Affinity interactions drive post-implantation drug filling, even in the presence of bacterial biofilm

Cyphert, Erika L.; Zuckerman, Sean T.; Korley, Julius N.; Recum, Horst A. von

doi:10.1016/j.actbio.2017.04.015

Cited by 32 publications

(46 citation statements)

References 42 publications

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“…However this amount is similar to the amount of RM remaining in non‐templated polymers as determined by colorimetric spectroscopy (data not shown) and FTIR analysis (Figure ). Past work by our lab has shown that any drug remaining in the device was unavailable for further delivery even after extensive washing with organic solvents, so total drug loading was calculated from the maximum released amount, rather than maximum loaded amount …”

Section: Resultssupporting

confidence: 52%

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Juric

Rohner

Recum

2018

Macromolecular Bioscience

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Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.

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Section: Resultssupporting

confidence: 52%

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Juric

Rohner

Recum

2018

Macromolecular Bioscience

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“…A zone of inhibition assay was used to determine the efficacy of the anti‐microbial properties of the loaded sutures in vitro . Dual‐loaded pCD coated sutures were evaluated against Staphylococcus aureus (S. aureus) according to previously published protocol . S. aureus was cultured overnight and 70 mL was then spread on a trypticase soy broth (BD BBL) agar plate.…”

Section: Methodsmentioning

confidence: 99%

“…Dualloaded pCD coated sutures were evaluated against Staphylococcus aureus (S. aureus) according to previously published protocol. 45 S. aureus was cultured overnight and 70 mL was then spread on a trypticase soy broth (BD BBL) agar plate. A dual-loaded pCD coated suture was placed on this fresh S. aureus lawn and incubated at 37 C overnight.…”

Section: Methodsmentioning

confidence: 99%

Use of affinity allows anti‐inflammatory and anti‐microbial dual release that matches suture wound resolution

Haley

Qian

Learn

et al. 2019

J Biomedical Materials Res

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Surgical sutures are vulnerable to bacterial infections and biofilm formation. At the suture site, pain and undesirable, excess inflammation are additionally detrimental to wound healing. The development of a polymerized cyclodextrin (pCD) coated surgical suture introduces the capability to locally deliver both anti‐inflammatory and anti‐microbial drugs throughout the phases of acute and chronic healing. Local delivery allows for the improvement of wound healing while reducing related systemic side effects and drug resistance. Through testing, it has been shown that the fabrication of our pCD coating minimally affects the suture's mechanical properties. In vitro studies show measurable and consistent drug delivery for nearly 5 weeks. The therapeutic level of this delivery is sufficient to show inhibition of bacterial growth for 4 weeks, and free‐radical scavenging (an in vitro anti‐inflammatory activity approximation) for 2 weeks. With this pCD coating technique, we maintain clinical performance standards while also introducing a long‐term dual delivery system relevant to the wound healing timeframe. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.

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“…However, using cyclodextrins (CD) in a different line of work, we sought to provide a sustained delivery of small molecules for longer than their short, diffusion-based half-lives to better match the timeline of fibrosis and wound healing. Thus, we developed insoluble polymer depots with a high concentration of CD units to support repeated inclusion complex formation and sustain release based upon the drug-CD affinity interactions, which have been previously leveraged in antibiotic and anti-inflammatory applications [10][11][12][13]. While RIF has shown extended delivery via affinity-based methods [14,15], the release profiles of DFOA, MTP, and PYR using affinity-based polymers have not been studied (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

2020

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For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes. 126To first predict the relative binding affinities of the chosen drugs for the β-CD versus dextran 127 (chemically similar control without inclusion complex), a molecular docking program was utilized 128 (PyRx with Autodock Vina software [28,35]). The β-CD monomer, dextran, and drug molecule 129 structure files were downloaded from online databases as specified in the methods section (Figure 130 1A). DFOA, RIF, MTP, and PYR were individually simulated to determine minimal binding energy 131 configurations with either β-CD or dextran as the target host macromolecule. The results were 132 converted to dissociation constants for each simulated pair. 133 134 Figure 1. (A) Molecular structures of rifampicin (RIF), metyrapone (MTP), pyrvinium (PYR), and 135 deferoxamine (DFOA) represented in 3D with JMOL software showing relative size and potential 136 binding conformations for the β-CD inclusion complex formation. (B) PyRx simulations were 137 performed to predict the binding affinity of drugs with β-CD versus dextran as a chemically similar, 138 but non-inclusion-forming, control, as dextran lacks the binding cavity of β-CD. 139The lowest KD (highest binding affinity) was predicted for RIF and β-CD (0.04 mM), while the 140 KD for MTP and PYR β-CD complexes were more than twice as large at 0.098 and 0.104 mM, 141 respectively ( Figure 1B). DFOA resulted in the highest KD out of all the β-CD simulations at 1.463 142 mM. When the drugs were simulated with dextran, the KD values were higher. The combination of 143 RIF and dextran demonstrated a KD of 1.776 mM, followed by PYR-dextran (4.770 m...

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Affinity interactions drive post-implantation drug filling, even in the presence of bacterial biofilm

Cited by 32 publications

References 42 publications

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Use of affinity allows anti‐inflammatory and anti‐microbial dual release that matches suture wound resolution

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

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