Enhancing neurogenesis and angiogenesis with target delivery of stromal cell derived factor-1 alpha using a dual ionic pH-sensitive copolymer

摘要

In this study, we hypothesized that the delivery of molecules that regulate the microenvironment after a cerebral infarction can influence regeneration potential after a stroke. Stromal cell-derived factor-1 alpha (SDF-1 alpha) is a chemoattractant molecule that plays a pivotal role in recruiting endothelial progenitor cells (EPCs) to the infarct region after stroke. Increased SDF-1 alpha expression leads to increased EPCs homing at the infarct region and induces neurogenesis, angiogenesis, neuroprotection, and stem cell homing. Thus, we evaluated the effects of targeted delivery of SDF-1 alpha using a pH-sensitive polymer poly (urethane amino sulfamethazine) (PUASM), a synthetic macromolecule with potential for targeted drug delivery in acidic conditions, to enhance therapeutic neurogenesis and angiogenesis in a rat model of permanent middle cerebral artery occlusion. A dual ionic pH-sensitive copolymer PUASM-based random copolymer was designed and synthesized for the controlled release of SDF-1 alpha in stroke. Owing to the unique characteristics of PUASM, it exhibited a dual ionic pH-sensitive property in an aqueous solution. At pH 8.5, the copolymer exhibited a negative charge and was water soluble. Interestingly, when the pH decreased to 7.4, PUASM could form a micelle and encapsulate protein effectively via the ionic interaction between a negatively charged polymer and a positively charged protein. At pH 5.5, the ionization of tertiary amines led to the disassembly of the micellar structure and released the protein rapidly. Then, we investigated the effect of systemic administration of SDF-1 alpha-loaded pH-sensitive polymeric micelles in a stroke induced rat model. An enzyme-linked immunosorbent assay showed increased expression of SDF-1 alpha in the ischemic region, indicating that the pH-sensitive micelles effectively delivered SDF-1 alpha into the ischemic region. In order to observe the biodistribution of SDF-1 alpha in the ischemic region, it was labeled with the near-infrared dye, Cy5.5. Optical imaging showed that the Cy5.5 signal increased in the infarct region 24 h after administration. Immunohistochemistry data showed that targeted delivery of SDF-1 alpha enhanced neurogenesis and angiogenesis, but did not influence cell survival or inflammation. These observations suggest that SDF-1 alpha-loaded pH-sensitive polymeric micelles can be used as pH-triggered targeting agents and can effectively modify the microenvironment to increase innate neurorestorative processes. (C) 2015 Elsevier Ltd. All rights reserved.