Microfluidic Platform for Controlled Synthesis of Polysaccharides-Based Nanoparticles for Anticancer DrugDelivery

Background: Nanotechnology has the potential to revolutionizecancer diagnosis and therapy. Various types of nanoparticles(NPs) have been used in delivering anticancer drugs to the siteof action. Among the various approaches for synthesizing therapeuticnanocarriers, microfluidic systems techniques whichwere originally developed in the microelectronics industry,have emerged as a promising platform for designing advanceddrug delivery systems with their capability for precise handlingand transport of small liquid quantities. This is particularlyimportant since the synthesis of biodegradable polymericnanoparticles by bulk mixing and nanoprecipitation of drugsand biodegradable polymeric precursors typically lacks controlover the mixing processes, which may compromise the propertiesof the resulting nanoparticles. Rapid and tunable mixing inmicrofluidics may allow for better control over the process ofnanoprecipitation and also enable screening of various formulationconditions on a single platform by varying parameters suchas flow rates, precursor composition, and mixing time. Thesetechniques enable production of mono dispersed and multifunctionaldrug carriers with highly tunable physical and chemicalproperties to promote efficacy of drug transport, release, distribution,and elimination during the course of treatment.Materials and Methods: In this study, we developed a T-shapemicrofluidic device to create hydrodynamically focused flowconsists of two inlets, one for tripolyphosphate (TPP) at basicpH (pH>۷), one for chitosan-drug at acidic pH (pH <۶), andone outlet for the fabricated nanoparticles. Chitosan as a naturalpolymer has some unique properties which highlight it asan excellent carrier for anti cancer drugs. Microfluidic deviceswere fabricated with poly (dimethylsiloxane) (PDMS) usinga standard micromolding process. To make the master molds,silicon wafers were spincoated with SU-۸ ۲۰۵۰ photocurableepoxy to a thickness of ۶۰ μm. The mixing channel was ۱۵۰ μmwide, ۶۰ μm high and ۱ cm long . Stability and hydrodynamicallyfocused of the flow at different flow rates was verifiedusing inverted microscope. Chitosan has the ability of gelationspontaneously, in contact with multivalent polyanions due tothe formation of inter- and intramolecular cross-linkage mediatedby the polyanions. The mixing time is controlled on themillisecond scale for the ionic crosslinking reaction by changingthe flow ratio. Size of on chip synthesized nanoparticles wasdetermined by DLS method.Results: Unfortunately, nanoparticle self-assembly with simplebulk mixing produces extremely polydisperse chitosan nanoparticles,which in turn exhibit a wide range of mechanical andchemical properties. However, we can create small and monodispersenanoparticles with microfluidic synthesis by creating anarrowly defined mixing regime via hydrodynamic flow focusing.A critical parameter in determining nanoparticle size is themixing time. The mixing time used for self-assembly is kept inthe millisecond range via changing the flow ratio of chitosandrugto TPP streams from ۰.۰۵ to ۰.۱(ml/min). We producekinetically locked nanoparticles, which prevents their furthergrowth, and keeps their final size smaller and more monodispersethan any bulk method. Chitosan-drug nanoparticle morphologytrends found through dynamic light scattering analysiswere confirmed with Scanning electron microscope (SEM).The diameter of the nanoparticles increases with an increasein flow ratio. Moreover, the polydispersity index (PI) for themicrofluidic nanoparticles was found to be remarkably lower(PI<۰.۲) than bulk synthesized particles.Conclusion: In summary, we have developed a microfluicassistedfabrication of complex chitosan- drug showing highlyefficient encapsulation capacity of hydrophobic drugs. Themonodisperse chitosan-drug in the range of ۱۰۰-۳۰۰ nm, idealsizes for drug delivery,

کلیدواژه ها:

Nanotechnology ، Drug Delivery ، Microfluidic System ، Controlled Synthesis ، Nanopercipitation