Differences in Physico-Chemical Properties and Immunological Response in Nanosimilar Complex Drugs: The Case of Liposomal Doxorubicin

Abstract

This study aims to highlight the impact of physicochemical properties on the behaviour of nanopharmaceuticals and how much carrier structure and physiochemical characteristics weigh on the effects of a formulation. For this purpose, two commercially available nanosimilar formulations of Doxil and their respective carriers were compared as a case study. Although the two formulations were “similar”, we detected different toxicological effects (profiles) in terms of in vitro toxicity and immunological responses at the level of cytokines release and complement activation (iC3b fragment), that could be correlated with the differences in the physicochemical properties of the formulations. Shedding light on nanosimilar key quality attributes of liposome-based materials and the need for an accurate characterization, including investigation of the immunological effects, is of fundamental importance considering their great potential as delivery system for drugs, genes, or vaccines and the growing market demand.

Flotation Coefficient Distributions of Lipid Nanoparticles by Sedimentation Velocity Analytical Ultracentrifugation

“…Various techniques are available for the determination of NP size and size distribution, including electron microscopy (EM), dynamic light scattering (DLS), field-flow fractionation (FFF), nanoparticle tracking analysis (NTA), and sedimentation-based approaches such as differential centrifugal sedimentation (DCS) and sedimentation velocity analytical ultracentrifugation (SV-AUC). − In the case of solid NPs, such as inorganic or polymeric particles, both EM and DLS are limited in their ability to accurately measure ultrasmall NPs, characterize polydisperse NP preparations, and handle the presence of NP aggregates. Moreover, DLS has limited hydrodynamic resolution, while EM, as a nonbulk technique, is associated with lower statistical data quality.…”

“…LNPs may be employed to encapsulate drugs, as pioneered with Doxil, a PEGylated nanoliposome approved by the US Food and Drug Administration (FDA) in 1995 for Karposi sarcoma and later for ovarian cancer and myeloma. 14 − 16 , 26 , 27 Recently, there has been growing interest in the application of SV-AUC for the characterization of lipid-based nanomedicines encapsulating drugs as well as nucleic acids. 28 − 30 A groundbreaking example of the latter is Onpattro, a LNP formulation containing short interfering RNA.…”

“…A class of NPs with distinctly different behavior in SV-AUC is lipid nanoparticles (LNPs), , which can cause flotation instead of sedimentation in which case they cannot be analyzed in the standard models. LNPs may be employed to encapsulate drugs, as pioneered with Doxil, a PEGylated nanoliposome approved by the US Food and Drug Administration (FDA) in 1995 for Karposi sarcoma and later for ovarian cancer and myeloma. − ,, Recently, there has been growing interest in the application of SV-AUC for the characterization of lipid-based nanomedicines encapsulating drugs as well as nucleic acids. − A groundbreaking example of the latter is Onpattro, a LNP formulation containing short interfering RNA . Onpattro received approval from the FDA in 2018 for the treatment of polyneuropathies.…”