RESUMO
Tyrosine kinases (TKs) are emerging as important targets in cancer therapy and some of their inhibitors, TKIs (e.g. imatinib and nilotinib), are FDA-approved drugs that are used as selective anti-cancer therapeutics against cell lines that overexpress TKs. Many examples of metal-based complexes functionalised with TKIs are reported in the literature but very few have been functionalised with platinum. Here we report the design, a detailed computational analysis/simulation, the complete chemical characterisation and the preliminary biological evaluation of two novel Pt(IV) anticancer pro-drugs based on cisplatin tethered with a derivative of either imatinib or nilotinib in the axial position. Pt(IV) complexes are a strategic scaffold in combination therapy due to their axial ligands that can be functionalised to form dual action drugs. The activation by reduction releases the Pt(II) core and the axial ligands upon cellular internalisation. The antiproliferative activity and the TK inhibition properties of the novel adducts are analysed with a theoretical approach and confirmed in vitro with preliminary biological assays.
Assuntos
Antineoplásicos , Complexos de Coordenação , Pró-Fármacos , Cisplatino/farmacologia , Cisplatino/química , Mesilato de Imatinib/farmacologia , Pró-Fármacos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Pirimidinas/farmacologia , Complexos de Coordenação/farmacologia , Linhagem Celular TumoralRESUMO
Chemotherapeutics such as platinum-based drugs are commonly used to treat several cancer types, but unfortunately, their use is limited by several side effects, such as high degradation of the drug before entering the cells, off-target organ toxicity and development of drug resistance. An interesting strategy to overcome such limitations is the development of nanocarriers that could enhance cellular accumulation in target cells in addition to decreasing associated drug toxicity in normal cells. Here, we aim to prepare and characterize a graphene-oxide-based 2D nanoplatform functionalised using highly branched, eight-arm polyethylene-glycol, which, owing to its high number of available functional groups, offers considerable loading capacity over its linear modalities and represents a highly potent nanodelivery platform as a versatile system in cancer therapy. The obtained results show that the GO@PEG carrier allows for the use of lower amounts of Pt drug compared to a Pt-free complex while achieving similar effects. The nanoplatform accomplishes very good cellular proliferation inhibition in osteosarcoma, which is strictly related to increased cellular uptake. This enhanced cellular internalization is also observed in glioblastoma, although it is less pronounced due to differences in metabolism compared to osteosarcoma. The proposed GO@PEG nanoplatform is also promising for the inhibition of migration, especially in highly invasive breast carcinoma (i.e., MDA-MB-231 cell line), neutralizing the metastatic process. The GO@PEG nanoplatform thus represents an interesting tool in cancer treatment that can be specifically tailored to target different cancers.