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

Abstract

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.

Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma

“…Some sunitinib analogue conjugates have been synthesized and evaluated as either lysozyme-based targeting agents [56,57], imaging tools [58], or GnRH-receptor directed agents [59], but no covalent and Fig. 5.…”

Renal fibrosis: Primacy of the proximal tubule

“…Thus, a therapeutic approach targeting the proximal tubule may be more effective than systemic alteration of growth factor pathways. Such an approach has been used in research settings by conjugating drugs to lysozyme which is reabsorbed by the proximal tubule[144, 145]. A platinum-based linker was used for conjugation in these studies which may be problematic for human studies given the known nephrotoxic effects of free platinum, but the concept remains useful for more targeted treatment of the proximal tubule.…”

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

“…Small molecule-drug conjugates represent a recent class of drugs with the potential to target tumor-specific or overexpressed antigens [11,12,22,23]. Since both RTK and some integrin subtypes such as α V β 3 are overexpressed in cancer cells, agents directed to both these targets appear to be extremely promising, also taking into account the tumor targeting properties of integrin ligands [18,19,24]. In particular, α V β 3 and VEGFR2, which are expressed in ovarian cancer, are implicated in signaling networks sustaining tumor cell survival and angiogenesis.…”