TY - JOUR

T1 - Cell medium-dependent dynamic modulation of size and structural transformations of binary phospholipid/ω-3 fatty acid liquid crystalline nano-self-assemblies

T2 - Implications in interpretation of cell uptake studies

AU - Bor, Gizem

AU - Salentinig, Stefan

AU - Şahin, Evrim

AU - Nur Ödevci, Begüm

AU - Roursgaard, Martin

AU - Liccardo, Letizia

AU - Hamerlik, Petra

AU - Moghimi, Seyed Moein

AU - Yaghmur, Anan

N1 - Funding Information: Financial support by the Danish Council for Independent Research | Technology and Production Sciences, reference DFF-7017-00065 (to AY & SMM) is gratefully acknowledged. AY further acknowledges financial support from the Danish Natural Sciences Research Council (DanScatt) for SAXS experiments. The authors are grateful to the beamline scientist Dr. Heinz Amenitsch (Institute of Inorganic Chemistry, Graz University of Technology) for the technical support at the Austrian SAXS beamline (ELETTRA, Trieste, Italy). They thank also Tillman Pape (Core Facility for Integrated Microscopy, University of Copenhagen) for the technical assistance with cryo-TEM imaging, and Dr. Tom André Jos Vosh and Cecilia Cerretani (Department of Chemistry, University of Copenhagen) for their support and technical assistance with quantum yield measurements. The authors acknowledge the CERIC-ERIC Consortium for the access to experimental facilities and financial support. Funding Information: Financial support by the Danish Council for Independent Research | Technology and Production Sciences, reference DFF-7017-00065 (to AY & SMM) is gratefully acknowledged. AY further acknowledges financial support from the Danish Natural Sciences Research Council (DanScatt) for SAXS experiments. The authors are grateful to the beamline scientist Dr. Heinz Amenitsch (Institute of Inorganic Chemistry, Graz University of Technology) for the technical support at the Austrian SAXS beamline (ELETTRA, Trieste, Italy). They thank also Tillman Pape (Core Facility for Integrated Microscopy, University of Copenhagen) for the technical assistance with cryo-TEM imaging, and Dr. Tom Andr? Jos Vosh and Cecilia Cerretani (Department of Chemistry, University of Copenhagen) for their support and technical assistance with quantum yield measurements. The authors acknowledge the CERIC-ERIC Consortium for the access to experimental facilities and financial support. Publisher Copyright: © 2021 The Author(s)

PY - 2022

Y1 - 2022

N2 - Lyotropic non-lamellar liquid crystalline (LLC) nanoparticles, with their tunable structural features and capability of loading a wide range of drugs and reporter probes, are emerging as versatile injectable nanopharmaceuticals. Secondary emulsifiers, such as Pluronic block copolymers, are commonly used for colloidal stabilization of LLC nanoparticles, but their inclusion often compromises the biological safety (e.g., poor hemocompatibility and enhanced cytotoxicity) of the formulation. Here, we introduce a library of colloidally stable, structurally tunable, and pH-responsive lamellar and non-lamellar liquid crystalline nanoparticles from binary mixtures of a phospholipid (phosphatidylglycerol) and three types of omega-3 fatty acids (ω-3 PUFAs), prepared in the absence of a secondary emulsifier and organic solvents. We study formulation size distribution, morphological heterogeneity, and the arrangement of their internal self-assembled architectures by nanoparticle tracking analysis, synchrotron small-angle X-ray scattering, and cryo-transmission electron microscopy. The results show the influence of type and concentration of ω-3 PUFAs in nanoparticle structural transitions spanning from a lamellar (Lα) phase to inverse discontinuous (micellar) cubic Fd3m and hexagonal phase (H2) phases, respectively. We further report on cell-culture medium-dependent dynamic fluctuations in nanoparticle size, number and morphology, and simultaneously monitor uptake kinetics in two human cell lines. We discuss the role of these multiparametric biophysical transformations on nanoparticle-cell interaction kinetics and internalization mechanisms. Collectively, our findings contribute to the understanding of fundamental steps that are imperative for improved engineering of LLC nanoparticles with necessary attributes for pharmaceutical development.

AB - Lyotropic non-lamellar liquid crystalline (LLC) nanoparticles, with their tunable structural features and capability of loading a wide range of drugs and reporter probes, are emerging as versatile injectable nanopharmaceuticals. Secondary emulsifiers, such as Pluronic block copolymers, are commonly used for colloidal stabilization of LLC nanoparticles, but their inclusion often compromises the biological safety (e.g., poor hemocompatibility and enhanced cytotoxicity) of the formulation. Here, we introduce a library of colloidally stable, structurally tunable, and pH-responsive lamellar and non-lamellar liquid crystalline nanoparticles from binary mixtures of a phospholipid (phosphatidylglycerol) and three types of omega-3 fatty acids (ω-3 PUFAs), prepared in the absence of a secondary emulsifier and organic solvents. We study formulation size distribution, morphological heterogeneity, and the arrangement of their internal self-assembled architectures by nanoparticle tracking analysis, synchrotron small-angle X-ray scattering, and cryo-transmission electron microscopy. The results show the influence of type and concentration of ω-3 PUFAs in nanoparticle structural transitions spanning from a lamellar (Lα) phase to inverse discontinuous (micellar) cubic Fd3m and hexagonal phase (H2) phases, respectively. We further report on cell-culture medium-dependent dynamic fluctuations in nanoparticle size, number and morphology, and simultaneously monitor uptake kinetics in two human cell lines. We discuss the role of these multiparametric biophysical transformations on nanoparticle-cell interaction kinetics and internalization mechanisms. Collectively, our findings contribute to the understanding of fundamental steps that are imperative for improved engineering of LLC nanoparticles with necessary attributes for pharmaceutical development.

KW - Cryogenic transmission electron microscopy

KW - Glioblastoma multiforme T10 cells

KW - Hexosomes

KW - ISAsomes

KW - Micellar cubosomes

KW - Monocytic THP-1 cells

KW - Synchrotron small angle X-ray scattering

U2 - 10.1016/j.jcis.2021.07.149

DO - 10.1016/j.jcis.2021.07.149

M3 - Journal article

C2 - 34399363

AN - SCOPUS:85112345721

VL - 606

SP - 464

EP - 479

JO - Journal of Colloid and Interface Science

JF - Journal of Colloid and Interface Science

SN - 0021-9797

ER -