Passive drug targeting and delivery of antitumor Pt(IV) prodrugs

Cisplatin and its analogues are important drugs for the treatment of many malignant tumors, but many side effects and deactivation processes may occur. In order to overcome these limits, the Pt(IV) complexes higher inertness can be exploited. They are activated to their corresponding Pt(II) active metabolite only in the tumor site, taking advantage of the hypoxic and reducing milieu of neoplastic cells: for this reason, they are considered prodrugs. Furthermore, passive Drug Targeting and Delivery (DTD) strategies can be developed to improve the selective accumulation of such species. The tumor tissue increased vascular permeability, due to an irregular architecture of the blood vessels, and the reduced drainage of the lymphatic system allow macromolecules of suitable dimensions (e.g. nanoparticles (NPs), liposomes, etc.) to extravasate and to be retained for longer time. Therefore, nanosized carriers decorated with anticancer molecules should be accumulated into the tumor cells increasing the drug selectivity. This Ph.D. work is focused on the exploration of several passive DTD methods. The first phase consists in the synthesis of Pt(IV) complexes, containing suitable functionalities to be exploited in coupling reactions with nanosized vectors. Alternatively, Pt complexes can be encapsulated into liposomes. Then, the loading of selected nanocarriers with the metal complexes and the biological evaluation of the resulting conjugates are performed. The developed projects are listed below: - synthesis, characterization of Pt(IV) complexes, their couplings with different types of amino-functionalized nonporous silica NPs and in vitro tests of the resulting conjugates; - coupling reactions of the previously prepared Pt(IV) compounds with chitosan and its derivatives; - synthesis, characterization of Pt(IV) prodrugs able to link magnetic iron oxide NPs and their couplings with such vectors; - encapsulation of antitumor drugs into liposomes and their in vitro studies.