tem1-targeting pegylated plga shikonin nanoformulation for immunomodulation and eradication of ovarian cancer

introduction: tumor endothelial marker 1 (tem1) is expressed by tumor vascular endothelial cells in various cancers. methods: here, we developed poly(lactic-co-glycolic acid) (plga) nanoparticles (nps) pegylated with polyethylene glycol (peg) and functionalized with anti-tem1 antibody fragment (78fc) and loaded them with necroptosis-inducing agent shikonin (shk) (78fc-plga-shk nps). results: the nanoformulation showed a smooth spherical shape (~120 nm; the ζ potential of –30 mv) with high drug entrapment and bioconjugation efficiencies (~92% and ~90%, respectively) and a sustained-release profile in serum. having significant toxicity in vitro (e.g., ms1 and tc1 cells), the nanoformulation dramatically increased the cytotoxicity in the tc1 murine lung carcinoma subcutaneous and intravenous/metastatic models as aggressive tumor models. the injection of the 78fc-plga-shk nps to the ms1-xenograft mice resulted in significantly higher accumulation and effects in the tem1-positive tumor targets, while they were excreted via urine track without retaining in the liver/spleen. in the tc1 subcutaneous model, c57/bl6 mice treated with the 78fc- plga-shk nps revealed a significant therapeutic effect. the mice, which were tumor-free after receiving the nanoformulation, were re-challenged with the tc1 cells to investigate the immune response. these animals became tumor-free a week after the injection of tc1 cells. conclusion: based on these findings, we propose the 78fc-plga-shk nps as a highly effective immunostimulating nanomedicine against the tem1-expressing cells for targeted therapy of solid tumors including ovarian cancer.