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Asymmetrical Flow Field Flow Fractionation Coupled to Nanoparticle Tracking Analysis for Rapid Online Characterization of Nanomaterials.

ABSTRACT: Increasing applications of nanomaterials in consumer goods, industrial products, medical practices, etc., calls for the development of tools for rapid separation, quantification, and sizing of nanoparticles to ensure their safe and sustainable employment. While many techniques are available for characterization of pure, homogeneous nanomaterial preparations, particle sizing and counting remains difficult for heterogeneous mixtures that resulted from imperfect synthesis conditions, aggregation from product instability, or degradation during storage. Herein, nanoparticle tracking analysis (NTA) was coupled to asymmetrical flow field flow fraction (AF4) using a splitter manifold to enable online particle separation and counting. The high pressure and flow rate in AF4 were reduced to the levels compatible with NTA by the proper flow splitting design, and a syringe pump was employed to withdraw fluid through the exit port of the NTA and maintain consistent flow rates entering NTA for proper particle sizing. Successful AF4-NTA coupling was demonstrated by analyzing a mixture of polystyrene particles with the average diameters of ∼50, 100, and 200 nm. Good correlation was observed between the amount of each type of particle injected to and measured by the hyphenated system. The particle concentrations acquired using online and offline coupling of AF4-NTA also agreed well with each other. The nonspherical nanoparticles like gold nanorods and hexagonal boron nitride nanosheets were also analyzed to demonstrate the versatile applicability of this system. Our work has proved that AF4-NTA can achieve accurate online particle counting on different populations of the nanomaterials in a mixture, which cannot be done by either AF4 or NTA alone. It will be a valuable tool for rapid characterization of heterogeneous nanomaterial solutions without purification to fulfill the regulation requirement on the nanomaterial-containing products.

SUBMITTER: Adkins GB

PROVIDER: S-EPMC7340584 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Liposomal formulations for the treatment of cancer and other diseases are the most common form of nanotechnology enabled pharmaceuticals (NEPs) submitted for market approval and in clinical application today. The accurate characterization of their physical-chemical properties is a key requirement; in particular, size, size distribution, shape, and physical-chemical stability are key among properties that regulators identify as critical quality attributes. Here we develop and validate an optimized method, based on multi-detector asymmetrical-flow field flow fractionation (MD-AF4) to accurately and reproducibly separate liposomal drug formulations into their component populations and to characterize their associated size and size distribution, whether monomodal or polymodal in nature. In addition, the results show that the method is suitable to measure liposomes in the presence of serum proteins and can yield information on the shape and physical stability of the structures. The optimized MD-AF4 based method has been validated across different instrument platforms, three laboratories, and multiple drug formulations following a comprehensive analysis of factors that influence the fractionation process and subsequent physical characterization. Interlaboratory reproducibility and intra-laboratory precision were evaluated, identifying sources of bias and establishing criteria for the acceptance of results. This method meets a documented high priority need in regulatory science as applied to NEPs such as Doxil and can be adapted to the measurement of other NEP forms (such as lipid nanoparticle therapeutics) with some modifications. Overall, this method will help speed up development of NEPS, and facilitate their regulatory review, ultimately leading to faster translation of innovative concepts from the bench to the clinic. Additionally, the approach used in this work (based on international collaboration between leading non-regulatory institutions) can be replicated to address other identified gaps in the analytical characterization of various classes of NEPs. Finally, a plan exists to pursue more extended interlaboratory validation studies to advance this method to a consensus international standard.

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Asymmetrical Flow Field Flow Fractionation Coupled to Nanoparticle Tracking Analysis for Rapid Online Characterization of Nanomaterials.

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