ABSTRACT
Spinal cord injury is a kind of nerve injury disease with high disability rate. The bioscaffold, which presents a biomimetic structure, can be used as "bridge" to fill the cavity formed by the liquefaction and necrosis of spinal nerve cells, and connects the two ends of the fracture to promote the effective recovery of nerve function. Tubasatin A (TUBA) is a potent selective histone deacetylase 6 (HDAC6) inhibitor, which can inhibit the overexpression of HDAC6 after spinal cord injury. However, TUBA is limited by high efflux ratios, low brain penetration and uptake in the treatment of spinal cord injury. Therefore, an effective carrier with efficient load rate, sustained drug release profile, and prominent repair effect is urgent to be developed. In this study, we have prepared a bionic multichannel Tubasatin A loaded nanofiber conduit (SC-TUBA(+)) through random electrospinning and post-triple network bond crosslinking for inhibiting HDAC6 as well as promoting axonal regeneration during spinal cord injury treatment. The Tubasatin A-loaded nanofibers were shown to be successfully contained in poly(glycolide-co-ε-caprolactone) (PGCL)/silk fibroin (SF) matrix, and the formed PGCL/SF-TUBA nanofibers exhibited an uniform and smooth morphology and appropriate surface wettability. Importantly, the TUBA loaded nanofibers showed a sustained-release profile, and still maintains activity and promoted the extension of axonal. In addition, the total transection large span model of rat back and immunofluorescent labeling, histological, and neurobehavioral analysis were performed for inducing spinal cord injury at T9-10, evaluating therapeutic efficiency of SC-TUBA(+), and elucidating the mechanism of TUBA release system in vivo. All the results demonstrated the significantly reduced glial scar formation, increased nerve fiber number, inhibited inflammation, reduced demyelination and protected bladder tissue of TUBA-loaded nanofibers for spinal cord injury compared to SC-TUBA, SC and Control groups, indicating their great potential for injured spinal cord healing clinically.
ABSTRACT
Diabetic ulcers, a difficult problem faced by clinicians, are strongly associated with an increase in cellular senescence. Few empirical studies have focused on exploring a targeted strategy to cure diabetic wounds by eliminating senescent fibroblasts (SFs) and reducing side effects. In this study, poly-l-lysine/sodium alginate (PLS) is modified with talabostat (PT100) and encapsulates a PARP1 plasmid (PARP1@PLS-PT100) for delivery to target the dipeptidyl peptidase 4 (DPP4) receptor and eliminate SFs. PARP1@PLS-PT100 releases encapsulated plasmids, displaying high selectivity for SFs over normal fibroblasts by targeting the DPP4 receptor, decreasing senescence-associated secretory phenotypes (SASPs), and stimulating the secretion of anti-inflammatory factors. Furthermore, the increased apoptosis of SFs and the disappearance of cellular senescence alleviates SASPs, accelerates re-epithelialization and collagen deposition, and significantly induces macrophage M2 polarization, which mediates tissue repair and the inflammatory response. This innovative strategy has revealed the previously undefined role of PARP1@PLS-PT100 in promoting diabetic wound healing, suggesting its therapeutic potential in refractory wound repair.
