Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair

Abstract

Proper selection and effective delivery of combination drugs targeting multiple pathophysiological pathways key to spinal cord injury (SCI) hold promise to address the thus far scarce clinical therapeutics for improving recovery after SCI. In this study, we aim to develop a clinically feasible way for targeted delivery of multiple drugs with different physiochemical properties to the SCI site, detail the underlying mechanism of neural recovery, and detect any synergistic effect related to combination therapy.Methods: Liposomes (LIP) modified with a scar-targeted tetrapeptide (cysteine-alanine-glutamine-lysine, CAQK) were first constructed to simultaneously encapsulate docetaxel (DTX) and brain-derived neurotrophic factor (BDNF) and then were further added into a thermosensitive heparin-modified poloxamer hydrogel (HP) with affinity-bound acidic fibroblast growth factor (aFGF-HP) for local administration into the SCI site (CAQK-LIP-GFs/DTX@HP) in a rat model. In vivo fluorescence imaging was used to examine the specificity of CAQK-LIP-GFs/DTX binding to the injured site. Multiple comprehensive evaluations including biotin dextran amine anterograde tracing and magnetic resonance imaging were used to detect any synergistic effects and the underlying mechanisms of CAQK-LIP-GFs/DTX@HP both in vivo (rat SCI model) and in vitro (primary neuron).Results: The multiple drugs were effectively delivered to the injured site. The combined application of GFs and DTX supported neuro-regeneration by improving neuronal survival and plasticity, rendering a more permissive extracellular matrix environment with improved regeneration potential. In addition, our combination therapy promoted axonal regeneration via moderation of microtubule function and mitochondrial transport along the regenerating axon.Conclusion: This novel multifunctional therapeutic strategy with a scar-homing delivery system may offer promising translational prospects for the clinical treatment of SCI.

Niosomes encapsulated in biohydrogels for tunable delivery of phytoalexin resveratrol

“…21 Studies employing this kind of systems have been focused in the eld of pharmacotherapeutics for the treatment of cancer, [22][23][24][25] acne, 26 pain, 27 psoriasis, 28 ocular hypertension, 29,30 alopecia, 31 vitiligo, 32 among other diseases. [33][34][35][36] Among different biopolymers commonly used for the preparation of hydrogels, gelatin and carrageenans have been extensively studied and used in numerous applications. Gelatin is a mixture of peptides and proteins produced by partial and irreversible hydrolysis of collagen extracted from bones, skin, and connective tissues of animals.…”

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Various nanoparticles have been introduced as potential drug carries: organic, liposomes, micelles, nanoerythrosomes, dendrimers, carbon-based, fullerenes, or inorganic nanoparticles, silicon nanoparticles, metal or quantum dots [16,19]. These particles can be loaded with drugs to offer advantages like prolongation of drug release, tissue deposition for efficient drug absorption and simultaneous delivery of multiple therapeutic drugs [101][102][103][104][105][106]. Nanoparticles offer an option to modify them on their surface, by applying targeting elements to the surface of the particles.…”

Cell and Tissue Instructive Materials for Central Nervous System Repair

“…Due to their capacity to mimic the native neural extracellular matrix (ECM), both physically and chemically, hydrogels are amply used in the design of SCI treatments. [23,40] Hydrogels have been made using natural materials, such as agarose, [41] collagen, [42,43] fibrin, [44] alginate, [45] Matrigel, [46] hyaluronic acid (HA), [47] and gellan gum, [11,48] or synthetic ones, such as poly(ethylene glycol) (PEG) [49] poloxamer, [50] among others. [51] Notably, both natural and synthetic hydrogels have shown to promote some degree of regeneration in SCI animal models ( Table 1).…”