Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.

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For peripheral endovascular intervention, self-expanding (SE) stents are commonly oversized in relation to target arteries to assure optimal wall apposition and prevent migration. However, the consequences of oversizing have not been well studied. The purpose of this study was to examine the effects of SE stent oversizing (OS) with respect to the kinetics of late stent expansion and the long-term histological effects of OS. Pairs of overlapped 8 x 28-mm Nitinol SE stents were implanted into the iliofemoral arteries of 14 Yucatan swine. Due to variations in target artery size, the stent-to-artery ratio ranged from 1.2:1 to 1.9:1. Lumen and stent diameters were assessed by quantitative angiography at the time of implantation. Following angiographic assessment at 6 months, stented arteries were perfusion-fixed, sectioned, and stained for histological analysis. Immediately following implantation, the stents were found to be expanded to a range of 4.7-7.1 mm, largely conforming to the diameter of the recipient target artery. The stents continued to expand over time, however, and all stents had enlarged to nearly their 8-mm nominal diameter by 6 months. The histological effects of OS were profound, with marked increases in injury and luminal area stenosis, including a statistically significant linear correlation between stent-to-artery ratio and area stenosis. In this experimental model of peripheral endovascular intervention, oversized Nitinol SE stents are constrained by their target artery diameter upon implantation but expand to their nominal diameter within 6 months. Severe OS (stent-to-artery ratio >1.4:1) results in a profound long-term histological response including exuberant neointimal proliferation and luminal stenosis.

Background Drug-coated balloons are increasingly utilized for peripheral vascular disease and yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used Paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined Zotarolimus pharmacokinetics. Methods and results Animal studies, bench-top experiments and computational modeling were integrated to quantify arterial distribution after Zotarolimus-coated balloon (ZCB) use. Drug diffusivity and binding parameters for use in computational modeling were estimated from kinetics of Zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like Paclitaxel, Zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with Zotarolimus concentration decreasing with transmural depth as opposed to multiple peaks displayed by Paclitaxel. Drug release kinetics was measured by inflating ZCBs in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion but binding determined drug retention. Conclusions Large bolus of Zotarolimus releases during balloon inflation, some of which pervades the tissue and a fraction of the remaining drug adheres to the tissue-lumen interface. As a result, duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.

Background-Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine. Methods and Results-A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 g/cm 2 ) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 g/cm 2 , nϭ16), low-dose (300 g/cm 2 , nϭ16), or paired uncoated balloons (high-dose ZCB control, nϭ16; low-dose ZCB control, nϭ16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, Pϭ0.007; low-dose ZCB 22% reduction, Pϭ0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups. Conclusions-The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine. (Circ Cardiovasc Interv. 2011;4:447-455.)