Conserved Activity of Reassociated Homotetrameric Protein Subunits Released from Mesoporous Silica Nanoparticles

Deodhar, Gauri; Adams, Marisa L.; Joardar, Sutapa; Joglekar, Madhura; Davidson, Malcolm R.; Smith, William C.; Mettler, Madelyn; Toler, Sydney A; Davies, Fiona K.; Williams, S. Kim Ratanathanawongs; Trewyn, Brian G.

doi:10.1021/acs.langmuir.7b03310

Cited by 6 publications

(6 citation statements)

References 37 publications

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“…54 To overcome this limitation and further enhance lysis speed, we develop here a µwheel-based strategy of delivering both tPA and plasminogen using tPAµwheels coupled with mesoporous silica nanoparticles (MSN), which can provide controlled release of proteins. [55][56][57] These co-laden µwheels break the biochemical speed limit by supplementing fresh plasminogen and burrowing their way into plasma clots (Figure 1D).…”

Section: F I G U R Ementioning

confidence: 99%

Breaking the fibrinolytic speed limit with microwheel co‐delivery of tissue plasminogen activator and plasminogen

Disharoon

Trewyn

Herson

et al. 2022

Journal of Thrombosis and Haemostasis

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Background:To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot and by the depletion of its substrate, plasminogen. Objectives:To overcome these rate limitations, a platform was designed to co-deliver tPA and plasminogen based on microwheels (µwheels), wheel-like assemblies of superparamagnetic colloidal beads that roll along surfaces at high speeds. Methods:The biochemical speed limit was determined by measuring fibrinolysis of plasma clots at varying concentrations of tPA (10-800 nM) and plasminogen (1-6 µM).Biotinylated magnetic mesoporous silica nanoparticles were synthesized and bound to streptavidin-coated superparamagnetic beads to make studded beads. Studded beads were loaded with plasminogen and tPA was immobilized on their surface.Plasminogen release and tPA activity were measured on the studded beads. Studded beads were assembled into µwheels with rotating magnetic fields and fibrinolysis of plasma clots was measured in a microfluidic device. Results:The biochemical speed limit for plasma clots was ~15 µm/min. Plasminogenloaded, tPA-immobilized µwheels lyse plasma clots at rates comparableto the biochemical speed limit. With the addition of a corkscrew motion, µwheels penetrate clots, thereby exceeding the biochemical speed limit (~20 µm/min) and achieving lysis rates 40-fold higher than 50 nM tPA. Conclusions:Co-delivery of an immobilized enzyme and its substrate via a microbot capable of mechanical work has the potential to target and rapidly lyse clots that are inaccessible by mechanical thrombectomy devices or recalcitrant to systemic tPA delivery.

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Section: F I G U R Ementioning

confidence: 99%

Breaking the fibrinolytic speed limit with microwheel co‐delivery of tissue plasminogen activator and plasminogen

Disharoon

Trewyn

Herson

et al. 2022

Journal of Thrombosis and Haemostasis

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“…The MSN with large pores has been synthesized by adding mesitylene as a pore‐expanding agent to a CTAB‐templated base‐catalyzed condensation reaction of silicate as reported previously . The catalysts were obtained by impregnating the l ‐MSN support in the ethanolic solution of Yb (NO 3 ) 3 ·5H 2 O, followed by calcination.…”

Section: Resultsmentioning

confidence: 99%

“…All solvents were of analytical grade and distilled before use. Large pore MCM‐41 type mesoporous silica with ( l‐ MSN) was synthesized via the method of Slowing et al . using CTAB and mesitylene as template and pore‐expanding agent, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Mesoporous silica supported ytterbium as catalyst for synthesis of 1,2‐disubstituted benzimidazoles and 2‐substituted benzimidazoles

Samanta

Banerjee

Richards

et al. 2018

Applied Organom Chemis

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The benzimidazole ring is an important pharmacophore in contemporary drug discovery. Thus, effort to identifying new compounds containing benzimidazole scaffolds have gained much attention in recent years. In the present study, MCM‐41 type mesoporous silica with large pore (l‐MSN) supported ytterbium was successfully prepared by wet impregnation method. Among rare earth metal salts, ytterbium triflate has already been widely investigated as a catalyst in organic synthesis but less toxic ytterbium oxide has yet to be explored. Relatively high abundance and low cost of ytterbium with respect to many catalytically active metals (e.g. Pd, Au, Ru, Ir, Pt) offer an opportunity to develop sustainable catalysts for organic conversions. The catalyst has been characterized by various techniques including nitrogen adsorption, FT‐IR, TEM, SEM, EDX technique and elemental mapping. The obtained materials exhibit high surface area and a narrow distribution of mesoporosity. The catalytic performance of the Yb@l–MSNs was tested by synthesis of 1,2‐disubstituted benzimidazoles and 2‐substituted benzimidazoles through the coupling of aldehydes with o‐phenylenediamine. The catalyst resulted in excellent yields in short reaction times and the reaction showed tolerance toward both electron‐donating and electron‐withdrawing functional groups at room temperature. A particularly interesting finding was the solvent selectivity of this reaction; namely, 1,2‐disubstituted benzimidazoles generated as major product in water‐ethanol, while the 2‐substituted benzimidazoles was generated exclusively in non‐polar solvents like toluene.

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“…49 To overcome this limitation and further enhance lysis speed, we develop here a µwheel-based strategy of delivering both tPA and plasminogen using tPA-µwheels coupled with mesoporous silica nanoparticles (MSN), which we have previously used to achieve controlled release of proteins. [50][51][52] These co-laden µwheels break the biochemical speed limit by supplementing fresh plasminogen and burrowing their way into plasma-derived clots (Fig. 1D).…”

Section: Introductionmentioning

confidence: 99%

Breaking the fibrinolytic speed limit with microwheel co-delivery of tissue plasminogen activator and plasminogen

Disharoon

et al. 2021

Preprint

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Fibrinolysis is the enzymatic degradation of fibrin, the biopolymer that gives blood clots their mechanical integrity. To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot and by the depletion of its substrate, plasminogen. To overcome these rate limitations, we design a platform to co-deliver tPA and plasminogen based on microwheels (μwheels), wheel-like assemblies of superparamagnetic colloidal beads that roll along surfaces at high speeds and carry therapeutic payloads in applied magnetic fields. By experimentally measuring fibrinolysis of plasma clots at varying concentrations of tPA and plasminogen, the biochemical speed limit was first determined. These data, in conjunction with measurements of μwheel translation, activity of immobilized tPA on beads, and plasminogen release kinetics from magnetic mesoporous silica nanoparticles (mMSN), were used in a mathematical model to identify the optimal tPA:plasminogen ratio and guide the coupling of plasminogen-loaded mMSN to tPA functionalized superparamagnetic beads. Once coupled, particle-bead assemblies form into a co-delivery vehicle that rolls to plasma clot interfaces and lyses them at rates comparable to the biochemical speed limit. With the addition of mechanical action provided by rotating μwheels to penetrate clots, this barrier was exceeded by rates 40-fold higher lysis by 50 nM tPA. This co-delivery of an immobilized enzyme and its substrate via a microbot capable of mechanical work has the potential to target and rapidly lyse clots that are inaccessible by mechanical thrombectomy devices or recalcitrant to systemic tPA delivery.

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Conserved Activity of Reassociated Homotetrameric Protein Subunits Released from Mesoporous Silica Nanoparticles

Cited by 6 publications

References 37 publications

Breaking the fibrinolytic speed limit with microwheel co‐delivery of tissue plasminogen activator and plasminogen

Breaking the fibrinolytic speed limit with microwheel co‐delivery of tissue plasminogen activator and plasminogen

Mesoporous silica supported ytterbium as catalyst for synthesis of 1,2‐disubstituted benzimidazoles and 2‐substituted benzimidazoles

Breaking the fibrinolytic speed limit with microwheel co-delivery of tissue plasminogen activator and plasminogen

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