All-Trans Retinoic Acid and Doxorubicin Delivery by Folic Acid Modified Polymeric Micelles for the Modulation of Pin1-Mediated DOX-Induced Breast Cancer Stemness and Metastasis.

Stemness and metastasis are the two main challenges in cancer therapy and are related to disease relapse post-treatment. They both have a strong correlation with chemoresistance and poor prognosis, ultimately leading to treatment failure. It has been reported that chemotherapy can induce stemness and metastasis in many cancer types, especially treatment with the chemotherapeutic agent doxorubicin (DOX) in breast cancer. A combination treatment is an efficient and elegant approach in cancer therapy through simultaneous delivery of two or more drugs with a delivery system for its synergistic effect, which is not an additive of two individual drugs. Herein, we report a combinatorial system with DOX and all-trans retinoic acid (ATRA) to address both of the above issues. As a common critical regulatory factor for oncogenic signal transduction pathways, Pin1 is a specific isomerase highly expressed within various tumor cells. ATRA, a newly identified Pin1 inhibitor, can abolish several oncogenic pathways by effectively inhibiting and degrading overexpressed Pin1. We successfully developed a folic acid (FA)-modified chitosan (CSO)-derived polymer (FA-CSOSA) and obtained FA-CSOSA/DOX and FA-CSOSA/ATRA drug-loaded micelles. FA modification can improve the uptake of the nanoparticles in tumor cells and tumor sites via folate receptor-mediated cell internalization. Compared to treatment with DOX alone, the combined treatment induced 4T1 cell apoptosis in a synergistic manner. Reduced stemness-related protein expression and inhibited metastasis were observed during treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA and were found to be associated with Pin1. Further experiments showed that treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA resulted in 85.5% tumor inhibition, which was 2.5-fold greater than that of cells treated with DOX·HCl alone. This work presents a new paradigm for addressing chemotherapy-induced side effects via degradation of Pin1 induced by tumor-targeted delivery of DOX and ATRA.