DEVELOPING CAPILLARY MICROFLUIDIC DEVICES TO GENERATE EMULSIONS AND PARTICLES FOR DRUG DELIVERY APPLICATIONS

Abstract

Targeted delivery of pharmaceutical compounds enhances efficacy of the drug at the site of activity while reducing interactions with off-target tissues and organs. Using this technology, scientists have been able to take drugs discarded years ago due to harmful side effects and reformulate them for use. In this work, we have been motivated by enhanced efficacy of camptothecin in lung cancer treatment through the use of passive targeting within the capillary bed in the lungs. We have developed a nanocomposite, drug loaded hydrogel microparticle to deliver drugs to cancer tissue in the lungs through venous filtration. Critical to the success of this method is the control of the size and modulus of the hydrogel particles injected. In order to closely control the size, we have developed a glass capillary microfluidic device and a shear emulsification process for generation of drug loaded hydrogel microparticles from 12 μm to 100 μm in diameter.

We developed a low cost, modular glass capillary microfluidic device, using commercial components, to simply and reproducibly generate microparticles using microfluidic droplet generation. We then studied the effects of multiple parameters on the generation of small droplets using the device. After establishing the microfluidics, a bulk emulsification technique was developed to generate large quantities of microparticles for in vivo studies in mice. A thiol-acrylate Michael addition polymerization was used to solidify our droplets, containing fluorescent nanoparticles for imaging, into particles. We performed in vivo pilot studies in mice to demonstrate the targeting of the microparticles. A dosing strategy was developed using particles produced through bulk emulsification methods. We then compared our bulk emulsification methods with the dosing of monodisperse hydrogel particles to determine the benefits of microfluidic particle production. We found that small particles, 36 μm in diameter, stay in the lungs for a week, with nonspecific targeting to the liver and spleen. Larger particles tended to lodge in the lungs for up to seven weeks undergoing degradation by macrophages, with small satellite particles targeting other organs. Monodisperse particles, 91 μm in diameter, generated by microfluidics had even better targeting of the lungs due to removal of satellite particles.