title: An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome.
abstract: 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.
authors.affiliation: Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Wibroe
authors.affiliation: Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Davoud
authors.initials: D
authors.lastname: Ahmadvand
authors.affiliation: Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Oghabian
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Anan
authors.initials: A
authors.lastname: Yaghmur
authors.affiliation: Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark; NanoScience Centre, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark. Electronic address: moein.moghimi@gmail.com.
authors.forename: S Moein
authors.initials: SM
authors.lastname: Moghimi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology*; D003167:Complement Activation / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000276:immunology / Q000648:ultrastructure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Complement system; Cryo-TEM; Nanomedicine; Nanosimilars; Non-biological complex drugs