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Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a highly robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cell lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate-modified nanoparticles containing 40 wt % drug caused S-phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. The most striking feature of nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.

A three-component drug-delivery system has been developed consisting of multi-walled carbon nanotubes (MWCNTs) coated with a non-classical platinum chemotherapeutic agent ([PtCl(NH3)2(L)]Cl (P3A1; L = N-(2-(acridin-9-ylamino)ethyl)-N-methylproprionimidamide) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (DSPE-mPEG). The optimized P3A1-MWCNTs are colloidally stable in physiological solution and deliver more P3A1 into breast cancer cells than treatment with the free drug. Furthermore, P3A1-MWCNTs are cytotoxic to several cell models of breast cancer and induce S-phase cell cycle arrest and non-apoptotic cell death in breast cancer cells. By contrast, free P3A1 induces apoptosis and allows progression to G2/M phase. Photothermal activation of P3A1-MWCNTs to generate mild hyperthermia potentiates their cytotoxicity. These findings suggest that delivery of P3A1 to cancer cells using MWCNTs as a drug carrier may be beneficial for combination cancer chemotherapy and photothermal therapy.

A range of ketones flanked by a combination of an aromatic and a heterocyclic ring (furan, thiophene, N-methylimidazole) were reduced under asymmetric transfer hydrogenation (ATH) conditions. Using a range of [(arene)Ru(TsDPEN)Cl] precatalysts, including tethered derivatives, the reduction enantioselectivity was high (up to 99 % ee) in cases where the aromatic ring contained an ortho-substituent. The enantioselectivity is influenced by a combination of steric and electronic factors which for the furan and thiophene series, follow literature precedents. In the case of the N-methylimidazole-containing ketones, an unexpected switch in enantioselectivity took place upon variation of the opposing aromatic group. Pyrrole-containing ketones were resistant to reduction. This study demonstrates the asymmetric transfer hydrogenation (ATH) of a range of hindered heterocyclic ketones, in high conversion and ee, using Noyori-Ikariya catalysts.