RESUMO
Objective:Magnetic fluid hyperthermia (MFH) is a still experimental technique found to have a potential application in the treatment of cancer. The method aims to reach around 41 °C-47 °C in the tumor site by exciting magnetic nanoparticles with an externally applied alternating magnetic field (AMF), where cell death is expected to occur. Applying AMFs with high spatial resolution is still a challenge. The AMFs from current and prospective MFH applicators cover relatively large areas; being not suitable for patients having metallic implants near the treatment area. Thus, there will be a clinical need for smaller magnetic field applicators. To this end, a laparoscopic induction heater (LIH) and a transrectal induction heater (TRIH) were developed.Methods:Miniature 'pancake' coils were wound and inserted into 3D printed enclosures. Ovarian (SKOV-3, A2780) and prostate (PC-3, LNCaP) cancer cell lines were used to evaluate the instruments' capabilities in killing cancer cellsin vitro, using Synomag®-D nanoparticles as the heat mediators. NIH3T3 normal cell lines were also used with both devices to observe if these cells tolerated the conditions applied.Results:Magnetic field intensities reached by the LIH and TRIH were 42.6 kA m-1at 326 kHz and 26.3 kA m-1at 303 kHz, respectively. Temperatures reached in the samples were 41 °C by the LIH and 43 °C by the TRIH. Both instruments successfully accomplished killing cancer cells, with minimal effects on normal cells.Conclusion:This work presents the first line of handheld medical induction heaters and have the potential to be a complement to existing cancer therapies.Significance:These instruments could enable the development of MFH modalities that will facilitate the clinical translation of this thermal treatment.
Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Neoplasias da Próstata , Masculino , Camundongos , Animais , Humanos , Feminino , Neoplasias da Próstata/terapia , Hipertermia Induzida/métodos , Linhagem Celular Tumoral , Neoplasias Ovarianas/terapia , Células NIH 3T3 , Estudos Prospectivos , Campos MagnéticosRESUMO
Magnetic fluid hyperthermia as a cancer treatment method is an attractive alternative to other forms of hyperthermia. It is based on the heat released by magnetic nanoparticles subjected to an alternating magnetic field. Recent studies have shown that magnetic fluid hyperthermia-treated cells respond significantly better to chemotherapeutic treatment compared with cells treated with hot water hyperthermia under the same temperature conditions. We hypothesized that this synergistic effect is due to an additional stress on the cellular membrane, independent of the thermal heat dose effect that is induced by nanoparticles exposed to an alternating magnetic field. This would result in an increase in Cis-diammine-dichloroplatinum (II) (cDDP, cisplatin) uptake via passive transport. To test this hypothesis, we exposed cDDP-treated cells to extracellular copper in order to hinder the human cell copper transporter (hCTR1)-mediated active transport of cDDP. This, in turn, can increase the passive transport of the drug through the cell membrane. Our results did not show statistically significant differences in surviving fractions for cells treated concomitantly with magnetic fluid hyperthermia and cDDP, in the presence or absence of copper. Nonetheless, significant copper-dependent variations in cell survival were observed for samples treated with combined cDDP and hot water hyperthermia. These results correlated with platinum uptake studies, which showed that cells treated with magnetic fluid hyperthermia had higher platinum uptake than cells treated with hot water hyperthermia. Changes in membrane fluidity were tested through fluorescence anisotropy measurements using trimethylamine-diphenylhexatriene. Additional uptake studies were conducted with acridine orange and measured by flow cytometry. These studies indicated that magnetic fluid hyperthermia significantly increases cell membrane fluidity relative to hot water hyperthermia and untreated cells, and hence this could be a factor contributing to the increase of cDDP uptake in magnetic fluid hyperthermia-treated cells. Overall, our data provide convincing evidence that cell membrane permeability induced by magnetic fluid hyperthermia is significantly greater than that induced by hot water hyperthermia under similar temperature conditions, and is at least one of the mechanisms responsible for potentiation of cDDP by magnetic fluid hyperthermia in Caco-2 cells.
Assuntos
Cisplatino/farmacologia , Neoplasias do Colo/terapia , Hipertermia Induzida/métodos , Nanopartículas de Magnetita/química , Fluidez de Membrana/efeitos dos fármacos , Laranja de Acridina/farmacocinética , Células CACO-2 , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Cobre/farmacologia , Humanos , Concentração Inibidora 50 , Fluidez de Membrana/efeitos da radiaçãoRESUMO
Replacement of the ancillary ligand in titanocene dichloride by amino acids provides titanocene species with high water solubility. As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of Cp(2)TiCl(2) and three water soluble titanocene-amino acid complexes - [Cp(2)Ti(aa)(2)]Cl(2) (aa=L-cysteine, L-methionine, and D-penicillamine) and one water soluble coordination compound, [Ti(4)(maltolato)(8)(micro-O)(4)] on the human colon adenocarcinoma cell line, Caco-2. At pH of 7.4 all titanocene species decompose extensively while [Ti(4)(maltolato)(8)(micro-O)(4)] is stable for over seven days. In terms of cytotoxicity, the [Cp(2)Ti(aa)(2)]Cl(2) and [Ti(4)(maltolato)(8)(micro-O)(4)] complexes exhibited slightly higher toxicity than titanocene dichloride at 24h, but at 72h titanocene dichloride and [Ti(4)(maltolato)(8)(micro-O)(4)] have higher cytotoxic activity. Cellular titanium uptake was quantified at various time intervals to investigate the possible relationship between Ti uptake and cellular toxicity. Results indicated that there was not a clear relationship between Ti uptake and cytotoxicity. A structure-activity relationship is discussed.
Assuntos
Antineoplásicos/toxicidade , Compostos Organometálicos/toxicidade , Titânio/toxicidade , Antineoplásicos/metabolismo , Ligação Competitiva/efeitos dos fármacos , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , DNA/biossíntese , DNA/genética , Relação Dose-Resposta a Droga , Etídio/metabolismo , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Compostos Organometálicos/metabolismo , Espectrofotometria Atômica , Espectroscopia de Infravermelho com Transformada de Fourier , Titânio/metabolismoRESUMO
Multidrug resistance (MDR) has been recognized by the scientific community as one of the major hurdles in the bioavailability of broad spectrum of drugs. This work focuses on the examination of the effects of the variables involved in hydrogel design on the multidrug resistance phenomenon. Hydrogels were synthesized using monomer lengths of 200, 400 and 1000 g/mol and a crosslinker length of 1000 and 600 g/mol. Hydrogels were characterized by the determination of release of model substrate Fluorescein sodium salt (FLUO), a multidrug resistance-associated protein (MRP) substrate, from the networks, and its transport trough Caco-2 cells. The effect of the hydrogels on the cytotoxicity of the chemotherapeutic agent 5-Fluoracil, an MRP substrate, was also assessed. The release profile of the model substrate FLUO indicated an anomalous release for all the morphologies with both Fickian and relaxation effects playing a role in the release of the substrate, making these hydrogels excellent candidates for controlled drug delivery applications. Preliminary results on the fluorescein sodium salt transport across Caco-2 cell monolayer in contact with 10 mg/mL PEG hydrogels suspensions showed a transport enhancement of up to 152%. Finally, cytotoxicity of Caco-2 cells with chemotherapeutic agent 5-Fluoracil was enhanced in the presence of the hydrogels. This data suggests that PEG hydrogels are acting as MRP inhibitors.