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A Ligand‐Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery

ABSTRACT: Abstract Here we report the first use of ligand‐directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand‐directed in situ bioconjugation of a prodrug payload to a protein. The transient nature of our conjugation chemistry renders the protein a depot for time‐dependent release of active drug following hydrolysis and self‐immolation. In our model system, using an immunostimulant prodrug, biotin ligand, and avidin protein, we observe release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co‐crystalized with the nitrophenolate directing group verified the binding pose of the ligand and offered insight into the mechanism of in situ bioconjugation. Overall, this scaffold warrants further investigation for the time‐dependent delivery of therapeutics and use in protein ligand pairs beyond biotin and avidin used for this work. Ligand‐directed proximity accelerated bioconjugation to deliver a therapeutic payload using a novel nitrophenol carbonate derivative. In this work, we demonstrate the utility for the ligand‐directed in situ labeling of a protein avidin with an immunostimulant prodrug. This renders the target protein a depot for time‐dependent release of active drug. The mechanism is probed using crystallography, and time‐dependent drug release is demonstrated in vitro.

SUBMITTER: Burt A

PROVIDER: S-EPMC7702144 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Perivascular delivery of anti-proliferative agents is an attractive approach to inhibit hyperplasia that causes stenosis of synthetic hemodialysis grafts and other vascular grafts. Perivascular drug delivery systems typically release drugs to both the vascular wall and non-target extravascular tissue. The objective of this study was to develop a biodegradable, perivascular delivery system for localized, sustained and unidirectional drug release in the context of synthetic arteriovenous (AV) grafts used for chronic hemodialysis. To this end, a dense non-porous polymer barrier layer was laminated to either i) a drug-loaded non-porous polymer layer or ii) a porous polymer layer. To provide tunability, the porous layer could be loaded with drug during casting or later infused with a drug-loaded hydrogel. The polymer bilayer wraps were prepared by a solvent casting, thermal-phase inversion technique using either polylactide-co-glycolide (PLGA) or polycaprolactone (PCL). Sunitinib, a multi-target receptor tyrosine kinase inhibitor, was used as a model drug. In a modified transwell chamber system, the barrier function of the non-porous PLGA backing was superior to the non-porous PCL backing although both markedly inhibited drug diffusion. As assessed by in vitro release assays, drug release duration from the drug-loaded non-porous PCL construct was almost 4-fold greater than release from the porous PCL construct infused with drug-laden hydrogel (22 days vs. 5 days); release duration from the drug-loaded non-porous PLGA construct was prolonged approximately 3-fold over release from the porous PLGA construct infused with drug-laden hydrogel (9 days vs. 3 days). Complete in vitro degradation of the PLGA porous and non-porous constructs occurred by approximately 35 days whereas the PCL constructs remained intact even after most of the drug was released (49 days). The PLGA non-porous bilayer wrap containing 143±5.5mg sunitinib in the inner layer was chosen for further pharmacokinetic assessment in vivo where the construct was placed around the external jugular vein in a porcine model. At 1 week, no drug was detected by HPLC/MS/MS in any examined extravascular tissue whereas high levels of drug were detected in the wrapped vein segment (1048 ng g?¹ tissue). At 4 weeks, drug was detected in adjacent muscle (52 ng g?¹ tissue) but 13-fold greater amounts were detected in the wrapped vein segment (1742 ng g?¹ tissue). These results indicate that the barrier layer effectively impedes extravascular drug loss. Tensile testing showed that the initially flexible PLGA construct stiffened with hydration, a phenomenon also observed after in vivo placement. This characteristic may be useful to resist undue circumferential venous tensile stress produced in AV grafting. The PLGA wrap bilayer formulation is a promising perivascular drug delivery design for local treatment of hemodialysis AV graft hyperplasia and possibly other hyperplastic vascular disorders.

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A Ligand‐Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery

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