Translating the fabrication of protein-loaded poly(lactic-co-glycolic acid) nanoparticles from bench to scale-independent production using microfluidics

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Abstract

In the formulation of nanoparticles, poly(lactic-co-glycolic acid) (PLGA) is commonly employed due to its Food and Drug Administration and European Medicines Agency approval for human use, its ability to encapsulate a variety of moieties, its biocompatibility and biodegradability and its ability to offer a range of controlled release profiles. Common methods for the production of PLGA particles often adopt harsh solvents, surfactants/stabilisers and in general are multi-step and time-consuming processes. This limits the translation of these drug delivery systems from bench to bedside. To address this, we have applied microfluidic processes to develop a scale-independent platform for the manufacture, purification and monitoring of nanoparticles. Thereby, the influence of various microfluidic parameters on the physicochemical characteristics of the empty and the protein-loaded PLGA particles was evaluated in combination with the copolymer employed (PLGA 85:15, 75:25 or 50:50) and the type of protein loaded. Using this rapid production process, emulsifying/stabilising agents (such as polyvinyl alcohol) are not required. We also incorporate in-line purification systems and at-line particle size monitoring. Our results demonstrate the microfluidic control parameters that can be adopted to control particle size and the impact of PLGA copolymer type on the characteristics of the produced particles. With these nanoparticles, protein encapsulation efficiency varies from 8 to 50% and is controlled by the copolymer of choice and the production parameters employed; higher flow rates, combined with medium flow rate ratios (3:1), should be adopted to promote higher protein loading (% wt/wt). In conclusion, herein, we outline the process controls for the fabrication of PLGA polymeric nanoparticles incorporating proteins in a rapid and scalable manufacturing process.

Scale-independent production of polymer nanoparticles

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Most cited references 32

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Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses.

Zhengrong Cui, Moses O. Oyewumi, Amit Kumar Gupta (2010)

The development of novel immune adjuvants is emerging as a significant area of vaccine delivery based on the continued necessity to amplify immune responses to a wide array of new antigens that are poorly immunogenic. This article specifically focuses on the application of nanoparticles and microparticles as vaccine adjuvants. Many investigators are in agreement that the size of the particles is crucial to their adjuvant activities. However, reports on correlating the size of particle-based adjuvants and the resultant immune responses have been conflicting, with investigators on both sides of the fence with impressive data in support of the effectiveness of particles with small sizes (submicron) over those with larger sizes (micron) and vice versa, while other investigators reported data that showed submicron- and micron-sized particles are effective to the same degree as immune adjuvants. We have generated a list of biological, immunological and, more importantly, vaccine formulation parameters that may have contributed to the inconsistency from different studies and made recommendations on future studies attempting to correlate the size of particulate adjuvants and the immune responses induced. The information gathered could lead to strategies to optimize the performance of nano-microparticles as immune adjuvants.

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In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems.

Ndealilia Swai, E L Booysen, Yolandy Lemmer … (2010)

The remarkable physicochemical properties of particles in the nanometer range have been proven to address many challenges in the field of science. However, the possible toxic effects of these particles have raised some concerns. The aim of this article is to evaluate the effects of poly(lactide-co-glycolide) (PLGA) nanoparticles in vitro and in vivo compared to industrial nanoparticles of a similar size range such as zinc oxide, ferrous oxide, and fumed silica. An in vitro cytotoxicity study was conducted to assess the cell viability following exposure to PLGA nanoparticles. Viability was determined by means of a WST assay, wherein cell viability of greater than 75% was observed for both PLGA and amorphous fumed silica particles and ferrous oxide, but was significantly reduced for zinc oxide particles. In vivo toxicity assays were performed via histopathological evaluation, and no specific anatomical pathological changes or tissue damage was observed in the tissues of Balb/C mice. The extent of tissue distribution and retention following oral administration of PLGA particles was analyzed for 7 days. After 7 days, the particles remained detectable in the brain, heart, kidney, liver, lungs, and spleen. The results show that a mean percentage (40.04%) of the particles were localized in the liver, 25.97% in the kidney, and 12.86% in the brain. The lowest percentage was observed in the spleen. Thus, based on these assays, it can be concluded that the toxic effects observed with various industrial nanoparticles will not be observed with particles made of synthetic polymers such as PLGA when applied in the field of nanomedicine. Furthermore, the biodistribution of the particles warrants surface modification of the particles to avoid higher particle localization in the liver. The aim of this study was to evaluate the effects of poly(lactide-co-glycolide) (PLGA) nanoparticles in vitro and in vivo compared to industrial nanoparticles including zinc oxide, ferrous oxide, and fumed silica. The authors concluded that the toxic effects observed with various industrial nanoparticles is unlikely to be observed with particles made of PLGA. The biodistribution of these particles warrants surface modification to avoid particle accumulation in the liver. Copyright © 2010 Elsevier Inc. All rights reserved.

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Microfluidic mixing and the formation of nanoscale lipid vesicles.

Christopher Hong, Leandro M. Gaitán, Andreas Jahn … (2010)

We investigate the formation of unilamellar lipid vesicles (liposomes) with diameters of tens of nanometers by controlled microfluidic mixing and nanoparticle determination (COMMAND). Our study includes liposome synthesis experiments and numerical modeling of our microfluidic implementation of the batch solvent injection method. We consider microfluidic liposome formation from the perspective of fluid interfaces and convective-diffusive mixing, as we find that bulk fluid flow parameters including hydrodynamically focused alcohol stream width, final alcohol concentration, and shear stress do not primarily determine the vesicle formation process. Microfluidic device geometry in conjunction with hydrodynamic flow focusing strongly influences vesicle size distributions, providing a coarse method to control liposome size, while total flow rate allows fine-tuning the vesicle size in certain focusing regimes. Although microfluidic liposome synthesis is relatively simple to implement experimentally, numerical simulations of the mixing process reveal a complex system of fluid flow and mass transfer determining the formation of nonequilibrium vesicles. These results expand our understanding of the microfluidic environment that controls liposome self-assembly and yield several technological advances for the on-chip synthesis of nanoscale lipid vesicles.

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Author and article information

Contributors

Yvonne Perrie: yvonne.perrie@strath.ac.uk

Journal

Journal ID (nlm-ta): Drug Deliv Transl Res

Journal ID (iso-abbrev): Drug Deliv Transl Res

Title: Drug Delivery and Translational Research

Publisher: Springer US (New York )

ISSN (Print): 2190-393X

ISSN (Electronic): 2190-3948

Publication date (Electronic): 9 January 2020

Publication date PMC-release: 9 January 2020

Publication date (Print): 2020

Volume: 10

Issue: 3

Pages: 582-593

Affiliations

[1 ]GRID grid.11984.35, ISNI 0000000121138138, Strathclyde Institute of Pharmacy and Biomedical Sciences, , University of Strathclyde, ; 161 Cathedral St, Glasgow, G4 0RE Scotland

[2 ]GRID grid.6203.7, ISNI 0000 0004 0417 4147, Center for Vaccine Research, , Statens Serum Institut, ; Copenhagen, Denmark

Article

Publisher ID: 699

DOI: 10.1007/s13346-019-00699-y

PMC ID: 7228990

PubMed ID: 31919746

SO-VID: d1bf2700-afea-4d31-a249-46f188b45bd9

License:

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