Design Parameters Modulating Intracellular Drug Delivery: Anchoring to Specific Cellular Epitopes, Carrier Geometry, and Use of Auxiliary Pharmacological Agents

Muro, Silvia; Muzykantov, Vladimir R.

doi:10.1002/9780470875780.ch24

Cited by 5 publications

(3 citation statements)

References 102 publications

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“…It is over-expressed in vascular pathologies involving inflammation, thrombosis, atherosclerosis, oxidative stress, ischemia-reperfusion, altered blood flow, and diabetes 1, 2 , representing an interesting target for vascular drug delivery 3–5 . Multivalent engagement of ICAM-1 by anti-ICAM-coated polymer carriers used for targeting of therapeutics, results in uptake of said carriers via cell adhesion molecule (CAM)-mediated endocytosis (supplemental Table S1) 6 .…”

mentioning

confidence: 99%

Intercellular Adhesion Molecule 1 Engagement Modulates Sphingomyelinase and Ceramide, Supporting Uptake of Drug Carriers by the Vascular Endothelium

Serrano

Bhowmick

Chadha

et al. 2012

ATVB

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140

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Objective Engagement of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells (ECs) by ICAM-1-targeted carriers induces cell adhesion molecule (CAM)-mediated endocytosis, providing intra-endothelial delivery of therapeutics. This pathway differs from classical endocytic mechanisms and invokes aspects of endothelial signaling during inflammation. ICAM-1 interacts with Na+/H+ exchanger NHE1 during endocytosis, but it is unclear how this regulates plasmalemma and cytoskeletal changes. We studied such aspects in this work. Methods and Results We used fluorescence and electron microscopy, inhibitors and knockout tools, cell culture and mouse models. ICAM-1 engagement by anti-ICAM carriers induced sphingomyelin-enriched engulfment structures. Acid sphingomyelinase (ASM), an acidic enzyme that hydrolyzes sphingomyelin into ceramide (involved in plasmalemma deformability and cytoskeletal reorganization), redistributed to ICAM-1-engagement sites at ceramide-enriched areas. This induced actin stress fibers and carrier endocytosis. Inhibiting ASM impaired ceramide enrichment, engulfment structures, cytoskeletal reorganization, and carrier uptake, which was rescued by supplying this enzyme activity exogenously. Interfering with NHE1 rendered similar outcomes, suggesting that Na+/H+ exchange might provide an acidic microenvironment for ASM at the plasmalemma. Conclusions These findings are consistent with the ability of ECs to internalize relatively large ICAM-1-targeted drug carriers, and expand our knowledge on the regulation of the sphingomyelin/ceramide pathway by the vascular endothelium.

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mentioning

confidence: 99%

Intercellular Adhesion Molecule 1 Engagement Modulates Sphingomyelinase and Ceramide, Supporting Uptake of Drug Carriers by the Vascular Endothelium

Serrano

Bhowmick

Chadha

et al. 2012

ATVB

Self Cite

140

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“…However, alternative mechanisms regulating access to spatially clustered receptors or noncanonical internalization routes can favor the uptake of other NP types. [22,45,46] Conclusion: Our computational analysis shows that tuning NP stiffness impacts enthalpic and entropic contributions to multivalent adhesion and uptake through both cytoskeletal dependent and curvature dependent mechanisms. The results also show cellular targeting and uptake can be rationally engineered by the tuning of both NP and cell mechanical properties.…”

Section: Discussionmentioning

confidence: 87%

“…However, alternative mechanisms regulating access to spatially clustered receptors or noncanonical internalization routes can favor the uptake of other NP types. [ 22,45,46 ]…”

Section: Discussionmentioning

confidence: 99%

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

Farokhirad

Kandy

Tsourkas

et al. 2021

Adv Materials Inter

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gene therapy [1][2][3] and their application as biomarkers for imaging and detection. [4][5][6] Functional nanoparticles are finding applications in genome editing, immune modulation, cell therapies, and molecular diagnostics to stratify patients based on biomarkers. However, the functional NPs' design, optimization, and deployment are hampered by our lack of understanding of their biological barriers and pharmacokinetics. [7] While such barriers have contributions that are systemic and span multiple scales, the specificity for a given application has essential contributions from the cellular scale. Cellular targeting is governed by avidity (adhesion) and uptake (internalization), which depend on the properties of the NPs and the cellular microenvironment.Adhesion between an NP and a cell surface typically involves the simultaneous binding [8,9] of many hundreds of ligands on the NP's surface to a similar number of receptors on the cell surface. [9][10][11][12][13] The physiological outcome of such multivalent adhesion, which can mediate diverse phenomena, including cell crowding and cell uptake, [14] depends on the strength of ligandreceptor binding interactions. Other factors that can modulate multivalent adhesion strength include physiochemical properties of both the NPs and the cell surfaces. [15] Previous How nanoparticle (NP) mechanical properties impact multivalent ligandreceptor-mediated binding to cell surfaces, the avidity, propensity for internalization, and effects due to crowding remains unknown or unquantified. Through computational analyses, the effects of NP composition from soft, deformable NPs to rigid spheres, effect of tethers, the crowding of NPs at the membrane surface, and the cell membrane properties such as cytoskeletal interactions are addressed. 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 are reported; moreover, for the case of flexible NP, NP stiffness is tuned by varying the internal crosslinking density. Biophysical modeling of NP binding to membranes together with thermodynamic analysis powered by free energy calculations is employed, and it is shown 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. Rational design principles that confer tension, membrane excess area, and cytoskeletal sensing properties to the NP which can be exploited for cellspecific targeting of NP are uncovered.

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

Farokhirad

Kandy

Tsourkas

et al. 2021

Preprint

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It is becoming evident that engineered physicochemical characteristics of nanoparticles (NPs) are essential to improve their biological function for their cellular delivery and uptake. How NP mechanical properties impact multivalent ligand-receptor mediated binding to cell surfaces, the avidity of NP adhesion to cells, and cooperative effects due to crowding remain largely unknown or unquantified, and how tuning NPs' stiffness impacts their propensity for internalization is not clear. Here we focus on exploring the 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 employed our recent spatial 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 in a non-intuitive fashion because of 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. We find that the NP binding avidity can be engineered in a crowded environment by tuning their flexibility. We also find that when the cell membrane is bound to the cytoskeletal proteins via the pinning sites, the pinning sites' presence does not limit the binding avidity of both flexible and rigid-tethered NPs. Furthermore, we show that the membrane tension and pinning density, and the stiffness of flexible NPs can be tuned to alter the adhesion energy landscape and eventually improve the adhesion efficiency of flexible NPs. We also probed the effects of curvature-inducing proteins and receptor-ligand binding interactions on NP uptake. We found that complete uptake of both rigid-tethered NPs, and flexible NPs can be achieved by tuning NP stiffness and membrane tension even under moderate levels of ligand-densities in use for physiologically relevant applications. 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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Design Parameters Modulating Intracellular Drug Delivery: Anchoring to Specific Cellular Epitopes, Carrier Geometry, and Use of Auxiliary Pharmacological Agents

Cited by 5 publications

References 102 publications

Intercellular Adhesion Molecule 1 Engagement Modulates Sphingomyelinase and Ceramide, Supporting Uptake of Drug Carriers by the Vascular Endothelium

Intercellular Adhesion Molecule 1 Engagement Modulates Sphingomyelinase and Ceramide, Supporting Uptake of Drug Carriers by the Vascular Endothelium

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

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

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