Cellular Uptake and Intracellular Cargo Release From Dextran Based Nanogel Drug Carriers

Ferrer, M. Carme Coll; Sobolewski, Peter; Composto, Russell J.; Eckmann, David M.

doi:10.1115/1.4023246

Cited by 13 publications

(8 citation statements)

References 44 publications

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“…e), as dextrans have been reported inside acidic compartments (Carme Coll Ferrer et al . ). In addition, some of the S100B‐Alexa 488 ‐positive vesicles co‐localized (10 ± 1%; Fig.…”

Section: Resultsmentioning

confidence: 97%

Time‐dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes

Lasič

Galland

Vardjan

et al. 2016

Journal of Neurochemistry

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Astrocytes, the most heterogeneous glial cells in the central nervous system, contribute to brain homeostasis, by regulating a myriad of functions, including the clearance of extracellular debris. When cells are damaged, cytoplasmic proteins may exit into the extracellular space. One such protein is S100B, which may exert toxic effects on neighboring cells unless it is removed from the extracellular space, but the mechanisms of this clearance are poorly understood. By using time-lapse confocal microscopy and fluorescently labeled S100B (S100B-Alexa ) and fluorescent dextran (Dextran ), a fluid phase uptake marker, we examined the uptake of fluorescently labeled S100B-Alexa from extracellular space and monitored trafficking of vesicles that internalized S100B-Alexa . Initially, S100B-Alexa and Dextran internalized with distinct rates into different endocytotic vesicles; S100B-Alexa internalized into smaller vesicles than Dextran . At a later stage, S100B-Alexa -positive vesicles substantially co-localized with Dextran -positive endolysosomes and with acidic LysoTracker-positive vesicles. Cell treatment with anti-receptor for advanced glycation end products (RAGE) antibody, which binds to RAGE, a 'scavenger receptor', partially inhibited uptake of S100B-Alexa , but not of Dextran . The dynamin inhibitor dynole 34-2 inhibited internalization of both fluorescent probes. Directional mobility of S100B-Alexa -positive vesicles increased over time and was inhibited by ATP stimulation, an agent that increases cytosolic free calcium concentration ([Ca ] ). We conclude that astrocytes exhibit RAGE- and dynamin-dependent vesicular mechanism to efficiently remove S100B from the extracellular space. If a similar process occurs in vivo, astroglia may mitigate the toxic effects of extracellular S100B by this process under pathophysiologic conditions. This study reveals the vesicular clearance mechanism of extracellular S100B in astrocytes. Initially, fluorescent S100B internalizes into smaller endocytotic vesicles than dextran molecules. At a later stage, both probes co-localize within endolysosomes. S100B internalization is both dynamin- and RAGE-dependent, whereas dextran internalization is dependent on dynamin. Vesicle internalization likely mitigates the toxic effects of extracellular S100B and other waste products.

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“…e), as dextrans have been reported inside acidic compartments (Carme Coll Ferrer et al . ). In addition, some of the S100B‐Alexa 488 ‐positive vesicles co‐localized (10 ± 1%; Fig.…”

Section: Resultsmentioning

confidence: 97%

Time‐dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes

Lasič

Galland

Vardjan

et al. 2016

Journal of Neurochemistry

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“…Rigid polystyrene and Flexible nanogel particles (NGPs): Methods for preparation, characterization, and assaying of binding, uptake, and targeting of rigid and flexible particles were described in earlier works 19,20,22,41 and will not be repeated here. We discuss the protocols for rigid-tethered particles because experimental results for such particles are presented for the first time here.…”

Section: Np Uptake Through Curvature Effector Proteinsmentioning

confidence: 99%

Biophysical Considerations in the Rational Design and Cellular Targeting of Flexible Polymeric Nanoparticles

Farokhirad

Kandy

Tsourkas

et al. 2021

Preprint

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Physicochemical characteristics of nanoparticles (NPs) can be engineered for tuning their biological function in cellular delivery. How NP mechanical properties impact multivalent ligand-receptor mediated binding to cell surfaces, the avidity of NP adhesion to cells, propensity for internalization, and effects due to crowding remain unknown or unquantified. We report computational analyses of binding mechanisms of three distinct NPs that differ in type and rigidity (core-corona flexible NP, rigid NP, and rigid-tethered NP) but are otherwise similar in size and ligand surface density; moreover, for the case of flexible NP, we tune NP stiffness by varying the internal crosslinking density. We employ biophysical modeling of NP binding to membranes together with thermodynamic analysis powered by free energy calculations and show that efficient cellular targeting and uptake of NP functionalized with targeting ligand molecules can be shaped by factors including NP flexibility and crowding, receptor-ligand binding avidity, state of the membrane cytoskeleton, and curvature inducing proteins. Owing to this multitude of factors, we demonstrate that the binding avidity of a flexible NP depends on engineered changes in NP flexibility governed by significant enthalpy entropy compensations arising from multiple competing terms associated with NP, receptor density, and membrane. Analyses of the individual enthalpic and entropic contributions associated with NP, membrane, and receptor-ligand binding and receptor diffusion collectively illuminate this complex dependence of avidity on crosslinking. These findings provide strong evidence that NP flexibility is an important design parameter for rationally engineering NP targeting and uptake in a crowded cellular adhesion microenvironment.

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“…However, it should be stressed, that the problem of degradability of the NGs and the utilization of the products of their degradation are not deeply studied in vivo. Recently, the non-toxicity of the nanogel constituents, after the degradation process, was confirmed by in vivo studies for the glutathione (GSH)-responsive hybrid NGs combined from tetralysine and oligoethylenimine [83].…”

Section: Design Criteria For Degradable Nanogel and Biomolecule Hymentioning

confidence: 99%

Recent Advances in Degradable Hybrids of Biomolecules and NGs for Targeted Delivery

Stanisławska¹,

Liwinska

Łyp³

et al. 2019

Molecules

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Recently, the fast development of hybrid nanogels dedicated to various applications has been seen. In this context, nanogels incorporating biomolecules into their nanonetworks are promising innovative carriers that gain great potential in biomedical applications. Hybrid nanogels containing various types of biomolecules are exclusively designed for: improved and controlled release of drugs, targeted delivery, improvement of biocompatibility, and overcoming of immunological response and cell self-defense. This review provides recent advances in this rapidly developing field and concentrates on: (1) the key physical consequences of using hybrid nanogels and introduction of biomolecules; (2) the construction and functionalization of degradable hybrid nanogels; (3) the advantages of hybrid nanogels in controlled and targeted delivery; and (4) the analysis of the specificity of drug release mechanisms in hybrid nanogels. The limitations and future directions of hybrid nanogels in targeted specific- and real-time delivery are also discussed.

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Cellular Uptake and Intracellular Cargo Release From Dextran Based Nanogel Drug Carriers

Cited by 13 publications

References 44 publications

Time‐dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes

Time‐dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes

Biophysical Considerations in the Rational Design and Cellular Targeting of Flexible Polymeric Nanoparticles

Recent Advances in Degradable Hybrids of Biomolecules and NGs for Targeted Delivery

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