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The structural fate of lipid nanoparticles in the extracellular matrix.

ABSTRACT: Drug-loaded liposomes are the most successful nanomedicine to date, with multiple FDA-approved systems for a myriad of diseases. While liposome circulation time in blood and retention in tissues have been studied in detail, the structural fate of liposomes-and nanoparticles in general-in the body has not been extensively investigated. Here, we explore the interactions of liposomes with synthetic and natural hydrogel materials to understand how the natural extracellular matrix influences liposome structural characteristics. Small angle X-ray scattering, confocal microscopy, and cryogenic transmission electron microscopy data demonstrate that poly(ethylene glycol) (PEG), gelatin, alginate, and Matrigel® hydrogels cause 200-nm liposomes of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) to transform into micrometer-sized aggregates. These aggregates are composed of multilamellar vesicles around 100 nm in diameter with a mean interlamellar separation of 5.5 nm. Protecting the liposomes with a corona of PEG damps this restructuring effect, making the multilamellar vesicles less stable. We attribute this unilamellar to multilamellar transition to an osmotic driving force from the hydrogel environment. This lipid restructuring has broad ramifications in the design and use of nanomedicines, and in understanding the fate and function of natural lipid-based materials within the tissue microenvironment.

SUBMITTER: Bandara SR

PROVIDER: S-EPMC6961836 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The structural fate of lipid nanoparticles in the extracellular matrix.

Bandara Sarith R SR Molley Thomas G TG Kim Hojun H Bharath Priyalini A PA Kilian Kristopher A KA Leal Cecilia C

Materials horizons 20190731 1

Drug-loaded liposomes are the most successful nanomedicine to date, with multiple FDA-approved systems for a myriad of diseases. While liposome circulation time in blood and retention in tissues have been studied in detail, the structural fate of liposomes-and nanoparticles in general-in the body has not been extensively investigated. Here, we explore the interactions of liposomes with synthetic and natural hydrogel materials to understand how the natural extracellular matrix influences liposome ...[more]

PMID: 31942243

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Project description:Mesenchymal stem cells (MSCs) participate in the repair/remodeling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFÎ²-activated RhoA/ROCK functions as a molecular switch regarding the fate of MSCs in arterial repair/remodeling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell-ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration. Mouse bone marrow MSCs were purchased from Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine. All MSCs were cultured in Î±MEM supplied with 10% FCS. The transfection of DNA plasmids were performed with LipofectamineÂ® LTX with Plus Reagent (Life Technologies). Myc-L63RhoA or empty vector (control) was transfected into mouse bone marrow MSCs. Three days later, the cells were harvested and total RNA was isolated using RNeasy Mini kit (Qiagen). A total of four independent experiments were performed. RNA samples were assessed for quality and integrity using Synergy HT (Biotek, Winooski, VT). Microarray expression profiles were generated using the Illumina MouseRef-8 v2.0 Expression BeadChip (Illumina, San Diego, CA). Biotin-labeled cRNA was synthesized by the total prep RNA amplification kit from Ambion (Austin, TX). cRNA was quantified and normalized to 75 ng/Âµl, and then 1Âµg was hybridized to Beadchips. The hybridized chip was scanned using the Illumina iScan system and background corrected signal intensities were extracted using the GenomeStudio software (Illumina). The lumi R package was used to transform the data using a Variance Stabilizing Transformation (VST) and normalized using quantile normalization. Differential expression analysis was performed using the R/Mannova package. P-values were calculated by performing 1000 permutations, then corrected for multiple comparisons by false-discovery rate (FDR) transformation, using a 20% FDR cutoff.

Dataset Information

The structural fate of lipid nanoparticles in the extracellular matrix.

Publications

The structural fate of lipid nanoparticles in the extracellular matrix.

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