Silibinin And Cryptotanshineone Co-loaded Functional Oral Nanoparticles For In Vitro Inhibition Of Breast Cancer Invasion And Metastasis

Oral nanocarriers have many advantages in promoting oral absorption and bioavailability of active ingredients from Chinese materia medica.However,due to biological barrier in gastrointestinal tract,mucus penetration,cellular uptake under transport are hindered.Based on our previous research,N-(2-hydroxypropyl)methyl acryloyl chloride(p HPMA)was used as hydrophilic polymers.It was attachable through the mucus layer.p HPMA coated wheat germ agglutinin modified lipid nanoparticles(p W-LPNs)were prepared.The p W-LPNs were designed to promote nanoparticles through the mucus layer and enhance cell specific uptake mediated by WGA.Silibinin(SLB)and Cryptotanshinone(CRY),poorly soluble active ingredients from Chinese materia medica,can inhibit the invasion and migration,as well as proliferation of breast cancer cells,respectively.Therefore,the combination of SLB with CRY was expected to act on different targets for enhancing the therapeutic efficacy.In this study,a functional oral nanoparticle delivery system co-loaded with SLB and CRY was developed to overcome the mucus and cell-barriers,to improve oral bioavailability and enhance inhibition effect on breast cancer metastasis.Modified nanoprecipitation method and post insert method were used to prepared W-LPNs Then,they were coated with p HPMA as outer layer to form p W-LPNs.Transmission electron microscopy showed that nanoparticles were a uniform spherical shape with core-shell structure.In vitro drug release results showed that the cumulative drug release was about 80% in 24 hours.The results of silica gel rotating method showed that the p HPMA enhanced the penetration the nanoparticles in porcine mucus.In addition,the results of jejunum intestinal distribution and coverage in rats showed that p HPMA coating could promote the distribution of nanoparticles on the intestinal mucosa,thus which is beneficial for promoting intestinal absorption of nanoparticles.Caco-2 cells and HT29-MTX-E12 cells were used to evaluate the cell uptake.The results showed that WGA modification promoted cell uptake of nanoparticles.The effects of combination SLB with CRY nanoparticles were investigated and evaluated on the proliferation,migration and invasion in metastatic breast cancer of 4T1 cells.The results showed that combination SLB with CRY nanoparticles could significantly enhance inhibition the proliferation,migration and invasion of 4T1 cells compared with individual drug nanoparticles.In vivo pharmacokinetic results of oral administration showed that LPNs,W-LPNs and p W-LPNs improved the bioavailability of SLB and CRY in rats,compared with the suspension.Among them,the relative bioavailability of SLB and CRY in p W-LPNs was 1554.83% and 1145.28%,respectively,as compared with that of suspensions,indicating the drugs oral bioavailability was improved.