Microfluidic One-step Preparation Of Magnetic Poly(Vinyl Alcohol) Microspheres And Their Applications In Interventional Embolization Therapy

Transcatheter arterial chemoembolization(TACE) therapy takes the advantages of transcatheter arterial embolization(TAE) combined with local chemotherapy. It has been regarded as a preferred method for the advanced liver cancer patients with a small wound, low risk, little side effects and high treatment efficiency. However, the present embolic materials have some shortcomings including un-uniform particle size, lack of self-radiopacity and single function, resulting in not easy to be injected, hard to evaluate postoperation and low therapy efficiency. In this paper, various magnetic poly(vinyl alcohol)(PVA) microspheres have been prepared using a droplet-based microfluidic technique in one step and loaded with anti-cancer drugs to overcome the shortcomings mentioned above. The main contents and results are as follows:(1) In a T-junction microfluidic device, PVA aqueous solution containing a certain amount of Fe2+/Fe3+ salts and thermosensitive nanogels was used as a dispersed phase and liquid paraffin added with some surfactant was used as a continuous phase. The formed droplets in the microchannel were dripped into an alkaline solution to get PVA microspheres loaded with Fe3O4 nanoparticles(NPs) and thermosensitive nanogels. Herein, Fe3O4 NPs were in situ-synthesized via the reaction of Fe2+/Fe3+ and alkali. The micromorphology and size of the prepared microspheres were observed on an optical microscope and an environmental scanning electron microscope(ESEM). The morphology and size of Fe3O4 NPs formed in situ were characterized using a transmission electron microscope(TEM). The magnetism and magnetothermal effect of the prepared microspheres were measured on a vibrating sample magnetometer(VSM) and under an alternating magnetic field, respectively. In addition, anticancer drug- doxorubicin hydrochloride was loaded into microspheres via swelling equilibrium. And the drug loading efficiency, release behavior and cytotoxicity of the magnetic PVA microspheres were also studied. The results show that the prepared PVA microspheres are spherical with uniform size and possess superparamagnetic property and good magnetothermal effect. The temperature of the dispersion of mPVA microspheres can increase up 8-16 ℃ under an alter magnetic field(AMF). The drug release profiles from the magnetic PVA microspheres can be tuned by changing the temperature and the concentration of nanogels in microspheres. The cytotoxicity of the microspheres increases with an increasing temperature, which indicates that hyperthermia therapy combined with chemotherapy has the greatest lethality to tumor cell.(2) In a flow-focusing microfluidic device, PVA aqueous solution containing Fe2+/Fe3+ salts and/or Gd3+ salt was used as a dispersed phase and the same solutions used in(1) as a continuous phase and collection solution to prepare various PVA microspheres. These PVA microspheres encapsulated with in situ-synthesized Fe3O4 NPs and/or Gd2O3 NPs, which were denoted as Fe3O4@PVA, Gd2O3@PVA and Gd2O3/Fe3O4@PVA microspheres, respectively. The micromorphology and size of these microspheres were observed on an optical microscope and an ESEM. And TEM was used to observe the morphology and size of the in situ-synthesized Fe3O4 NPs and Gd2O3 NPs. The crystal structure, magnetism, magnetothermal effect and thermal stability of the various microspheres were characterized. The contents of Fe and Gd in microspheres were determined by using atomic emission spectroscopy. Furthermore, the magnetic resonance imagings(MRI) of these microspheres were observed in vitro and in vivo using a clinical MR scanner. These measured results indicate that Fe3O4@PVA microspheres have superparamagnetic property and good magnetothermal effect. The rate and the extent of the increased temperature are related to the concentration of microspheres in the dispersion and the intensity of the applied magnetic field. In addition, the Fe3O4@PVA microspheres can be tracked with enhanced T1-weighted MRI and Gd2O3@PVA microspheres can enhance T2-weighted MRI. Especially, Gd2O3/Fe3O4@PVA microspheres can be visible on both T1-weighted and T2-weighted MRI.In conclusion, various magnetic PVA microspheres with uniform size were fabricated conveniently via a one-step droplet-based microfluidic technique. When these prepared microspheres used as embolic materials, they have the potential to achieve multifunction combined embolization, local chemotherapy and hyperthermia therapy with MR-visibility. In addition, the drug release profiles from the magnetic microspheres can be controlled by adding some thermosensitive nanogels in the microspheres and changing the temperature regulated by applying an AMF.