A biodegradable perivascular wrap for controlled, local and directed drug delivery

Abstract

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 tuneability, 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 drug was released (49 days). The PLGA non-porous bilayer wrap containing 143±5.5 mg 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 one 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 tissue). At four weeks, drug was detected in adjacent muscle (52 ng/g tissue) but 13-fold greater amounts were detected in the wrapped vein segment (1742 ng/g 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.

Ophthalmic Uses of a Thiol-Modified Hyaluronan-Based Hydrogel

“…For example, wound healing was accelerated in a diabetic mouse model when basic fibroblast growth factor was continuously released from the CMHA-S hydrogels into full-thickness wounds. 23,40 Other proteins and small molecules that have been delivered both in vitro and in vivo from these CMHA-S gels and films include the following growth factors: 28,[41][42][43][44][45] Basic…”

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

“…However, perivascular drug delivery systems could be employed for localised, sustained release of a CK2 inhibitor to a grafted vein. Such a system has been used to deliver sunitinib in a biocompatible hyaluronic acid-based hydrogel within a polyactide-co-glycolide perivascular wrap [81]. Other approaches for delivery include drug-eluting nanoparticles and drug-linked antibodies [82].…”

Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery

“…This hydrogel has a life-span of 60 days with continuous release of rapamycin throughout[29]. By adding a second layer that covers the hydrogel and directionally “caps” drug diffusion, Sanders et al was able to significantly reduce drug loss to the surrounding tissues[30]. In order to prevent the initial drug loss due to burst release, Chun et al covalently crosslinked paclitaxel to the hydrogel resulting in markedly prolonged drug release[31].…”

“…Sanders et al elegantly addressed this issue with a bilayer polymer wrap employing a drug-free non-porous outer barrier laminated onto a drug-loaded porous inner layer which is in direct contact with the vessel wall [30]. Using Sunitinib as the drug in a pig model of arteriovenous (AV) hemodialysis graft access, they found this bilayer PLGA wrap was able to provide unidirectional drug delivery to the vessel with minimal drug loss to extravascular tissues.…”