TY - JOUR
T1 - An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome
AU - Wibroe, Peter P.
AU - Ahmadvand, Davoud
AU - Oghabian, Mohammad Ali
AU - Yaghmur, Anan
AU - Moghimi, S. Moein
N1 - Funding Information:
This work was supported by the Danish Agency for Science, Technology and Innovation , reference 09-065736 (Det Strategiske Forskningsråd) (SMM). PPW is a recipient of a PhD Scholarship Award from the Faculty of Health and Medical Sciences, University of Copenhagen. We also acknowledge Dr. Marina A. Dobrovolskaia (Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Ledios Biomedical Research, Inc., Frederick, MD, USA) for providing samples of Doxil® and DOXOrubicin, as well as for the fruitful discussion throughout this work. We are also grateful to the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen for technical support in sample preparation and acquisition of cryo-transmission electron microscopy images.
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/1/10
Y1 - 2016/1/10
N2 - In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil® and Caelyx®. Notably, these included differences in vesicular population aspect ratios and particle number. Among the tested products, only SinaDoxosome, in addition to the presence of unilamellar vesicles with entrapped doxorubicin crystals, contained empty circular disks. Differences were also found in complement responses, which may be related to some morphological differences. This study has demonstrated an integrated biophysical and immunological toolbox for improved analysis and detection of physical differences among vesicular populations that may modulate their clinical performance. Combined, these approaches may help better product selection for infusion to the patients as well as for improved design and characterization of future vesicular NBCDs with enhanced clinical performance and safety.
AB - In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil® and Caelyx®. Notably, these included differences in vesicular population aspect ratios and particle number. Among the tested products, only SinaDoxosome, in addition to the presence of unilamellar vesicles with entrapped doxorubicin crystals, contained empty circular disks. Differences were also found in complement responses, which may be related to some morphological differences. This study has demonstrated an integrated biophysical and immunological toolbox for improved analysis and detection of physical differences among vesicular populations that may modulate their clinical performance. Combined, these approaches may help better product selection for infusion to the patients as well as for improved design and characterization of future vesicular NBCDs with enhanced clinical performance and safety.
KW - Complement system
KW - Cryo-TEM
KW - Nanomedicine
KW - Nanosimilars
KW - Non-biological complex drugs
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U2 - 10.1016/j.jconrel.2015.11.021
DO - 10.1016/j.jconrel.2015.11.021
M3 - Article
C2 - 26608877
AN - SCOPUS:84948464298
SN - 0168-3659
VL - 221
SP - 1
EP - 8
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -