Glycolipid-like Drug Delivery System Applied In Treating Autonomic Or Treatment-induced Tumor Metastasis

Tumor metastasis is an important reason of cancer related death.The unpredictable metastasis sites,the invisible early metastasis and the deficient drug concentration at the metastasis sites is the main cause of refractory cancer metastasis.Tumor metastasis is divided into autonomic metastasis and treatment induced metastasis.CXCR4 receptor is high expressed on autonomic metastatic tumor cells,while RAC1 is upregulated in chemotherapy induced metastatic cells.The key proteins in the process of autonomic and treatment-induced metastases are important targets for tumor metastasis therapy.Our study designed a BKT-140 peptide modified glycolipid-like drug delivery system,BKT-CSOSA,aiming at treating CXCR4 high expressed metastatic tumor.BKT-CSOSA could self-aggregate into micelles in an aqueous medium.The particle size,zeta potential and the critical micelle concentration(CMC)of BKT-CSOSA micelles are 195.5±2.0nm,19.9±0.2mV and 61.96μg/mL respectively.BKT-140 peptide modification changed the cell uptake pathways of glycolipid micelles from the original cathepsin-mediated endocytosis into the CXCR4 receptor-mediated uptake pathway or the cytoplasmic route,which significant improved the uptake of BKT-CSOSA in CXCR4 overexpressing tumor cells by 1.4-fold.BKT-CSOSA/DOX was prepared by BKT-140 peptide-modified glycolipid polymer with doxorubicin(DOX)as model drug.Compared with CSOSA/DOX,the cytotoxicity and the ability to inhibit cell migration and invasion of BKT-CSOSA/DOX were significantly enhanced.BKT-140 peptide modification can increase the effective distribution of glycolipid micelles in primary tumor sites and around lung metastases.Compared with non-modified drug-loaded nanoparticles,the inhibitory rate of BKT-CSOSA/DOX in melanoma animal model increased by 34.8%,and the number of lung metastatic lesions decreased by 28.5%.On the other side,chemotherapy may cause treatment induced metastasis.Thus,we studied the mechanism under the tumor cell metastatic changing induced by DOX.Transwell assays showed that low concentration of doxorubicin increased the invasion of tumor cells by DOX metabolic intermediates.While the glycolipid drug loaded nanoparticles(CSOSA/DOX)avoid tumor cell invasion change,due to alternation of the intracellular pathways.Immuno-histochemical studies of tumor tissue sections confirmed that doxorubicin could promote tumor epithelial-mesenchymal transition(EMT),which is associated to ROS-related RAC1 protein.In order to silent RAC1,redox-responsive glycolipid drug delivery system(CSO-ss-SA)was selected to carry siRNA,forming the gene delivery system(CSO-ss-SA/siRNA).CSO-ss-S A/siRNA can effectively transmit siRNA into tumor cells,reduce the expression of RAC 1 protein by 38.2%,and reduce the number of tumor-induced tumor invasion cells by 42.5%.Model animal studies have shown that CSO-ss-SA/siRNA can inhibit chemotherapeutic drug-induced tumor EMT transformation.