Despite considerable progress in recent years, various disease’ diagnosis and treatments continue to present constraints, such as low sensitivity or specificity, drug toxicity, and severe side effects1. Cancer represents one of the best examples of a disease where localized delivery of therapeutics is of high importance, as the potent yet toxic mechanisms of action of such compounds can lead to an effective response or side effects. Today, most drug formulations are not capable of targeting specific sites of interest. Nanoparticle-based drug delivery platforms have emerged as suitable vehicles for overcoming these limitations2. Nanoparticles, such as liposomes, have proven advantageous at preserving therapeutic material and allowing for extended half-lives of drugs within the body3.
Liposomes were discovered in the 1960s. These hollow nanoparticles are phospholipid vesicles consisting of at least one lipid bilayer (figure 1). This bilayer is usually composed of amphiphilic phospholipids that have a hydrophilic phosphate head and a hydrophobic tail consisting of two fatty acid chains. This structural feature has facilitated liposomes’ applications, including their use as artificial cell membranes, carriers for drug delivery systems, encapsulating agents for food ingredients, and analytical tools4–8.
During the COVID-19 pandemic, the first vaccines to reach clinical trials were based on viral vector and nucleic acid technologies. One of the most promising vaccine candidates was based on nucleoside-modified mRNA and encapsulated within lipid nanoparticles (LNP)9. This only confirms the need for lipidic nanoparticles for present and future drug delivery applications.
Comparison with another production method
|Batch method||Fluigent microfluidic method|
|Particle size distribution||Low||High|
|Live particle size control||No||Precise|
|Range of particle size||Limited size range||Wide size range|
|Continuous (/in line) production||No||Yes|
Materials and methods
Liposome nanoparticles prove advantageous at solubilizing therapeutic substances. Macroscale batch methods widely employed for liposome production lack control on liposome morphology, size, and distribution. Microfluidic systems allow for the production of highly monodisperse liposome nanoparticles. We have demonstrated the production of liposomes using a microfluidic system consisting of pressure-based flow controllers and the Raydrop™ microfluidic device with standard configuration. Liposomes ranging from 30 to 150 nm were generated. Sizes can be adjusted by controlling the device flow input parameters, particularly the flow rate ratio (FRR). The polydispersity index (PDI) ranges from 0,07 to 0,15. This system enables the synthesis of liposomes for drug delivery applications, as encapsulating agents for food ingredients, or for other applications requiring nano-sized and spherical liposomes.
A complete, cost-effective, and commercially-available platform for the on-demand production of monodisperse liposome nanoparticles is now available. This allows for control of liposome size and frequency by adjusting flow parameters.
- Bozzuto, G. & Molinari, A. Liposomes as nanomedical devices. Int. J. Nanomedicine 10, 975–999 (2015).
- Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).
- Torchilin, V. P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4, 145–160 (2005).
- Bally, M. et al. Liposome and lipid bilayer arrays towards biosensing applications. Small 6, 2481–2497 (2010).
- Fathi, M., Mozafari, M. R. & Mohebbi, M. Nanoencapsulation of food ingredients using lipid based delivery systems. Trends Food Sci. Technol. 23, 13–27 (2012).
- Grimaldi, N. et al. Lipid-based nanovesicles for nanomedicine. Chem. Soc. Rev. 45, 6520–6545 (2016).
- Andrew Pohorille & David Deamer. Artificial cells: prospects for biotechnology. Trends Biotechnol. Biotechnol. 31- (2002).
- Rongen, H. A. H., Bult, A. & Van Bennekom, W. P. Liposomes and immunoassays. J. Immunol. Methods 204, 105–133 (1997).
- Vogel, A. B. et al. A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. bioRxiv 2020.09.08.280818 (2020).
- Pattni, B. S., Chupin, V. V. & Torchilin, V. P. New Developments in Liposomal Drug Delivery. Chem. Rev. 115, 10938–10966 (2015).
- Mui, B., Chow, L. & Hope, M. J. Extrusion Technique to Generate Liposomes of Defined Size. Methods Enzymol. 367, 3–14 (2003).
- Carugo, D., Bottaro, E., Owen, J., Stride, E. & Nastruzzi, C. Liposome production by microfluidics: Potential and limiting factors. Sci. Rep. 6, 1–15 (2016).
- Hood, R. R., Devoe, D. L., Atencia, J., Vreeland, W. N. & Omiatek, D. M. A facile route to the synthesis of monodisperse nanoscale liposomes using 3D microfluidic hydrodynamic focusing in a concentric capillary array. Lab Chip 14, 2403–2409 (2014).
- Jahn, A., Vreeland, W. N., Devoe, D. L., Locascio, L. E. & Gaitan, M. Microfluidic directed formation of liposomes of controlled size. Langmuir 23, 6289–6293 (2007).
- Jahn, A. et al. Microfluidic mixing and the formation of nanoscale lipid vesicles. ACS Nano 4, 2077–2087 (2010).
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