Rational Design of RGD–Albumin Conjugates for Targeted Delivery of the VEGF‐R Kinase Inhibitor PTK787 to Angiogenic Endothelium

Temming, Kai; Lacombe, M.; Schaapveld, Roel Q.J.; Őrfi, László; Kéri, Gÿorgý; Poelstra, Klaas; Molema, Grietje; Kok, Robbert J.

doi:10.1002/cmdc.200600201

Cited by 31 publications

(25 citation statements)

References 19 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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“…We recently developed a versatile linking technology, the so-called Universal Linkage System (ULS), for the coupling of drugs to carrier systems, 20,21,23,24 which we now have applied for the conjugation of the Rho kinase inhibitor Y27632 to LZM. We investigated the potential activity of Y27632-LZM in the ischemia-reperfusion (I/R) injury model and demonstrated both enhanced activity and increased selectivity of the tubular-targeted Rho kinase inhibitor.…”

mentioning

confidence: 99%

Inhibition of Renal Rho Kinase Attenuates Ischemia/Reperfusion-Induced Injury

Prakash

Borst

Lacombe³

et al. 2008

Journal of the American Society of Nephrology

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The Rho kinase pathway plays an important role in dedifferentiation of epithelial cells and infiltration of inflammatory cells. For testing of the hypothesis that blockade of this cascade within the kidneys might be beneficial in the treatment of renal injury the Rho kinase inhibitor, Y27632 was coupled to lysozyme, a low molecular weight protein that is filtered through the glomerulus and is reabsorbed in proximal tubular cells. Pharmacokinetic studies with Y27632-lysozyme confirmed that the conjugate rapidly and extensively accumulated in the kidney. Treatment with Y27632-lysozyme substantially inhibited ischemia/reperfusion-induced tubular damage, indicated by reduced staining of the dedifferentiation markers kidney injury molecule 1 and vimentin, and increased E-cadherin relative to controls. Rho kinase activation was inhibited by Y27632-lysozyme within tubular cells and the interstitium. Y27632-lysozyme also inhibited inflammation and fibrogenesis, indicated by a reduction in gene expression of monocyte chemoattractant protein 1, procollagen I␣1, TGF-␤1, tissue inhibitor of metalloproteinase 1, and ␣-smooth muscle actin. Immunohistochemistry revealed reduced macrophage infiltration and decreased expression of ␣-smooth muscle actin, collagen I, collagen III, and fibronectin. In contrast, unconjugated Y27632 did not have these beneficial effects but instead caused systemic adverse effects, such as leukopenia. Neither treatment improved renal function in the bilateral ischemia/reperfusion model. In conclusion, the renally targeted Y27632-lysozyme conjugate strongly inhibits tubular damage, inflammation, and fibrogenesis induced by ischemia/reperfusion injury.

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“…195 Pt-NMR analysis of 17864-ULS showed a peak at d ¼ -2493, characteristic for Pt-N 3 coordination, [35] confirming the coupling of the ULS linker to one of the nitrogen atoms present in 17864. The observation that (Z)-3-{2,4-dimethyl-5-[(2-oxoindolin-3-ylidene)methyl]-1H-pyrrol-3-yl}propanoic acid (i.e., the sunitinib analogue SU6668) cannot be coordinated to the ULS linker (data not shown), indicates that a coordinative bond is formed between the platinum atom of the linker and the pyridine nitrogen in 17864.…”

Section: Synthesis and Characterization Of 17864-uls-nh 2 -Pamam-g3mentioning

confidence: 90%

“…In vivo biodistribution studies have shown that kinase inhibitor-ULS-carrier conjugates reside in the designated cells for several days and that the majority of the accumulated kinase inhibitor is present in the ULS-bound form. [33][34][35][36] Because sunitinib cannot be coordinated to the ULS linker, we synthesized a sunitinib analogue, that is, 17864, that has an extended pyridyl side chain. When the ATP-competitive kinase inhibitor sunitinib binds to its target kinases the oxindole moiety of sunitinib is localized deep in the ATP-binding pockets of the target kinases, while the N-2-(diethylamino)ethylene moiety is protruding outwards.…”

mentioning

confidence: 99%

Dendrimer‐Based Macromolecular Conjugate for the Kidney‐Directed Delivery of a Multitargeted Sunitinib Analogue

Dolman

Dorenmalen

Pieters

et al. 2011

Macromolecular Bioscience

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The development of a macromolecular conjugate of a multitargeted tyrosine kinase inhibitor is described that can be used for renal-specific delivery into proximal tubular cells. A novel sunitinib analogue, that is, 17864, is conjugated to a NH(2) -PAMAM-G3 dendrimer via the platinum (II)-based Universal Linkage System (ULS™). The activity of 17864 is retained after coordination to the ULS linker alone or when coupled to NH(2) -PAMAM-G3. 17864-UlS-NH(2) -PAMAM-G3 is non-toxic to proximal tubular cells in vitro. After intravenous administration to mice, 17864-UlS-NH(2) -PAMAM-G3 rapidly and efficiently accumulates in the kidneys. These results are encouraging for future studies focusing on the development of novel therapeutics for the treatment of renal diseases.

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Rational Design of RGD–Albumin Conjugates for Targeted Delivery of the VEGF‐R Kinase Inhibitor PTK787 to Angiogenic Endothelium

Cited by 31 publications

References 19 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

Inhibition of Renal Rho Kinase Attenuates Ischemia/Reperfusion-Induced Injury

Dendrimer‐Based Macromolecular Conjugate for the Kidney‐Directed Delivery of a Multitargeted Sunitinib Analogue

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