Synthesis of Biodegradable Polymer Micro- and Nanoparticles for Controlled Drug Delivery by Multiplexed Electrosprays

The goal of controlled drug delivery is to administer sustained amounts of a therapeutic agent over a prolonged period of time, improving the drug efficacy as compared to conventional, bolus doses that lead to variable concentrations of drug in blood. Although there are several systems capable to provide such a continuous-dose-based treatment, the use of biodegradable polymer micro- and, especially, nanoparticles offers multiple advantages with respect to other platforms. Their small size allows them to pass through physical barriers in the body and reach the site of treatment, allowing for a localized delivery, reducing side effects and toxicity. Polymer nanoparticles have lower clearance by the immune system, and are especially useful in intracellular delivery, delivery to the lymphatic system and the treatment of tumors, where the site of treatment is difficult to reach by larger particles.;Conventional methods for biodegradable particle production rely predominately on batch, emulsion preparation methods and suffer from several shortcomings: low encapsulation efficiency (∼10% for hydrophilic drugs), difficulty to generate sufficiently small (d<100nm) particles, poor control over particle size distribution, broad size distributions at the micro scale, and poor repeatability.;We have developed an alternative process based on electrospray (ES) that offers distinct advantages and overcomes all of these limitations. We demonstrate this process with the Poly(DL-lactic-co-glycolic acid) (PLGA) system encapsulating agents such as Doxorubicin, Rhodamine B and Rhodamine B octadecyl ester prechlorate. We also employ this method for the generation of theranostic systems that combine their therapeutic mission with imaging capabilities to detect the biodistribution of particles inside the body.;PLGA microparticles in different sizes, morphologies and compactness are generated using the electrospray-drying route. The size of the synthesized particles is primarily controlled by the delicate tuning of the solution physical properties and the ES operational parameters. The compactness of the polymer matrix is defined by the competition between the solvent evaporation and polymer diffusion process occurring inside the droplets during their flight towards the collector plate. Finally, by judiciously selecting polymer molecular weight, concentration, and solution flow rate, we can control the order in which polymer entanglements and Coulomb fission occur in the droplets and their relative significance, which subsequently governs the morphology of the resulting polymer particles.;In a single-step flow process, particles can be made to encapsulate the agent with high efficiency and be coated with emulsifiers that either stabilizes their suspension in solution or facilitate further functionalization for targeted drug delivery. The coating process allows for the surface modification of the particles without changes in particle size or morphology, with excellent particulate reproducibility and with minimal loss of drug (>94% encapsulation efficiency). This synthesis technique is well suited for massive scale-up using microfabricated, multiplexed arrays consisting of multiple electrospray nozzles operating in parallel.;Importantly, throughout this series of studies efforts were made to remove the synthesis approach from the all too common empiricism of a large fraction of the literature on materials synthesis, and to establish fundamental criteria that would allow for the generation of particles of prescribed size, morphology and consistency from first principles. As a result, the extension of the approach to different drug/polymer combinations should be facilitated.