We report here on a novel system composed of self-assembling ultrashort peptides conjugated to an oxaliplatin analog.  This platinum peptide conjugate can be injected into the tumor site, providing a localized therapeutic within a supporting self-assembled scaffold.Oxaliplatin functionalized peptides were synthesized utilizing click chemistry. For this purpose, alkyne functionalized peptides were synthesized by SPPS utilizing Fmoc chemistry and oxaliplatin analogs were designed to bear the azide functionality on the biscarboxylato ligand. Subsequently, the oxaliplatin analog and the peptide were linked via a copper-catalyzed 1,3-dipolar cycloaddition reaction.  The final compound could form hydrogels with its parent peptide with up to 40% drug loading. The cytotoxicities of the compounds were determined in three different cell lines and IC50 values in the low micromolar range were found for all investigated compounds.In order to test the possibility of a localized therapy, the in vivo efficacy was tested in a mouse breast cancer model.  Four treatment groups were evaluated using PBS and the parent peptide as negative controls, oxaliplatin as a positive control and the test compound as a hybrid hydrogel with the parent peptide. Treatment was started 7 days post-tumor inoculation and repeated with half the dose after 21 days and the study was completed on day 28. The platinum-peptide conjugate showed significant tumor recession and better systemic tolerance after three weeks of treatment, compared to the free platinum drug. This observation could also be confirmed with a significant lower platinum level in the kidneys and the liver when compared with oxaliplatin. Furthermore, the test compound showed a significantly higher platinum content in the tumor when compared to oxaliplatin.The functionalization of self-assembling ultrashort peptides with oxaliplatin analogs offers promising alternatives for current anti-cancer therapies, by enabling localized treatment and providing support as a 3D-scaffold for lost or damaged tissue.

Functionalization of self-assembling ultrashort peptides with oxaliplatin analogs by click chemistry for localized cancer therapy

248th National Meeting (2014)

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