Sequential Release of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor at the Appropriate Time for Improved Angiogenesis.

Sequential release of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) was proposed to enhance therapeutic angiogenesis, however, it remains a challenge to accomplish distinct sequential release of the two proteins. More importantly, the appropriate timing of PDGF release remains an open question. Herein to solve these problems, a new time-controlled release system was designed in which tannic acid/Pluronic F127 (TA/F127) layer-by-layer (LBL) films were used as erodible coatings. The hydrogen-bonded TA/F127 films disintegrate in water at a constant rate. Therefore this system can not only achieve distinct sequential release of two proteins, but can finely control the lag time of the second protein by the TA/F127 coating thickness. In this way drug carriers for sequential release of VEGF and PDGF were prepared. Their angiogenic effects were evaluated using a mouse model of lower limb ischemia. Improved therapeutic efficiency was observed when VEGF and PDGF were sequentially released. More importantly, it was observed that the therapeutic efficiency first increased with increasing TA/F127 film thickness, reached a maximum, and then dropped with further increased TA/F127 film thickness. The results demonstrated that it is important to release PDGF at the appropriate time point to further improve angiogenesis. For the first time, the appropriate timing for PDGF application was determined to be 5-7 days after the application of VEGF. STATEMENT OF SIGNIFICANCE: It remains a challenge to accomplish distinct sequential release of VEGF and PDGF to enhance therapeutic angiogenesis. The appropriate timing for PDGF release is also an open question. In this study, a new time-controlled release system using a TA/F127 layer-by-layer film as an erodible coating was designed. Not only can distinct sequential release of VEGF and PDGF be achieved, but the lag time of PDGF release can also be finely controlled by the coating thickness. In this way, the appropriate timing for PDGF application was successfully determined.