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

Abstract

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...

Local Delivery of Pirfenidone by PLA Implants Modifies Foreign Body Reaction and Prevents Fibrosis

“…The efficiency of an IDDS depends on its drug loading capacity, as well as on the biocompatibility and biodegradation that together contribute to the resulting drug release profile [1,9,17,[67][68][69]. In the presented work, a high PF entrapment efficiency of the PLA@PF implants (97.9 ± 13.8% of the original 500 µg PF dose per 0.3 g PLA powder)…”

“…The efficiency of an IDDS depends on its drug loading capacity, as well as on the biocompatibility and biodegradation that together contribute to the resulting drug release profile [ 1 , 9 , 17 , 67 , 68 , 69 ]. In the presented work, a high PF entrapment efficiency of the PLA@PF implants (97.9 ± 13.8% of the original 500 μg PF dose per 0.3 g PLA powder) was achieved by co-foaming of the dry PLA and PF powders in supercritical CO 2 by the methodology proposed by us earlier [ 61 ], that allowed to bypass a problem of poor compatibility of a hydrophobic carrier material (PLA) [ 58 ] and a highly hydrophilic drug (PF) [ 54 ].…”

Polymer microparticles prolong delivery of the 15-PGDH inhibitor SW033291

“…CD systems have been previously shown to enhance the solubility and bioavailability of drugs by complexing smallmolecule, hydrophobic payloads within its interior pocket, forming an 'inclusion complex' 9 . Furthermore, CD systems with high densities of neighboring inclusion complexes are able to leverage their thermodynamic interactions with the payload to yield a controlled-release delivery system that can deliver drug for 28-70 days [10][11][12][13][14] .…”

Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291

“…CD systems have previously been shown to enhance the solubility and bioavailability of drugs by complexing small-molecule, hydrophobic payloads within its interior pocket, forming an 'inclusion complex' [11]. Furthermore, CD systems with high densities of neighboring inclusion complexes are able to leverage their thermodynamic interactions with the payload to yield a controlled-release delivery system that can deliver drug for 28-70 days [12][13][14][15][16]. Our group has also shown that implanted cyclodextrin-based systems have the potential to 'refill' after being exposed to a second bolus dose in situ, which would present the opportunity for an adjustable and tunable window of drug delivery, as opposed to similar polymeric delivery systems which are single-use, such as PLGA [14,16].…”