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Enhanced potentiation of anticancer drugs using magnetic fluid hyperthermia (MFH): In vitro and in vivo studies

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Abstract
Clinical studies have demonstrated the effectiveness of combined hyperthermia and anticancer drug treatments. Challenges related to effective heat transfer have limited its clinical application. The use of magnetic fluids to induce hyperthermia is an attractive alternative to other forms of hyperthermia. It is based on the heat released by magnetic nanoparticles subjected to magnetic field. Recent studies have shown that magnetic fluid hyperthermia (MFH) enhances the therapeutic effects of chemotherapeutic agents. Knowledge regarding the underlying cellular and molecular mechanisms by which such phenomena occur requires more in depth understanding, and it is the focus of this work. It is hypothesized that by inducing hyperthermia via magnetic nanoparticles (MFH) significant cellular effects will be induced that will result in enhanced cytotoxicity of anticancer drugs, which currently possess limited clinical applications. For this purpose, in vitro therapeutic enhancement of bortezomib (BZ) and cisplatin (cDDP) using heat dissipated by magnetic nanoparticles was evaluated. Potential mechanisms to explain our observations of potentiation of these anti-cancer drugs by MFH were also elucidated. Finally, the in vivo therapeutic effects of cisplatin combined with MFH were assessed. Our results conclusively demonstrate that MFH produced marked cellular effects such as membrane fluidity, protein damage and microtubule instability, which were responsible for the in vitro enhanced potentiation between MFH and BZ or cDDP. In vivo studies showed therapeutic enhancement of cisplatin when combined with MFH. These results are significant because this approach could become a potentially effective anticancer therapy platform even in those cell lines that show intrinsic resistance to the drug.
Estudios clĂ­nicos han demostrado que hipertermia mejora la efectividad de drogas anti cĂ¡ncer. Sin embargo, retos relacionados a la transferencia de calor ha limitado su aplicaciĂ³n a nivel clĂ­nico. El uso de fluidos magnĂ©ticos para inducir hipertermia (MFH) es una alternativa atractiva cuando es comparado con otras formas de hipertermia. Este tratamiento estĂ¡ basado en la liberaciĂ³n de calor de nanoparticulas magnĂ©ticas en presencia de un campo magnĂ©tico. Estudios recientes han demostrado que hipertermia usando fluido magnĂ©tico mejora el efecto terapĂ©utico de agentes quimioterapĂ©uticos. Sin embargo, los mecanismos celulares y moleculares por los cuales se produce este fenĂ³meno requieren un conocimiento mas profundo, el cual es el enfoque de este trabajo. La hipĂ³tesis planteada es que al inducir hipertermia con nanopartĂ­culas magnĂ©ticas (MFH) inducirĂ¡ efectos celulares importantes los cuales producirĂ¡n una mayor citotoxicidad de drogas anti cĂ¡ncer que han mostrado efectos clĂ­nicos limitados. Con el fin de probar esta hipĂ³tesis el efecto terapĂ©utico de bortezomib (BZ) y cisplatin (cDDP) en combinaciĂ³n con MFH fue evaluado. Potenciales mecanismos para explicar nuestras previas observaciones sobre la potenciaciĂ³n terapĂ©utica de estas drogas utilizando el calor disipado por nanopartĂ­culas magnĂ©ticas fueron elucidados. Finalmente, estudios preliminares in vivo fueron realizados con el fin de evaluar los efectos terapĂ©uticos de cisplatino en combinaciĂ³n con MFH en modelos de animales. Nuestros resultados demuestran de forma concluyente que MFH produce marcados efectos celulares tales como fluidez membranal, daño de proteĂ­nas e inestabilidad de los microtĂºbulos, los cuales son responsables de la potenciaciĂ³n observada entre BZ o cDDP y MFH. Estudios in vivo mostraron que MFH aumentĂ³ la efectividad terapĂ©utica de cisplatino. Este tratamiento podrĂ­a convertirse en una plataforma potencialmente eficaz para el tratamiento de cĂ¡ncer, incluso en aquellas lĂ­neas celulares que muestran resistencia intrĂ­nseca a dichas drogas.
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Date
2014
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Research Projects
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Keywords
Anticancer drugs, Magnetic fluid hyperthermia
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