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

Qingqing Wang, Hongyu Zhang, Helin Xu, Yingzheng Zhao, Zhengmao Li, Jiawei Li, Haoli Wang, Deli Zhuge, Xin Guo, Huazi Xu, Salazar Jones, Xiaokun Li, Xiaofeng Jia, Jian Xiao

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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-alanineglutamine- 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.

Original languageEnglish
Pages (from-to)4429-4446
Number of pages18
JournalTheranostics
Volume8
Issue number16
DOIs
StatePublished - 2018
Externally publishedYes

Keywords

  • Combination therapy
  • Hybrid hydrogel
  • Neuro-regeneration
  • Scar-homing liposome
  • Spinal cord injury

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