Back to Journals » International Journal of Nanomedicine » Volume 7

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Authors Dolman MEM, Harmsen S, Pieters EHE, Sparidans RW, Lacombe M, Szokol B, Őrfi L, Kéri G, Storm G, Hennink WE, Kok RJ

Received 23 September 2011

Accepted for publication 15 December 2011

Published 31 January 2012 Volume 2012:7 Pages 417—433

DOI https://doi.org/10.2147/IJN.S26485

Review by Single-blind

Peer reviewer comments 2

ME (Emmy) M Dolman1, Stefan Harmsen1, Ebel HE Pieters1, Rolf W Sparidans2, Marie Lacombe3, Bálint Szokol4, László Orfi4, György Kéri4, Gert Storm1, Wim E Hennink1, Robbert J Kok1
1Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 2Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands; 3Kreatech Biotechnology BV, Amsterdam, The Netherlands; 4Vichem Chemie Ltd, Budapest, Hungary

Background: Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis.
Methods: A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice.
Results: The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects.
Conclusion: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.

Keywords: drug delivery, sunitinib, fibrosis, platinum linker

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]

 

Other article by this author:

Docosahexaenoic acid liposomes for targeting chronic inflammatory diseases and cancer: an in vitro assessment

Alaarg A, Jordan NY, Verhoef JJF, Metselaar JM, Storm G, Kok RJ

International Journal of Nanomedicine 2016, 11:5027-5040

Published Date: 5 October 2016

Readers of this article also read:

The therapeutic effect of monocyte chemoattractant protein-1 delivered by an electrospun scaffold for hyperglycemia and nephrotic disorders

Yong C, Wang ZX, Zhang X, Shi XM, Ni ZJ, Fu H, Ding GS, Fu ZR, Yin H

International Journal of Nanomedicine 2014, 9:985-993

Published Date: 17 February 2014

FGF1-gold nanoparticle conjugates targeting FGFR efficiently decrease cell viability upon NIR irradiation

Szlachcic A, Pala K, Zakrzewska M, Jakimowicz P, Wiedlocha A, Otlewski J

International Journal of Nanomedicine 2012, 7:5915-5927

Published Date: 29 November 2012

Impact of surface coating and particle size on the uptake of small and ultrasmall superparamagnetic iron oxide nanoparticles by macrophages

Saito S, Tsugeno M, Koto D, Mori Y, Yoshioka Y, Nohara S, Murase K

International Journal of Nanomedicine 2012, 7:5415-5421

Published Date: 10 October 2012

Evaluation of the genotoxicity of cellulose nanofibers

de Lima R, Feitosa LO, Maruyama CR, Barga MA, Yamawaki PC, Vieira IJ, Teixeira EM, Corrêa AC, Mattoso LH, Fraceto LF

International Journal of Nanomedicine 2012, 7:3555-3565

Published Date: 11 July 2012

Association between calcifying nanoparticles and placental calcification

Guo Y, Zhang D, Lu H, Luo S, Shen X

International Journal of Nanomedicine 2012, 7:1679-1686

Published Date: 27 March 2012

Cell-delivered magnetic nanoparticles caused hyperthermia-mediated increased survival in a murine pancreatic cancer model

Basel MT, Balivada S, Wang H, Shrestha TB, Seo GM, Pyle M, Abayaweera G, Dani R, Koper OB, Tamura M, Chikan V, Bossmann SH, Troyer DL

International Journal of Nanomedicine 2012, 7:297-306

Published Date: 18 January 2012

The efficacy of mitochondrial targeting antiresistant epirubicin liposomes in treating resistant leukemia in animals

Men Y, Wang XX, Li RJ, Zhang Y, Tian W, Yao HJ, Ju RJ, Ying X, Zhou J, Li N, Zhang L, Yu Y, Lu WL

International Journal of Nanomedicine 2011, 6:3125-3137

Published Date: 2 December 2011

Erratum

Iancu C, Mocan L

International Journal of Nanomedicine 2011, 6:2543-2544

Published Date: 21 October 2011

Practical preparation procedures for docetaxel-loaded nanoparticles using polylactic acid-co-glycolic acid

Keum CG, Noh YW, Baek JS, Lim JH, Hwang CJ, Na YG, Shin SC, Cho CW

International Journal of Nanomedicine 2011, 6:2225-2234

Published Date: 7 October 2011