Superior Chemotherapeutic Benefits from the Ruthenium-Based Anti-Metastatic Drug NAMI‑A through Conjugation to Polymeric Micelles

Abstract

Macromolecular ruthenium complexes are a promising avenue to better, and more selective, chemotherapeutics. NAMI-A is a ruthenium­(III) drug in Phase II clinical trials that has low cytotoxicity and is inactive against primary tumors. However, it displays both antiangiogenic and anti-invasive properties and has been shown to specifically target tumor metastases, preventing both development and growth. To increase the cytotoxicity and cell uptake of this promising drug, we designed a biocompatible amphiphilic block copolymer capable of self-assembling into polymeric micelles. An appropriate method for the synthesis of a macromolecular NAMI-A drug was identifiedthe polymerization of vinyl imidazole and subsequent addition of a ruthenium­(III) precursor complex. The cytotoxicity of these polymeric moieties was tested on ovarian cancer A2780 and Ovcar-3 and pancreatic AsPC-1 cancer cell lines. On average, across the tested cell lines, a 1.5 times increase in toxicity was found for the NAMI-A copolymer micelles when compared to the NAMI-A molecule. Furthermore, the antimetastatic potential was assessed by evaluating the inhibitory effects on the migration and invasion of cells against three cell lines characterized by differing degrees of malignancy (MDA-MB-231 > MCF-7 > CHO). The NAMI-A micelles were shown to have an improved antimetastatic potential in comparison to NAMI-A