v)β₃-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 α(v)β₃-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.

• Authors: Dipanjan Pan, Anne H Schmieder, Kezheng Wang, Xiaoxia Yang, Angana Senpan, Grace Cui, Kendall Killgore, Benjamin Kim, John S Allen, Huiying Zhang, Shelton D Caruthers, Baozhong Shen, Samuel A Wickline, Gregory M Lanza
• Journal: Theranostics (Theranostics) Vol. 4 Issue 6 Pg. 565-78 ( 2014) ISSN: 1838-7640 [Electronic] Australia
• PMID: 24723979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Bridged-Ring Compounds
• Fluorocarbons
• Integrin alphaVbeta3
• Prodrugs
• Taxoids
• Docetaxel
• taxane
• Phospholipases

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology, therapeutic use)
• Animals
• Apoptosis
• Bridged-Ring Compounds (chemistry, pharmacology, therapeutic use)
• Cells, Cultured
• Docetaxel
• Endothelial Cells (drug effects)
• Fluorocarbons (chemistry)
• Integrin alphaVbeta3 (antagonists & inhibitors, metabolism)
• Nanoparticles (chemistry, therapeutic use)
• Neoplasms, Experimental (drug therapy)
• Neovascularization, Pathologic (drug therapy)
• Phospholipases (metabolism)
• Prodrugs (chemistry, pharmacology, therapeutic use)
• Rabbits
• Taxoids (chemistry, pharmacology, therapeutic use)