Abstract
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.
Highlights
Lyotropic non-lamellar liquid crystalline (LLC) nanoparticles, collectively referred to as ISAsomes (Internally Self-Assembled somes), are versatile drug delivery platforms [1,2,3,4,5,6,7,8,9,10,11]
The binary DOPG/x-3 PUFA mixtures were vortexed for 1 min and emulsified in 10 mM excess phosphate buffered saline (PBS), pH 7.4, by using the ultrasonic processor Qsonica 500 (Qsonica LLC, Newtown, CT, USA) for 5 min in pulse mode (5 s pulses interrupted by 2 s breaks) at 30% of its maximum power
Previous efforts have extensively studied the structural features of Pluronic F127-stabilized cubosomes or hexosomes based on unsaturated monoglycerides or phytantriol [59,68]
Summary
Lyotropic non-lamellar liquid crystalline (LLC) nanoparticles, collectively referred to as ISAsomes (Internally Self-Assembled somes), are versatile drug delivery platforms [1,2,3,4,5,6,7,8,9,10,11]. The inclusion of x-3 PUFAs is advantageous due to their reported health-promoting effects such as in the prevention and treatment of inflammatory conditions, neurodegenerative diseases, viral infections, and brain cancer [41,42,43,44], and could lead to the development of effective LLC nanopharmaceuticals with broad therapeutic indications In line with these possibilities, we further selected a well-characterized LLC formulation for uptake studies by human monocytic THP-1 cells (as model scavengers for assessing nanoparticle susceptibility to immune cell clearance) and a patient-derived xenograft glioblastoma GBM T10 cell line. We discuss the importance of these findings in relation to interpretation of LLC nanoparticle-cell interaction kinetics
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