Intervention in growth factor activated signaling pathways by renally targeted kinase inhibitors

Fretz, Marjan M.; Dolman, M. Emmy M.; Lacombe, M.; Prakash, Jai; Nguyen, Tri Q.; Goldschmeding, Roel; Pató, János; Storm, Gert; Hennink, Wim E.; Kok, Robbert J.

doi:10.1016/j.jconrel.2008.08.013

Cited by 21 publications

(12 citation statements)

References 24 publications

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“…The successful formation of a coordinative bond between the platinum (II) linker and the aromatic nitrogen of the pyridine ring in 17864 was proven by mass spectrometry and 195 Pt-NMR analysis. 195 Pt-NMR analysis showed a peak at −2493 ppm which, as has been demonstrated for different drug-ULS-carrier conjugates, 38,39 is characteristic for a Pt-N 3 coordination. The fact that the sunitinib analog SU6668 (ie, the product also contained 14% of the dimeric adduct, ie, (17864) 2 -ULS.…”

Section: Immunostaining Of Fibrotic Markers In Kidney Sectionssupporting

confidence: 68%

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

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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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.

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Section: Immunostaining Of Fibrotic Markers In Kidney Sectionssupporting

confidence: 68%

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

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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“…Buffered formaldehyde solutions were from Added Pharma (Oss, The Netherlands). LZM-007 was coupled to chicken egg white lysozyme (Sigma-Aldrich) via the Lx linker (LinXis B.V., Breda, The Netherlands) as described previously for other conjugates, 25,26,41,42 resulting in a LZM-drug conjugate with a 1.1:1 drug/LZM molar ratio.…”

Section: Reagentsmentioning

confidence: 99%

Epac-Rap Signaling Reduces Oxidative Stress in the Tubular Epithelium

Stokman

Qin

Booij

et al. 2014

Journal of the American Society of Nephrology

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Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-29-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-29-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-29-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate-induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-29-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-29-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stress.

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“…Previous publications on cisplatin loaded PEG‐ b ‐poly( l ‐glutamic acid) micelles also reported a slightly negative zeta potential of the developed micelles . Drug loading content of the micelles was determined by disruption of the drug‐platinum(II) coordination bond by adding an excess of a platinophilic ligand, thiocyanate (SCN − ), after incubation at 80 °C for 24 h . The drug loading capacity at a feed ratio of [Lx‐dactolisib]/[COO − ] = 0.5 (mol/mol) was 16.5% and 18.7% for S‐dacto/m and L‐dacto/m micelles, respectively (Table ).…”

Section: Resultsmentioning

confidence: 95%

Polymeric Micelles Employing Platinum(II) Linker for the Delivery of the Kinase Inhibitor Dactolisib

Shi

Lou

Steenbergen

et al. 2019

Part & Part Syst Charact

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Polymeric micelles are attractive nanocarriers for hydrophobic drug molecules such as the kinase inhibitor dactolisib. Two different poly(ethylene glycol)–poly(acrylic acid) (PEG‐b‐PAA) block‐copolymers are synthesized, PEG(5400)‐b‐PAA(2000) and PEG(10000)‐b‐PAA(3700), respectively. Polymeric micelles are formed by self‐assembly once dactolisib is conjugated via the ethylenediamine platinum(II) linker (Lx) to the PAA block of the block copolymers. Dactolisib micelles with dactolisib loading content of 17% w/w show good colloidal stability and display sustained release of Lx‐dactolisib over 96 h in PBS at 37 °C, while media containing reagents that compete for platinum coordination (e.g., glutathione (GSH) or dithiothreitol (DTT)) effectuate release of the parent inhibitor dactolisib at similar release rates. Dactolisib/lissamine‐loaded micelles are internalized by human breast adenocarcinoma cells (MCF‐7) in a dose and time‐dependent manner as demonstrated by confocal microscopy. Dactolisib‐loaded micelles inhibit the PI3K/mTOR signaling pathway at low concentrations (400 × 10−9 m) and exhibit potent cytotoxicity against MCF‐7 cells with IC50 values of 462 ± 46 and 755 ± 75 × 10−9 m for micelles with either short or longer PEG‐b‐PAA block lengths. In conclusion, dactolisib loaded PEG‐b‐PAA micelles are successfully prepared and hold potential for nanomedicine‐based tumor delivery of dactolisib.

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Intervention in growth factor activated signaling pathways by renally targeted kinase inhibitors

Cited by 21 publications

References 24 publications

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

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

Epac-Rap Signaling Reduces Oxidative Stress in the Tubular Epithelium

Polymeric Micelles Employing Platinum(II) Linker for the Delivery of the Kinase Inhibitor Dactolisib

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