Suppression of Inflammation in a Mouse Model of Rheumatoid Arthritis Using Targeted Lipase-labile Fumagillin Prodrug Nanoparticles

Overview

Journal Biomaterials

Specialty Biomedical Engineering

Date 2012 Aug 28

PMID 22922023

Citations 30

Authors

Hui-Fang Zhou

Huimin Yan

Angana Senpan

Samuel A Wickline

Dipanjan Pan

Gregory M Lanza

Christine T N Pham

Affiliations

Soon will be listed here.

Abstract

Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that α(v)β(3)-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases.

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References

GARRETT E, EBLE T . Studies on the stability of fumagillin. I. Photolytic degradation in alcohol solution. J Am Pharm Assoc Am Pharm Assoc. 1954; 43(7):385-90. DOI: 10.1002/jps.3030430702. View

ARFIN S, Kendall R, Hall L, Weaver L, Stewart A, Matthews B . Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent enzymes. Proc Natl Acad Sci U S A. 1995; 92(17):7714-8. PMC: 41216. DOI: 10.1073/pnas.92.17.7714. View

Boles K, Schmieder A, Koch A, Carano R, Wu Y, Caruthers S . MR angiogenesis imaging with Robo4- vs. alphaVbeta3-targeted nanoparticles in a B16/F10 mouse melanoma model. FASEB J. 2010; 24(11):4262-70. PMC: 3066028. DOI: 10.1096/fj.10-157933. View

Wang J, Lou P, Henkin J . Selective inhibition of endothelial cell proliferation by fumagillin is not due to differential expression of methionine aminopeptidases. J Cell Biochem. 2000; 77(3):465-73. View

Schmieder A, Caruthers S, Zhang H, Williams T, Robertson J, Wickline S . Three-dimensional MR mapping of angiogenesis with alpha5beta1(alpha nu beta3)-targeted theranostic nanoparticles in the MDA-MB-435 xenograft mouse model. FASEB J. 2008; 22(12):4179-89. PMC: 2614609. DOI: 10.1096/fj.08-112060. View

Schmieder A, Winter P, Caruthers S, Harris T, Williams T, Allen J . Molecular MR imaging of melanoma angiogenesis with alphanubeta3-targeted paramagnetic nanoparticles. Magn Reson Med. 2005; 53(3):621-7. DOI: 10.1002/mrm.20391. View

Sin N, Meng L, Wang M, Wen J, Bornmann W, Crews C . The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci U S A. 1997; 94(12):6099-103. PMC: 21008. DOI: 10.1073/pnas.94.12.6099. View

Cai K, Caruthers S, Huang W, Williams T, Zhang H, Wickline S . MR molecular imaging of aortic angiogenesis. JACC Cardiovasc Imaging. 2010; 3(8):824-32. PMC: 3425389. DOI: 10.1016/j.jcmg.2010.03.012. View

Pan D, Sanyal N, Schmieder A, Senpan A, Kim B, Yang X . Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug. Nanomedicine (Lond). 2012; 7(10):1507-19. PMC: 3498609. DOI: 10.2217/nnm.12.27. View

10.

Klimiuk P, Sierakowski S, Domyslawska I, Fiedorczyk M, Chwiecko J . Reduction of soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular endothelial growth factor levels in serum of rheumatoid arthritis patients following multiple intravenous infusions of infliximab. Arch Immunol Ther Exp (Warsz). 2004; 52(1):36-42. View

11.

Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N . GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene. 2006; 26(18):2606-20. DOI: 10.1038/sj.onc.1210074. View

12.

Hannig G, Bernier S, Hoyt J, Doyle B, Clark E, Karp R . Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI-2458. Arthritis Rheum. 2007; 56(3):850-60. DOI: 10.1002/art.22402. View

13.

Ma A, Fung T, Lin R, Chung M, Yang D, Ekker S . Methionine aminopeptidase 2 is required for HSC initiation and proliferation. Blood. 2011; 118(20):5448-57. PMC: 3342862. DOI: 10.1182/blood-2011-04-350173. View

14.

Jorgensen K, Davidsen J, Mouritsen O . Biophysical mechanisms of phospholipase A2 activation and their use in liposome-based drug delivery. FEBS Lett. 2002; 531(1):23-7. DOI: 10.1016/s0014-5793(02)03408-7. View

15.

Koch A . Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis. 2003; 62 Suppl 2:ii60-7. PMC: 1766740. DOI: 10.1136/ard.62.suppl_2.ii60. View

16.

Davidsen J, Jorgensen K, Andresen T, Mouritsen O . Secreted phospholipase A(2) as a new enzymatic trigger mechanism for localised liposomal drug release and absorption in diseased tissue. Biochim Biophys Acta. 2003; 1609(1):95-101. DOI: 10.1016/s0005-2736(02)00659-4. View

17.

Winter P, Neubauer A, Caruthers S, Harris T, Robertson J, Williams T . Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2006; 26(9):2103-9. DOI: 10.1161/01.ATV.0000235724.11299.76. View

18.

Andresen T, Jensen S, Kaasgaard T, Jorgensen K . Triggered activation and release of liposomal prodrugs and drugs in cancer tissue by secretory phospholipase A2. Curr Drug Deliv. 2005; 2(4):353-62. DOI: 10.2174/156720105774370203. View

19.

Winter P, Caruthers S, Kassner A, Harris T, Chinen L, Allen J . Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel alpha(nu)beta3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging. Cancer Res. 2003; 63(18):5838-43. View

20.

Pham C, Mitchell L, Huang J, Lubniewski C, Schall O, Killgore J . Variable antibody-dependent activation of complement by functionalized phospholipid nanoparticle surfaces. J Biol Chem. 2010; 286(1):123-30. PMC: 3012966. DOI: 10.1074/jbc.M110.180760. View