Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair.
Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair.
复制标题
使用疤痕归巢脂质体的新型多药物递送水凝胶可改善脊髓损伤修复
作者：
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
正确选择和有效递送针对脊髓损伤（SCI）关键的多种病理生理途径的联合药物有望解决迄今为止缺乏的临床治疗方法，以改善脊髓损伤后的恢复。在本研究中，我们的目标是开发一种临床可行的方法，将不同理化性质的多种药物靶向递送到脊髓损伤部位，详细研究神经恢复的潜在机制，并检测联合治疗的协同效应。方法：首先构建瘢痕靶向四肽（半胱氨酸-丙氨酸-谷氨酰胺-赖氨酸，CAQK）修饰的脂粒（LIP），同时包封多西他赛（DTX）和脑源性神经营养因子（BDNF），然后将其添加到具有亲和力结合的酸性成纤维细胞生长因子（aFGF-HP）的热敏肝素修饰的poloxamer水凝胶（HP）中，局部给药到大鼠模型的SCI部位（CAQK-LIP- gfs /DTX@HP）。体内荧光成像检测CAQK-LIP-GFs/DTX与损伤部位结合的特异性。通过生物素、葡聚糖胺顺行示踪和磁共振成像等多种综合评价，检测CAQK-LIP-GFs/DTX@HP在体内（大鼠SCI模型）和体外（原代神经元）的协同作用及其潜在机制。结果：多种药物均能有效输送至损伤部位。GFs和DTX的联合应用通过改善神经元的存活和可塑性来支持神经再生，提供更宽松的细胞外基质环境，提高再生潜力。此外，我们的联合治疗通过调节微管功能和沿再生轴突的线粒体运输来促进轴突再生。结论：基于瘢痕归巢传递系统的新型多功能治疗策略为脊髓损伤的临床治疗提供了良好的应用前景。
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.
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影响因子：
5.3
作者：
Gaudet, Andrew D.;Popovich, Phillip G.
通讯作者：
Popovich, Phillip G.
影响因子：
5.3
作者：
Fischer, D;He, ZG;Benowitz, LI
通讯作者：
Benowitz, LI
抑制内质网应激可保持脊髓损伤的糖尿病大鼠血脊髓屏障的完整性。
影响因子：
4.6
作者：
He Z;Zou S;Yin J;Gao Z;Liu Y;Wu Y;He H;Zhou Y;Wang Q;Li J;Wu F;Xu HZ;Jia X;Xiao J
通讯作者：
Xiao J
影响因子：
4.2
作者：
Koopmans, GC;Deumens, R;Joosten, EAJ
通讯作者：
Joosten, EAJ
星形胶质细胞疤痕形成有助于中枢神经系统轴突再生。
影响因子：
64.8
作者：
Anderson MA;Burda JE;Ren Y;Ao Y;O'Shea TM;Kawaguchi R;Coppola G;Khakh BS;Deming TJ;Sofroniew MV
通讯作者：
Sofroniew MV