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

Abstract

Hepatocellular 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-trans retinoic 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 C and 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 IC by 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 significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted drug for HCC therapy as PLLA is biocompatible, biodegradable and nontoxic to humans.

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

“…Recent series of studies have demonstrated that PIN1 degradation majorly influenes the effects of ATRA treatments . For normal immortalized cells or hepatocelluar carcinoma cells with PIN1KD, ATRA treatments showed no effect on inhibition of cell proliferation, which was also observed in our PIN1KD cells. Thus, PIN1 is a mainly target for ATRA treatment and PIN1 degradation is important for anticancer therapy in PDAC.…”

“…Traditional prognostic tools and common therapeutic targets have not achieved satisfactory results in clinical studies of high intratumor heterogeneity in PDAC . Targeting PIN1, to block multiple signaling pathways, has been demonstrated to exhibit potent antitumor effects in tumors with poor prognosis but limited therapeutic efficiency in clinical practice . As for the devastating disease of PDAC, our present study indicated that PIN1 may be an attractive predictive marker and targeting PIN1 could exert potent antitumor activity.…”

“…ATRA can bind to the catalytically active sites of PIN1 and subsequently inhibit its activity, resulting in PIN1 protein degradation. Furthermore, ATRA exerts potent antitumor activity against multiple refractory cancers through inhibiting and ablating PIN1 to inactivate multiple oncogenes or activate tumor suppressors simultaneously in vivo . However, the role of ATRA and its targeting PIN1 in PDAC remain elusive.…”

Targeting PIN1 as a Therapeutic Approach for Hepatocellular Carcinoma

“…In addition, PIN1 over-expression not only promotes malignant transformation of hepatocytes (Pang et al, 2006), but also enhances hepatocarcinogenesis through interaction with the x-protein of hepatitis B virus (HBx), the inhibitor of apoptosis protein survivin, and the cycle-dependent kinase inhibitor p27 (Pang et al, 2007;Cheng et al, 2013Cheng et al, , 2017. Notably, compelling evidence shows that inhibition of PIN1 suppresses the proliferation of HCC cells in vitro and in vivo (Liao et al, 2017;Zheng et al, 2017;Pu et al, 2018;Yang et al, 2018;Sun et al, 2019). Currently, there is no effective conventional chemotherapy and molecular targeting therapy for advanced HCC.…”

Predictive Value of Pin1 in Cervical Low-Grade Squamous Intraepithelial Lesions and Inhibition of Pin1 Exerts Potent Anticancer Activity against Human Cervical Cancer

“…The activation of oncogenes and the low expression levels of Pin1 in normal tissues make Pin1 an attractive target for anticancer drugs [17]. Although many inhibitors, including juglone, PiB and buparvaquone, have been isolated thus far, their unsatisfactory pharmacological performance with respect to potency, specificity, solubility, cell permeability and stability has limited their clinical trial phase progression [9,18]. KPT-6566 is a novel Pin1-specific inhibitor that was discovered and synthesized by Elena Campaner et al Furthermore, KPT-6566 covalently binds to the catalytic site of it and targets Pin1 for degradation.…”