Two advanced nano-systems loaded isoliquiritigenin to enhance efficacy of breast cancer treatment

Abstract

Breast cancer is the most common women cancer diagnosed around the world, especially in USA, the new cases of breast cancer occupied about 30% among women in 2018. Even worse, it is also the second leading cause of women cancer death which accounted for about 14%. Moreover, in China, the incidence rate of breast cancer also ranked first from 2000 to 2011. Although the advanced neoadjuvant approaches and traditional chemotherapeutic treatment have been used in clinic, the breast cancer issues have been not overcome as so far. Therefore, developing the specific methods or drugs in treating breast cancer is a big clinical challenge and an urgent issue. Traditional Chinese Medicine is a vast treasure trove of information in screening active anti-cancer compounds by our team. Isoliquiritigenin (ISL), a natural anti-breast cancer dietary compound can be isolated from Licorice and Suberect Spatholobus (SS), which showed good efficacy in anti-breast cancer with exact mechanisms. However, it is the fact that it has the poor solubility, poor delivery characteristic and low bioavailability, which has been limited its development in clinic. In order to promote the therapeutic outcome of ISL, two advanced nano-systems has been developed in this project, an injection nano-preparation and an oral nano-preparation. For the injection, the hybrid nanoparticles (NPs) were prepared by a modified single-step nanoprecipitation method to encapsulate ISL. iRGD peptides were anchored on the surface by a post-insertion method (ISL-iRGD NPs). The stable lipid-polymer structure of ISL-iRGD NPs with high encapsulation and loading efficiency has been confirmed. Compared with free ISL and non-iRGD modified counterpart, ISL-iRGD NPs showed higher cytotoxicity and cell apoptosis against the different types of breast cancer cells, which was attributed to the higher cellular accumulation mediated by the iRGD-integrin recognition and nano-scale effect. More importantly, based on the active tumor tissue accumulation by iRGD peptides and the prolonged in vivo circulation by the stealth nano-structure, ISL-iRGD NPs displayed higher tumor growth inhibition in 4T-1 bearing breast tumor mice models. For oral preparation, a novel human albumin nanosystems was processed in loading ISL by a simple process method (HSA-ISL NPs). This NPs demonstrated good stability in simulated gastric fluid, simulated intestinal fluid and rats blood plasma, which guaranteed the completed form of NPs during the process of oral delivery. Compared with Free ISL and Blank NPs, HSA-ISL NPs had better performance in inhibiting TNBC cells growth and metastasis in vitro, inducing TNBC cells apoptosis in vitro, and better ability in inhibiting tumor growth without obvious toxicity in vivo. Importantly, this oral HSA delivery system could enhance the cellular uptake rate of ISL to breast cancer cells and showed better targeting ability which can accumulate the drug around the tumor site via the real-time in vivo tracking technique research. All in all, this project would provide two promising drug delivery strategies to improve ISL in anti-breast cancer efficacy both in injection and oral administration, which is a typical research model in introducing advanced nano-tech in developing traditional Chinese medicine.