Theranostics 2018; 8(16):4429-4446. doi:10.7150/thno.26717 This issue

Research Paper

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

Qingqing Wang1,2#, Hongyu Zhang2#, Helin Xu2#, Yingzheng Zhao2, Zhengmao Li2, Jiawei Li1, Haoli Wang1, Deli Zhuge2, Xin Guo2, Huazi Xu1, Salazar Jones3, Xiaokun Li2, Xiaofeng Jia3,4,5✉, Jian Xiao1,2✉

1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang,325035 China
2. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
3. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
4. Department of Biomedical Engineering, Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5. Department of Orthopaedics, Anatomy Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
# The first three authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Wang Q, Zhang H, Xu H, Zhao Y, Li Z, Li J, Wang H, Zhuge D, Guo X, Xu H, Jones S, Li X, Jia X, Xiao J. Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair. Theranostics 2018; 8(16):4429-4446. doi:10.7150/thno.26717. Available from https://www.thno.org/v08p4429.htm

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Abstract

Graphic 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.

Keywords: spinal cord injury, scar-homing liposome, hybrid hydrogel, neuro-regeneration, combination therapy