ABSTRACT
Cisplatin is a platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors. However, a major challenge in the use of cisplatin and in the development of cisplatin derivatives, namely Pt(iv) prodrugs, is their premature reduction in the bloodstream before reaching cancer cells. To circumvent this problem, we designed liposomal nanoparticles coupled with a cholesterol-tethered amphiphilic Pt(iv) prodrug. The addition of cholesterol served to stabilize the formation of the liposome, while selectively incorporating cholesterol as the axial ligand also allowed the Pt(iv) prodrug to readily migrate into the liposomal bilayer. Notably, upon embedding into the nanoparticles, the Pt(iv) prodrug showed marked resistance against premature reduction in human plasma in vitro. Pharmacokinetic analysis in a mouse model also showed that the nanoparticles significantly extend the half-life of the Pt(iv) prodrug to 180 min, which represents a >6-fold increase compared to cisplatin. Importantly, such lipid modification did not compromise the genotoxicity of cisplatin, as the Pt(iv) prodrug induced DNA damage and apoptosis in ovarian cancer cell lines efficiently. Taken together, our strategy provides a novel insight as to how to stabilize a platinum-based compound to increase the circulation time in vivo, which is expected to enhance the efficacy of drug treatment.
Subject(s)
Antineoplastic Agents/pharmacology , Nanoparticles/chemistry , Organoplatinum Compounds/pharmacology , Prodrugs/pharmacology , Surface-Active Agents/pharmacology , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cholesterol/blood , Cholesterol/chemistry , Cholesterol/pharmacology , Cisplatin/blood , Cisplatin/chemistry , Cisplatin/pharmacology , DNA Damage , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Liposomes/blood , Liposomes/chemistry , Molecular Structure , Nanoparticles/metabolism , Organoplatinum Compounds/blood , Organoplatinum Compounds/chemistry , Prodrugs/chemistry , Prodrugs/metabolism , Structure-Activity Relationship , Surface-Active Agents/chemistry , Surface-Active Agents/metabolism , Time Factors , Tumor Cells, CulturedABSTRACT
Phenanthriplatin is a leading preclinical anticancer Pt complex distinguished by a phenanthridine ligand that facilitates DNA-targeted covalent binding via intercalation. We report here that Pt(ii) complexes incorporating phenanthridine into a chelating, multidentate ligand scaffold exhibit a superior in vitro therapeutic index compared with phenanthriplatin and cisplatin.