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Optimizing Nanoparticle Drug Delivery Systems Using Microfluidics

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Encapsulation is often used in drug delivery systems to prevent compounds from leaching out before reaching the target site, allowing for delayed or sustained release. However, with conventional batch methods it is difficult to achieve the consistent and reproducible production of monodisperse particles that is essential for reliable drug delivery and therapeutic efficacy. To overcome this issue, researchers are using a microfluidics approach to pioneer an autonomous manufacturing method for the high throughput production of equally dispersed liposomes for drug encapsulation.

Drug encapsulation conceals a compound inside a vesicle surrounded by a coating that slowly breaks down as it is transported around the body to allow controlled drug release, sustained medication or targeted, site-specific drug deliverance. It is widely used in oncology and immunology to overcome the limitations of chemical drug dosage forms, such as the side effects of burst release, toxicity and even the unpleasant taste and odor of some compounds. The biopolymer structure that houses the drug, usually constructed in a bilayer or single layer sphere, can influence therapeutic efficacy by determining how and when the compound is released. Chemotherapy, for example, requires extremely localized delivery of drugs, as incorrect dispersal may render treatment ineffective or produce adverse side effects due to the toxicity and potency of the chemicals used.

Versatile vehicles

Thus, successful delivery of drugs depends largely 
on its drug carrier and delivery route undertaken. No  matter how novel and powerful the drug it is, if it is poorly delivered and there is no drug released at the intended target area, it will result in a lot of loss in research and development of the drug.

Liposomes – spherical vesicles with at least one phospholipid bilayer – are usually the drug vehicle of choice for the administration of therapeutics, such as vaccines. The COVID-19 pandemic has recently prompted a lot of interest in liposomes, as the Pfizer BioNtech1 and Moderna2 vaccines encapsulate the mRNA that encodes the SARS-CoV-2 spike protein in lipid nanoparticles. The success of these formulations is largely down to their extreme versatility and capability of transporting both aqueous and lipophilic solutions – or a combination of the two – around the body to the target site, while protecting it from premature degradation. The chemical composition of liposomes can be altered depending on their mode of use, and targeted site-specific delivery is possible with the tagging of small molecules, although very few targeted chemistries have made it to clinic. When producing liposomal formulations, the consistency of membrane composition, lamellarity, size distribution and stability play a significant role in the success of drug encapsulation and deliverance, and therefore the therapeutic efficacy.3 However, conventional methods of liposomal preparation are often limited by their poor standardization of lipid shape and size, high manufacturing costs and batch-to-batch variability, making it difficult to achieve consistent and reliable particle dispersion.

Outdated approaches

Batch techniques – such as membrane extrusion, sonication, homogenization and freeze-thawing – are often used for drug encapsulation. Approximately 15 liposomal-based drug formulations have been approved for clinical use worldwide,4 and almost all of these rely on the thin-film batch method of production, despite the technique being characterized by low yields, unreliable fabrication of polydisperse liposomes and poor size distribution. These limitations require multiple downstream stages of size-selection to separate the desired liposomes from the rest of the batch, resulting in significant wastage, low particle yields and poor encapsulation efficiency.

Microfluidics offers an alternative method for the high throughput and continuous production of monodisperse liposomes to overcome these limitations. The process allows precise control over fluid flows and manufacturing parameters to help produce uniform and reliable compositions, removing the need for post-modification stages or downsizing to increase efficiency and yields.

Microfluidics for chemotherapy

Achieving monodispersity

Researchers have recently been exploring the potential of microfluidics for optimizing liposome formulations to fabricate PEGylated drug delivery systems for therapeutic applications.5 Doxorubicin – a potent water-soluble chemotherapeutic agent used in the treatment of breast cancer – was loaded in liposomal formulations using a microfluidic approach, and the resulting particles were compared to those produced using the traditional thin-film hydration method. The compound was loaded via active and passive microfluidic loading mechanisms, with both achieving high encapsulation efficiencies of at least 80%. The resulting liposomal formulations were comparable in size, stability and drug loading capacity to the equivalent formulations prepared using the thin-film approach, however, they were far more homogeneous in size and structure, and more toxic to breast cancer cell lines, providing greater therapeutic efficacy. The fast and straightforward microfluidic set-up provided greater control over distinct manufacturing parameters, to allow adjustments to the liposome size by altering the organic phase composition, total flow rate or flow rate ratio.

Credit: Annalisa Tirella, University of Manchester.

The researchers also found that co-loading doxorubicin with umbelliprenin – a lipophilic compound that shows powerful anti-inflammatory and anti-tumoral activity – using microfluidics further increased control over the particle size and added to the cytotoxicity of the liposomal formulation, without impacting the release of doxorubicin. The advanced liposome formulation co-encapsulated lipophilic umbelliprenin in the lipid bilayer and hydrophilic doxorubicin in the aqueous core, achieving morphological and size homogeneity across the formulations with greater efficacy against breast cancer.

The ease of scaling up

In a follow-up study, the researchers optimized the microfluidics approach to create a single-step fabrication method for the production of various liposomal formulations with phosphatidylcholines (PC) for the treatment of breast cancer.6 This enabled them to evaluate the impact of using PCs of different lengths on the characteristics of liposomes. The microfluidic device gave researchers greater control over fluidic parameters, allowing them to maintain a constant flow rate ratio while systematically varying the total flow rate settings to obtain monodispersed unilamellar liposomal formulations with a reproducible target size of 80-150 nm. This controlled single-step protocol provides a straightforward and affordable method for the research of future nanomedicines, offering the opportunity to reliably define variables, as well as easy scale-up without any post-modification steps.

Future research

Going forward, the researchers aim to understand the process of autonomous liposome production further and optimize the fabrication method for various particles and model drugs across other biopharmaceutical applications where controlled size and surface properties are crucial. This includes focusing on methods to increase the amount of loaded drug and overcome the dangers of burst release through the intelligent design of polymeric nanoparticles. Microfluidics has proven to be a fast, reliable and consistent method of producing monodisperse liposomal formulations by allowing greater control over variables than conventional methods, transforming the future and efficacy of drug encapsulation.

About the authors:

Dr Annalisa Tirella is a lecturer at the University of Manchester.
Dr Gurinder Vinner is a senior applications scientist for Dolomite Microfluidics. She is responsible for the brand’s applications activities with a keen interest in discovering novel ways of applying microfluidics. She has a background in microbiology and a PhD in Chemical Engineering, enabling her to bridge gaps between different disciplines. Her experience in encapsulation of phages for pharmaceutical, food, and agricultural industry allows her to understand formulation development challenges and the use of micro and nano-particles for targeted delivery.


1. The Facts about the Pfizer-BioNTech COVID-19 Vaccine. Pfizer. https://www.pfizer.com/news/hot-topics/the_facts_about_pfizer_and_biontech_s_covid_19_vaccine. Published 2021. Accessed 14th June, 2021.
2. Regulatory Approval of COVID-19 Vaccine Moderna. Medical & Healthcare products Regulatory Agency. https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna/information-for-uk-recipients-on-covid-19-vaccine-moderna. Published April 19th 2021. Accessed 14th June, 2021.
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