TY - JOUR
T1 - Practical aspects in size and morphology characterization of drug-loaded nano-liposomes
AU - Peretz Damari, Sivan
AU - Shamrakov, Dima
AU - Varenik, Maxim
AU - Koren, Erez
AU - Nativ-Roth, Einat
AU - Barenholz, Yechezkel
AU - Regev, Oren
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/8/25
Y1 - 2018/8/25
N2 - Size and morphology distributions are critical to the performance of nano-drug systems, as they determine drug pharmacokinetics and biodistribution. Therefore, comprehensive and reliable analyses of these properties are required by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). In this study, we compare two most commonly used approaches for assessing the size distribution and morphology of liposomal nano-drug systems, namely, dynamic light scattering (DLS) and cryogenic-transmission electron microscopy (cryo-TEM); an automated quantitative analysis method was developed for the latter method. We demonstrate the advantages and disadvantages of each of these two approaches for a commercial formulation of the anti-cancer drug doxorubicin - Doxil® in which the drug is encapsulated, mostly in the form of nano-rod crystals. With increasing drug concentration, these nano-rods change the shape of the liposomes from spherical, before drug loading, to prolate (oval), post drug loading. Cryo-TEM analysis provides a detailed size distribution of both the liposomes (minor and major axes) and the nano-rod drug. Both these values are relevant to the drug performance. In this study, we show that at elevated drug concentration (2.75 mg/ml) the drug grows mainly along the major axis and that this high concentration can result, in some cases, in liposome rupture. We show that the combination of cryo-TEM and DLS constitutes a reliable tool for demonstrating the stability of the formulation in human plasma at body temperature, a characteristic that is crucial for achieving therapeutic efficacy.
AB - Size and morphology distributions are critical to the performance of nano-drug systems, as they determine drug pharmacokinetics and biodistribution. Therefore, comprehensive and reliable analyses of these properties are required by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). In this study, we compare two most commonly used approaches for assessing the size distribution and morphology of liposomal nano-drug systems, namely, dynamic light scattering (DLS) and cryogenic-transmission electron microscopy (cryo-TEM); an automated quantitative analysis method was developed for the latter method. We demonstrate the advantages and disadvantages of each of these two approaches for a commercial formulation of the anti-cancer drug doxorubicin - Doxil® in which the drug is encapsulated, mostly in the form of nano-rod crystals. With increasing drug concentration, these nano-rods change the shape of the liposomes from spherical, before drug loading, to prolate (oval), post drug loading. Cryo-TEM analysis provides a detailed size distribution of both the liposomes (minor and major axes) and the nano-rod drug. Both these values are relevant to the drug performance. In this study, we show that at elevated drug concentration (2.75 mg/ml) the drug grows mainly along the major axis and that this high concentration can result, in some cases, in liposome rupture. We show that the combination of cryo-TEM and DLS constitutes a reliable tool for demonstrating the stability of the formulation in human plasma at body temperature, a characteristic that is crucial for achieving therapeutic efficacy.
KW - Cryo-TEM
KW - DLS
KW - Doxil®
KW - Doxorubicine
KW - Liposome
KW - Nano- drugs
KW - PeGylated
UR - http://www.scopus.com/inward/record.url?scp=85048979869&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2018.06.037
DO - 10.1016/j.ijpharm.2018.06.037
M3 - Article
C2 - 29913218
AN - SCOPUS:85048979869
SN - 0378-5173
VL - 547
SP - 648
EP - 655
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
IS - 1-2
ER -