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.
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.
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Dipanjan
D
Pan
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Anne H
AH
Schmieder
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.
Kezheng
K
Wang
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Xiaoxia
X
Yang
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Angana
A
Senpan
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Grace
G
Cui
3. Kereos, Inc., Center for Emerging Technology, St. Louis, MO 63108, USA.
Kendall
K
Killgore
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Benjamin
B
Kim
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
John S
JS
Allen
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Huiying
H
Zhang
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Shelton D
SD
Caruthers
2. Radiology Department and Molecular Imaging Center, 4th Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China.
Baozhong
B
Shen
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Samuel A
SA
Wickline
1. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Gregory M
GM
Lanza
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D000077143:Docetaxel; D042783:Endothelial Cells / Q000187:drug effects; D005466:Fluorocarbons / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010740:Phospholipases / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D001952:Bridged-Ring Compounds; D005466:Fluorocarbons; D039302:Integrin alphaVbeta3; D011355:Prodrugs; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D010740:Phospholipases
lipase-labile docetaxel prodrug; nanoparticles; perfluorocarbon