Collagen Hydrogel Loaded With 9-cisRA-Lip Is an Option for Treatment of Secondary Lymphedema after Surgery

Background: Secondary upper limb lymphedema is easy to occur after breast cancer surgery, for which treatment is limited. 9-cis-retinoic acid (9-cisRA) has been demonstrated to increase lymphangiogenesis without enhancing tumor metastasis but has the disadvantages of poor water solubility, easy decomposition in light, unstable to heat, and short half-life. Methods: Based on this, 9-cisRA-Lip with a particle size of roughly 143 nm and high dispersibility was prepared by thin-film dispersion method and verified by Malvern Laser Particle Size Analyzer and electron microscopy. Results: In vitro, 9-cisRA-Lip demonstrated good biosafety and tumor safety, promoting the proliferation of L929 cells while having no effect on 4T1 and Human Umbilical Vein Endothelial (HUVEC) cells. Compared with 9-cisRA, 9-cisRA-Lip was more effective at encouraging mouse lymphatic endothelial cell (SVEC4-10) migration, proliferation, and tube formation. In vivo, 9-cisRA-Lip-Gel showed good slow-release effect, mice treated with 9-cisRA-Lip-Gel one-time local injection had considerably less tail edema than the control group from day 9 to day 39 postsurgery (p < 0.05). This may be attributed to the greater capacity of 9-cisRA-Lip to enhance the phosphorylation of FGFR3 (Fibroblast Growth Factor Receptor 3) at Tyr 724. Conclusions: 9-cisRA-Lip-Gel presents a potential treatment option for lymphedema following surgery.