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Präklinische Untersuchungen der renoprotektiven Wirksamkeit nierenspezifischer Wirkstoff-Konjugate. Synthese, Pharmakokinetik und Wirksamkeit.

Janzer, Maria

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Abstract

For over 35 years, the highly potent cytostatic agent cisplatin plays a central role in the treatment of different solid tumors. With an overall cure rate of about 90%, and nearly 100% for early stage diseases, it’s especially successful for the treatment of testicular cancer. However, the application of cisplatin is limited by its strong nephrotoxic side effects. This has a substantial impact on the treatment success. So far, conventional supportive measures remain unsatisfied, in particular when high doses or cumulative doses of cisplatin are applied. Promising results of different protective agents and strategies against cisplatin nephrotoxicity are reported in many publications. However, only limited information is available concerning possible interferences of the tested drugs with the antitumor activity of cisplatin. Furthermore, besides amifostine none of these agents reached clinical use yet. The purpose of this work was to protect healthy kidney cells from cisplatin-induced nephrotoxicity, using the kidney-specific peptide (KKEEE)3K-NH2 as transporter of protective agents. In comparison to systemic drug applications, the developed drug targeting approach promises an improved dose-response relationship and reduced systemic effects. Both possibly increases the efficacy of cisplatin chemotherapies. α-Lipoic acid, silybin, carvedilol and apocynin already showed renoprotective effects against cisplatin-induced nephrotoxicity in various publications. Consequently, these compounds were selected for conjugation to the kidney-specific carrier. Depending on their functional groups, different linker strategies were used. Amide, ester and carbamate linkages showed sufficient stability in plasma. The pharmacokinetic properties of the conjugates were estimated in vivo with radio labeled drugs and szintigraphic distribution studies revealed their exclusive kidney-specific accumulation. The drugs and their corresponding conjugates showed no significant ameliorating effect on kidney function. Plasma creatinine and urea were used as parameters to evaluate the renal damages. A significant adverse effect on kidney function was determined in the group, which was treated with the lipoic acid conjugate. This effect was only detected for the conjugated form. Interestingly, the lipoic acid conjugate treated group showed an up to 43% increased platinum content in the kidneys. In vitro experiments revealed that under physiological conditions a trapping of cisplatin by the lipoic acid conjugate via its thiol groups occurs. This led to an increased renal uptake of cisplatin, probably promoted by simultaneous administration of cisplatin and lipoic acid conjugate. The high variances within all animal groups receiving cisplatin led to statistically non-significant results. However, in comparison to the untreated groups, all treated animals showed generally lower mean values in all parameters considered. Surprisingly, the unloaded carrier (KKEEE)3K-NH2 also had a protective effect on kidney function, together with low kidney platinum concentrations. In general, a correlation between platinum concentration and kidney deterioration was identified in all groups, but no antioxidative efficacy to protect the kidneys could be observed. The animals showed strong individual sensitivity to cisplatin. This results in high variances, in particular in the cisplatin control group. To obtain more conclusive results, larger group sizes should be used for further examinations. It can be summarized that the potential nephroprotective drugs and their conjugates did not show the expected positive effects. Other drugs, with other modes of action and without direct interaction to cisplatin, and optimized dosing schemes could offer new opportunities. Therefore, kidney-specific drug targeting via the carrier (KKEEE)3K-NH2 is still an attractive method to increase protective efficacy of drugs and decrease adverse systemic side effects.

Item Type: Dissertation
Supervisor: Mier, Prof. Dr. Walter
Date of thesis defense: 10 February 2017
Date Deposited: 13 Dec 2017 09:16
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Subjects: 570 Life sciences
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