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

<b><i>Background:</i></b> Secondary upper limb lymphedema commonly occurs 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 disadvantages of poor water solubility, ready decomposition in light, instability to heat, and a short half-life. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> <i>In vitro</i>, 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 stimulating mouse lymphatic endothelial cell (SVEC4-10) migration, proliferation, and tube formation. <i>In vivo</i>, 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 (<i>p</i> < 0.05). This may be attributed to the greater capacity of 9-cisRA-Lip to enhance the phosphorylation of <i>FGFR3</i> (Fibroblast Growth Factor Receptor 3) at <i>Tyr 724</i>. <b><i>Conclusions:</i></b> 9-cisRA-Lip-Gel presents a potential treatment option for lymphedema following surgery.