The Preparation And Application Of Drug Nanocarrier Based On Polylactic-co-glycolic Acid

Breast cancer stem cells(BCSCs) are a very small population in the breast cancer(< 10%), but they have an ability to transform into bulk cancer cells, promote tumor growth, and establish tumor metastasis. Conventional chemotherapies can effectively kill most of differentiated breast cancer cells, while a part of BCSCs remains untouched and may cause the relapse of breast cancer. During the past decade, development of cancer stem cells(CSC) targeted therapies has been a promising approach to improve the survival of cancer patients. However, most of CSC therapeutic agents cannot kill bulk breast cancer cells and only target one or two of the CSCs pathways dysregulated in many human breast cancers. Therefore, co-delivery of the traditional chemotherapy drug alongside the CSC therapeutic agents has a great pontential to be a powerful strategy to effectively inhibit tumor growth and prevent metastasis.In this study, we report the synthesis and characterization of a new amphiphilic polymer, hyaluronic acid-cystamine-polylactic-co-glycolic acid(HA-SS-PLGA), which is composed of a hydrophobic PLGA head and a hydrophilic HA segment linked by a bioreducible disulfide bond. With a double emulsion method, a nano delivery system was constructed to deliver doxorubicin(DOX) and cyclopamine(CYC, a primary inhibitor of the hedgehog signaling pathway of CSCs). The particle size, zeta potential and morphology were characterized by dynamic light scattering and transmission electron microscope, the obtained results revealed that the nanoparticles exhibited homogeneous spheres with positive charge around their surface. The release behavior was studied and exhibited redox-responsive drug release profile.We then investigated both the HA targeting efficacy and the in vitro and in vivo antitumor activity of the dual-drug delivery system. HA-SS-PLGA-DOX nanoparticles were much easier to enter MDA-MB-231 cells than PLGA-DOX nanoparticles owing to HA targeting efficacy. Drug-loaded HA-SS-PLGA nanoparticles showed enhanced inhibition to the tumor sphere formation compared with drugs-loaded PLGA nanoparticles. Few tumorspheres were formed in nude mice after the treatment of HA-SS-PLGA-DOX-CYC dual drug-loaded nanoparticles. These results showed that HA-SS-PLGA-DOX-CYC dual drug-loaded nanoparticles potently diminished the number and size of tumorspheres, and HA showed the targeting effect to breast CSCs. The co-delivery of conventional chemotherapy drug and CSC specific inhibitor toward targeted cancer chemotherapeutics provides an insight into anticancer strategy with facile control and high efficacy.