Hydrogel containing l-valine residues as a platform for cisplatin chemotherapy

Two acrylic hydrogels, of low cross-linking content and carrying the l-valine residues, were synthesized and studied as a platform to load and release the chemotherapeutic agent cisplatin. The platinum(II)-complex species showed a well-defined stoichiometric ratio in which two carboxylate groups of the collapsing gel coordinate a metal center; this was confirmed by FT-IR spectra. When loaded in water, a zero-order release rate of platinum(II)-species was shown in the physiologic solution (PBS, pH 7.40) for more than one week. Moreover, the amount of platinum(II)-species released from the hydrogel may be improved either by the cross-linking degree and by the temperature. Any increase of the cross-links results in a decreased slope of the straightline Pt(II)/gel (mg/g) versus time, whereas the increasing temperature results in a greater amount of platinum(II)-species in solution. The chemical- and swelling-controlled release are the main mechanisms supervising the whole release process. On the other hand, the loading of cisplatin and temsirolimus in DMF showed a characteristic two phase releasing pattern; the initial burst effect was always followed by the zero-order release rate for a week. In this case only a swelling-controlled mechanism was mainly invoked. The cytotoxic activity towards Me665/2/21 human melanoma cell line, afforded by the cisplatin-loaded hydrogel, was close and in some cases higher compared to the native cisplatin at the same concentration; an interesting synergy in term of cytotoxicity was observed when a combined treatment of temsirolimus and cisplatin was used, although temsirolimus exerted only a moderate inhibition of cell proliferation.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Hydrogels with l-valine residues were synthesized at low degree of crosslinking and loaded with cisplatin with a well-defined stoichiometry. ► The hydrogels showed multiple-stimuli responsiveness (pH and temperature). ► The cisplatin release from the hydrogels showed a zero-order release kinetics with no burst effect. ► The cytotoxicity of the cisplatin-loaded hydrogels towards the human melanoma cell line (Me665/2/21) showed a good relationship with the degree of crosslinking. The presence of temsirolimus enhanced the % of detached cells.