TY - JOUR

T1 - Preparation of Heat-Denatured Macroaggregated Albumin for Biomedical Applications Using a Microfluidics Platform

AU - Esposito, Tullio V.F.

AU - Stütz, Helene

AU - Rodríguez-Rodríguez, Cristina

AU - Bergamo, Marta

AU - Charles, Lovelyn

AU - Geczy, Reka

AU - Blackadar, Colin

AU - Kutter, Jörg P.

AU - Saatchi, Katayoun

AU - Häfeli, Urs O.

N1 - Funding Information: This research was made possible by a grant from Lundbeck Foundation of Denmark (UBC-SUND Lundbeck Foundation Professorship to UOH; project number 2014-4176). The authors also thank the Canada Foundation for Innovation (project number 25413) for its support of the imaging facility used in this study, the UBC in vivo Imaging Center ( http://invivoimaging.ca/ ). T.V.F.E. received financial support from a Killam Doctoral Fellowship and a Four-Year Doctoral Fellowship (4YF) from UBC. H.S. was given financial assistance by Niederoesterreich Topstipendium during her internship at UBC. L.C. is supported by the Isotopes for Science and Medicine (IsoSiM) program, which is funded through the Natural Science and Engineering Research Council (NSERC) of Canada. K.S. acknowledges the generous support of BWXT Isotope Technology Group (BWXT ITG) for the supply of the radioisotope. The authors also thank the workshop at the Department of Pharmacy, University of Copenhagen, especially Lasse Johansson, for building the microfluidic heating chamber and some of the connectors used in this study. We are grateful to Maryam Osooly and Dr. Laura Mowbray from the UBC Center for Comparative Medicine (CCM) for all their assistance with the animal studies. Finally, the authors thank David Bauer and Paulina Biniecka for their review and insights into the drafting of the manuscript. Publisher Copyright: ©

PY - 2021

Y1 - 2021

N2 - Albumin is widely used in pharmaceutical applications to alter the pharmacokinetic profile, improve efficacy, or decrease the toxicity of active compounds. Various drug delivery systems using albumin have been reported, including microparticles. Macroaggregated albumin (MAA) is one of the more common forms of albumin microparticles, which is predominately used for lung perfusion imaging when labeled with radionuclide technetium-99m (99mTc). These microparticles are formed by heat-denaturing albumin in a bulk solution, making it very challenging to control the size and dispersity of the preparations (coefficient of variation, CV, ∼50%). In this work, we developed an integrated microfluidics platform to create more tunable and precise MAA particles, the so-called microfluidic-MAA (M2A2). The microfluidic chips, prepared using off-stoichiometry thiol-ene chemistry, consist of a flow-focusing region followed by an extended and water-heated curing channel (85 °C). M2A2 particles with diameters between 70 and 300 μm with CVs between 10 and 20% were reliably prepared by adjusting the flow rates of the dispersed and continuous phases. To demonstrate the pharmaceutical utility of M2A2, particles were labeled with indium-111 (111In) and their distribution was assessed in healthy mice using nuclear imaging. 111In-M2A2 behaved similarly to 99mTc-MAA, with lung uptake predominately observed early on followed by clearance over time by the reticuloendothelial and renal systems. Our microfluidic chip represents an elegant and controllable method to prepare albumin microparticles for biomedical applications.

AB - Albumin is widely used in pharmaceutical applications to alter the pharmacokinetic profile, improve efficacy, or decrease the toxicity of active compounds. Various drug delivery systems using albumin have been reported, including microparticles. Macroaggregated albumin (MAA) is one of the more common forms of albumin microparticles, which is predominately used for lung perfusion imaging when labeled with radionuclide technetium-99m (99mTc). These microparticles are formed by heat-denaturing albumin in a bulk solution, making it very challenging to control the size and dispersity of the preparations (coefficient of variation, CV, ∼50%). In this work, we developed an integrated microfluidics platform to create more tunable and precise MAA particles, the so-called microfluidic-MAA (M2A2). The microfluidic chips, prepared using off-stoichiometry thiol-ene chemistry, consist of a flow-focusing region followed by an extended and water-heated curing channel (85 °C). M2A2 particles with diameters between 70 and 300 μm with CVs between 10 and 20% were reliably prepared by adjusting the flow rates of the dispersed and continuous phases. To demonstrate the pharmaceutical utility of M2A2, particles were labeled with indium-111 (111In) and their distribution was assessed in healthy mice using nuclear imaging. 111In-M2A2 behaved similarly to 99mTc-MAA, with lung uptake predominately observed early on followed by clearance over time by the reticuloendothelial and renal systems. Our microfluidic chip represents an elegant and controllable method to prepare albumin microparticles for biomedical applications.

KW - lab-on-a-chip

KW - macroaggregated albumin

KW - microfluidics

KW - SPECT/CT

U2 - 10.1021/acsbiomaterials.1c00284

DO - 10.1021/acsbiomaterials.1c00284

M3 - Journal article

C2 - 33826291

AN - SCOPUS:85105107351

VL - 7

SP - 2823

EP - 2834

JO - ACS Biomaterials Science and Engineering

JF - ACS Biomaterials Science and Engineering

SN - 2373-9878

IS - 6

ER -