Mesoporous silica nanocarrier-mediated delivery of Pt(II)-Ferrocene conjugates for enhanced antitumor activity and toxicity Mitigation.

Amino-functionalized mesoporous silica nanoparticles (MSNs) were investigated as nanocarriers for two organoheterobimetallic Pt(II)-ferrocene monocations intended for anticancer therapy. Each monocation contains a Pt(II) center bearing two cis-isopropylamine ligands and a p-ferrocenylaniline ligand directly bound to platinum, and the complexes differ only in the counterion (C1, triflate; C2, nitrate). These compounds had been previously synthesized, showing moderate cytotoxic activity against several cancer cell lines after short incubation times, in some cases surpassing cisplatin at high concentrations. Because MSNs are pharmaceutically relevant nanocarriers that can protect metal complexes, modulate exposure and sustain release, this work examines whether their incorporation into amino-functionalized MSNs enhances in vitro activity at low Pt-equivalent concentrations and prolonged exposure times. MSNs were synthesized, amino-functionalized with APTMS and loaded with the Pt(II)-ferrocene complexes predominantly through non-covalent interactions. The resulting formulations preserved spherical mesoporous morphology, displayed homogeneous Pt and Fe distribution, and released Pt in a sustained, pH-dependent manner, with higher release under mildly acidic conditions. Compared with the free complexes, C1@NH2@MSNs and C2@NH2@MSNs improved antiproliferative activity in colorectal, breast and kidney cancer cell lines, with the strongest response in HCT 116 cells. Confocal microscopy confirmed efficient cellular uptake of FITC-labelled MSNs. In zebrafish embryos, C2@NH2@MSNs markedly reduced the systemic and developmental toxicity associated with the free C2 complex and cisplatin. These results support amino-functionalized MSNs as a promising drug-delivery platform for Pt(II)-ferrocene metallodrugs.