Microfluidic remote loading for rapid single-step liposomal drug preparation

Abstract

Microfluidic-directed formation of liposomes is combined with in-line sample purification and remote drug loading for single step, continuous-flow synthesis of nanoscale vesicles containing high concentrations of stably loaded drug compounds. Using an on-chip microdialysis element, the system enables rapid formation of large transmembrane pH and ion gradients, followed by immediate introduction of amphipathic drug for real-time remote loading into the liposomes. The microfluidic process enables in-line formation of drug-laden liposomes with drug:lipid molar ratios of up to 1.3, and a total on-chip residence time of approximately 3 min, representing a significant improvement over conventional bulk-scale methods which require hours to days for combined liposome synthesis and remote drug loading. The microfluidic platform may be further optimized to support real-time generation of purified liposomal drug formulations with high concentrations of drugs and minimal reagent waste for effective liposomal drug preparation at or near the point of care.

Liposomes as nanomedical devices

“…The microfluidic platform may be further optimized to support real-time generation of purified liposomal drug formulations with high concentrations of drugs and minimal reagent waste for effective liposomal drug preparation at or near the point of care. 38 Real-time, highly sensitive, and low-cost monitoring of drug-loading and delivery dynamics in different pharmaceutical and biomedical environments could be very useful both for pharmaceutical manufacturing and for quality-assurance assays applied to liposomal formulations. Currently, the techniques used to investigate liposomal structures and their stability in different environments, as well as drug-loading and -delivery mechanisms, operate basically off-line and/or with prepared sampling.…”

Multiphase microfluidic synthesis of micro- and nanostructures for pharmaceutical applications

“…6) (Jahn et al, 2004). Because of the fast mixing in the MHF, liposomes with high reproducibility and controllable size were fabricated (Belliveau et al, 2012;Hood et al, 2014;Jahn et al, 2004) (Jahn et al, 2013;Jahn et al, 2010;Mijajlovic et al, 2013;Phapal and Sunthar, 2013). Furthermore, a VFF approach using a large microchannel aspect ratio (channel depth to channel width), up to 100:1, was developed for producing liposomes at a throughput of nearly 100 mg/h (Hood and DeVoe, 2015), which makes the microfluidic technology promising for fabricating liposomes for practical applications.…”

“…Furthermore, a VFF approach using a large microchannel aspect ratio (channel depth to channel width), up to 100:1, was developed for producing liposomes at a throughput of nearly 100 mg/h (Hood and DeVoe, 2015), which makes the microfluidic technology promising for fabricating liposomes for practical applications. Liposomes have been developed as nanocarriers by loading various functional cargoes for pharmaceutical applications, including drugs (Hood et al, 2014;Kastner et al, 2015) and genes (Balbino et al, 2013;Belliveau et al, 2012;Chen et al, 2012). The cargo can be loaded into liposomes either by active or passive loading.…”

“…The cargo can be loaded into liposomes either by active or passive loading. Hood et al prepared doxorubicin (Dox)-loaded liposomes in an integrated microfluidic mixing device using a one-step continuous-flow process which combined liposome synthesis and drug loading (Hood et al, 2014). Briefly, liposomes were first formed in an MHF section and then flowed to a counterflow microdialysis element where buffer exchange occurred.…”

Scalable preparation of poly(ethylene glycol)-grafted siRNA-loaded lipid nanoparticles using a commercially available fluidic device and tangential flow filtration

“…The use of microfluidic devices combined with the ethanol dilution method have been reported to be useful for preparing liposomes. Such methodology includes staggered herringbone structures [7], microfluidic devices with on-chip micro dialysis [8], multi-channel fluids [9], thermoplastic microfluidic devices [10], an ultra-sound assisted microfludic device [11] for the large-scale preparation of liposomes.…”