A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways

摘要

AbstractHepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The identification of all-transretinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher Cmaxand AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC50by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantl