COREL-07184; No of Pages 15 Journal of Controlled Release xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Controlled Release

Drug-eluting biostable and erodible stents

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Yingying Huang, Herr Cheun Anthony Ng, Xu Wen Ng, Venkatraman Subbu ⁎

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School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore

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Article history: Received 26 February 2014 Accepted 7 May 2014 Available online xxxx

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Keywords: Biostable drug eluting stent (BDES) Erodible drug eluting stent (EDES) Dual-drug eluting stent (DDES) Drug release kinetics

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This paper reviews the latest research and development of drug-eluting stents. The emphasis is on coronary stenting, and both biostable and bioerodible stents are covered in this review. The advantages and shortcomings of the bioactive molecules used in these stents are analyzed, along with the rationale for using bioerodible coatings. The overall emphasis is on the performance of these stents in the clinic. Based on the evaluation of the different stent types, we conclude that fully-erodible stents with a coating of antiproliferative drug will slowly gain market share in the near future, and that the search for a more selective anti-proliferative compound will continue. Dual-drug eluting stents (DDES) will have their market share but possibly a much smaller one than that for single-drug eluting stents due to the complexities and costs of DDES unless significantly superior performance is demonstrated in the clinic. © 2014 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biostable drug eluting stents (BDES) . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Mechanism of action of drugs . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Limus family . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Drug release kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Zotarolimus-eluting stent (ZES) . . . . . . . . . . . . . . . . . . . . 3.1.2. Everolimus-eluting stent (EES) . . . . . . . . . . . . . . . . . . . . 3.1.3. Biolimus A9 eluting stent (BES) . . . . . . . . . . . . . . . . . . . . Dual drug eluting stent (DDES) . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Anti-proliferative + anti-thrombotic . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost 4.1.2. Sirolimus and triflusal . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Paclitaxel and cilostazol (Cilotax stent) . . . . . . . . . . . . . . . . 4.2. Anti-proliferative + re-endothelialization promoter . . . . . . . . . . . . . . . 4.2.1. Sirolimus and estradiol. . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Sirolimus and anti CD-34 antibody (Combo stent) . . . . . . . . . . . 4.3. Dual anti-proliferative agents (independent pathways) . . . . . . . . . . . . . 4.3.1. Paclitaxel and pimecrolimus . . . . . . . . . . . . . . . . . . . . . 4.3.2. Sirolimus and paclitaxel . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Peptide/protein — eluting stent . . . . . . . . . . . . . . . . . . . . Polymer free drug eluting stent (PFDES) . . . . . . . . . . . . . . . . . . . . . . . 5.1. Micro- and nano-fabricated reservoirs on stent surface . . . . . . . . . . . . . 5.2. Novel methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Summary and prognosis: DES and DDES . . . . . . . . . . . . . . . . Fully-erodible drug-eluting stents (EDES) . . . . . . . . . . . . . . . . . . . . . . . 6.1. Commercially-available . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. In research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. Tel.: +65 6790 4259; fax: +65 6790 9081. E-mail address: [email protected] (V. Subbu).

http://dx.doi.org/10.1016/j.jconrel.2014.05.011 0168-3659/© 2014 Published by Elsevier B.V.

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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Y. Huang et al. / Journal of Controlled Release xxx (2014) xxx–xxx

6.2.1. Coronary stents . . . . 6.2.2. Tracheal/bronchial stents 7. Summary. . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . .

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The current family of drug-eluting stents can be classified into: (a) (b) (c) (d)

Limus-type elution from biostable coating Non-limus drug elution from biostable coating Limus-type elution from biodegradable coating Anti-proliferative in combination with another drug (dual-drug eluting stent).

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2.1. Mechanism of action of drugs

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Several immunosuppressive and antiproliferative molecules, such as dexamethasone, actinomycin D, cytochalasin D, 17-beta-estradiol, mycophenolic acid, and angiopeptin, have been tested during the last decade for their effect on inhibiting the pathway of neointimal hyperplasia, but the drugs that have been demonstrated to have superior performance in a consistent and reproducible fashion both in preclinical and clinical trials are the “Limus” family compounds and paclitaxel.

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The first generation of DES includes the sirolimus-eluting stent (Cypher®) and the paclitaxel-eluting stent (Taxus®) and demonstrated impressive reductions in restenosis. But their long-term use has been marred by the incidence of late stent thrombosis due to incomplete healing, especially after discontinuation of dual antiplatelet therapy [1]. In addition, the use of paclitaxel for this indication has been more or less discontinued due to fears of cardiotoxicity. The second generation of DES using limus derivatives such as the zotarolimus-eluting stent (Endeavor®) and everolimus-eluting stent (Xience V®) has been introduced with promising anti-restonotic efficacy as well as long-term safety. They differ from the first generation stents with respect to the antiproliferative agent, the polymer layer and the stent frame. In view of the differences in clinical success of the different drug types, it is instructive to examine the mode of action of these drugs briefly.

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2.1.2. Paclitaxel Paclitaxel is a lipophilic molecule with potent antiproliferative and antimigratory activity. The drug is a microtubule-stabilizing agent which enhances formation of microtubular polymerized structures and thus, decreases the concentration of tubulin required for new microtubule formation. Paclitaxel impacts primarily the M phase of the cell cycle inhibiting growth factor-induced DNA synthesis and cell proliferation, and leads to apoptosis or cell death. Compared with the limus family, the mode of action of paclitaxel is primarily cytotoxic (Fig. 1).

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2. Biostable drug eluting stents (BDES)

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In 2009, we published a review in Journal of Controlled Release [1] that surveyed the clinical success of drug-eluting stents, and some of the issues associated with controlled delivery of bioactive agents from such stents. At that point of time, the drug-eluting stents in the clinic or in the marketplace were all biostable and eluted a single drug, predominantly an anti-proliferative. This review updates their status in clinical practice, and also surveys the inroads made by fully degradable and dual-drug eluting stents.

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of the negative (through inhibitor p27 kip1) regulators of the cell cycle [2]; they stop the cell cycle at the G0/G1 phase inhibiting both cell (mainly smooth muscle cells) proliferation and migration, so the mechanism of action is cytostatic rather than cytotoxic. Tacrolimus and pimecrolimus are not analogs of the archetypal rapamycin; after they bind intracellularly to FKBP12, the complex in turn binds to and blocks calcineurin, and in this way inhibits the T-cell transduction pathways and the synthesis of pro-inflammatory cytokines [3]. In vitro cell work indicates that tacrolimus allows earlier endothelial regeneration than sirolimus; however, inhibitory activity on human vascular smooth muscle cells with tacrolimus is much less than sirolimus [4].

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2.1.1. Limus family Six limus family compounds are currently being used in DES: these compounds target either the mammalian target of rapamycin (mTOR) (sirolimus, everolimus, zotarolimus and biolimus A9) or calcineurin (tacrolimus and pimecrolimus). The mTOR inhibitors (sirolimus, everolimus, zotarolimus and biolimus A9) share an almost identical lipophilic chemical structure and bind to their major cytosolic FK-506 binding protein-12 (FKBP12) forming a complex which subsequently inhibits the mTOR. The major cellular effects include a decrease of the positive (blockage of the p70S6 kinase pathway of the cyclin-dependent kinases) and an increase

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3. Drug release kinetics

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3.1.1. Zotarolimus-eluting stent (ZES) Zotarolimus is the first ever drug synthesized exclusively for treatment of in-stent restenosis. Zotarolimus is produced by the tetrazole ring substitution of the hydroxyl group at the C40 position of sirolimus, as shown in Fig. 2. The presence of a tetrazole ring instead of a hydroxyl group makes zotarolimus extremely lipophilic. This hydrophobicity restricts the solubilization of zotarolimus in the luminal blood flow, leading to an immense decline in the systemic exposure risk; negligible concentrations of the anti-proliferative agent in the systemic circulation may also be conducive to stent re-endothelialization. Similar to sirolimus, the biologic effects of zotarolimus are mediated by the intracellular receptor FK506-binding protein 12, blocking progression from G1 to S in the cell cycle. To date, three ZESs were evaluated in human clinical trials: Endeavor ZES (Medtronic CardioVascular Inc., Santa Rosa, CA), ZoMaxx ZES (Abbott Vascular, Santa Clara, CA), and Resolute ZES (Medtronic CardioVascular Inc., Santa Rosa, CA). All three have the same zotarolimus loading of 10 μg/mm 2, but with different metallic platforms and polymeric coatings, exhibit different release profiles. The Endeavor ZES [7,8] combines zotarolimus with a phosphorylcholine (PC) coating, and a cobalt–chromium alloy stent as base. Unlike other durable or biodegradable polymer, PC coating mimics the cell membrane of red blood cells in the plasma, thereby avoiding hypersensitivity and inflammatory reactions. However, because of the structure of the PC and with no other top layer to control drug release, approximately 95% of total zotarolimus is released within 15 days. The Resolute ZES [9,10] is the second generation ZES developed by Medtronic. It uses a newly developed biodurable polymer — BioLinx™ (hydrophobic component C10: 60/40 (by weight) mixture of n-butyl methacrylate (BMA) and vinyl acetate (VA); hydrophilic

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Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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Q25 Fig. 1. Pathophysiological pathway of neointimal hyperplasia and primary mechanisms of action of drugs: sirolimus, everolimus, zotarolimus, biolimus A9, tacrolimus and pimecrolimus

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as a drug-control layer, that allows a slightly longer elution time; about 90% of zotarolimus being released within 30 days. It uses a stainless steel–tantalum stent as the platform. The only difference between Endeavor and Resolute stents is the polymer: PC coating (fast release) vs. BioLinx (slow release). The differences between the Endeavor and ZoMaxx stents are the polymer: PC

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C19: 25/27/48 (by weight) terpolymer of vinyl acetate (VA), N-vinyl pyrrolidone, and n-hexyl methacrylate; and polyvinyl pyrrolidone (PVP) that enables longer drug elution, with about 85% of the drug eluted within 60 days and continued elution up to 180 days. The ZoMaxx ZES [11,12] is developed by Abbott Vascular. It combines zotarolimus with a PC drug layer, and PC topcoat

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and paclitaxel [5].

Fig. 2. Zotarolimus' structure [6].

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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3.1.2.2. Human data. In a comparison trial of the XIENCE V EES (n = 900) and TAXUS PES (n = 895) at 2 years, significantly fewer EES patients took dual antiplatelet therapy (11.4% vs. 15.4%, p = 0.02). The primary composite of all death, nonfatal myocardial infarction, and target vessel revascularization occurred in 9.0% of EES patients and 13.7% of PES patients (relative risk [RR]: 0.66; 95% confidence interval [CI]: 0.50 to 0.86) [18]. In another two-year open-label randomized comparison of XIENCE V EES (n = 498) and SES (n = 479) study, there were no differences in both primary (composite of cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR)) and secondary endpoints (composite of cardiac mortality, MI, TVR, TLR (target lesion revascularization) and ST) between groups (EES = 10.7%, SES = 10.6%, HR1.00, 95% CI 0.68–1.48), and stent thrombosis was low for both groups [19]. In another 9 month follow-up study, neointimal hyperplasia did not differ between XIENCE V EES and SES (2.6 ± 4.0% vs. 2.5 ± 4.8%, p = 0.814), however, positive peri-stent vascular remodeling defined as an increase in vessel volume index N 10% (27.8 vs. 42%, p = 0.027) and late acquired stent malapposition (LASM, 1.9 vs. 15.9%, p b 0.001) were observed less frequently with EES than SES [20]. PROMUS EES (Boston Scientific, Massachusetts, USA) uses a new metal alloy–platinum chromium (PtCr) as stent base, with the same combination of durable polymer and drug as XIENCE V EES (CoCr-EES). The animal study showed that the PtCr-EES and CoCr-EES both provide comparable everolimus release kinetics [21]. A total of 1530 patients were randomized at 132 worldwide sites to CoCr-EES (n = 762) or PtCr-EES (n = 768) [22]. The 12-month follow-up shows that PtCr-EES was noninferior to CoCr-EES for TLF (3.2% vs. 3.5%, p = 0.72), cardiac death or MI (2.5% vs. 2.0%, p = 0.56) and TLR

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3.1.1.1. Human data. In comparison to sirolimus-eluting stents (SES) in the ENDEAVOR III trial, ZES was compared to SES: the ZES arm 189 had greater percentage of neointimal volume index (Endeavor ZES 190 1.1 ± 0.8 mm3/mm vs. SES 0.2 ± 0.1 mm3/mm, p b 0.01), resulting 191 in a smaller lumen volume (6.0 ± 2.0 mm3/mm vs. 7.0 ± 2.1 mm3/mm, 192 p b 0.05) [13]. Thus the Endeavor ZES failed to meet its non-inferiority 193 end point in terms of late lumen loss at 8 months [14]. 194 Q10 In comparison to paclitaxel-eluting stents (PES), Endeavor ZES 195 showed a relatively higher percent of neointimal obstruction of 196 16.6 ± 12% vs. 9.9 ± 8.9% for PES, p b 0.01 [8]. In addition, comparing 197 between ZoMaxx ZES with PES [11], after 9 months, late lumen loss was 198 significantly greater in the ZoMaxx group (in-stent 0.67 ± 0.57 mm vs. 199 0.45 ± 0.48 mm; p b 0.001; in-segment 0.43 ± 0.60 mm vs. 0.25 ± 0. 200 45 mm; p = 0.003), resulting in significantly higher rates of N 50% 201 angiographic restenosis (in-stent 12.9% vs. 5.7%; p = 0.03; in-segment 202 16.5% vs. 6.9%; p = 0.007). And ZoMaxx showed relatively higher per203 centage neointimal obstruction (15.4 ± 8.8% vs. 11.3 ± 9.7%) [12]. 204 However, the Resolute ZES with a new durable polymer showed smaller 205 late in-stent lumen loss at 0.22 ± 0.27 mm at 9-month [9], and much 206 smaller percent neointimal obstruction of 3.7% [10]. Moreover, the 207 neointima free frame ratio (an estimation of the extent of free lumen 208 volume, using ultrasound techniques) was 53.3%, 13.2%, 14.6%, and 209 6.6% for Resolute, Endeavor, ZoMaxx, and BMS, respectively [15]. 210 These clinical data do strongly indicate the influence of release kinetics 211 of the anti-proliferative on neointimal proliferation. 212 Previous clinical studies have shown that elution kinetics is one of 213 the key factors that determines the efficacy of DES. The PISCES trial, 214 which compared paclitaxel-eluting stents with different eluting proper215 ties, showed that stents with longer elution duration (N 30 days) 216 showed significantly lower percent neointimal volume as compared 217 with those with shorter elution (10 days) (8 ± 7% versus 17 ± 13%), 218 indicating that sustained release is preferred [1,16]. Considering that 219 the main difference between Resolute and Endeavor is the elution 220 time (60 days versus 14 days), which is greater than the elution time 221 difference between Endeavor and ZoMaxx (14 days versus 30 days), 222 we hypothesize that slow release (60 days) is more effective in terms 223 of neointimal suppression; however, fast- or moderate-release formula224 tions (14 days and 30 days) may not be associated with sufficient 225 neointimal suppression.

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3.1.2.1. Animal study. The XIENCE V everolimus-eluting stent system contains 100 μg/cm2 of everolimus. This formulation was selected based on results obtained from a 28 day pre-clinical dosing study conducted in a high-injury (balloon: artery ratio, B:A = 1.3:1) porcine coronary arterial model [17]. Three formulations of everolimus-eluting stents (EES ) (100 μg/cm2 with 80% release at 28 days, n = 11; 200 μg/cm2 with 80% release at 28 days, n = 11; and 260 μg/cm2 with 80% release at 60 days, n = 11) were compared with ML VISION metallic stent control (n = 8) at 28 days. All three formulations were equally effective at reducing the neointimal response. The mean percent area stenosis was markedly reduced (N 60%) for all EES as compared to the ML VISION control; all three formulations resulted in similar neointima covering all stent struts, and minimal-to-mild inflammatory response. All lumens were widely patent and the luminal surfaces were completely endothelialized. Based on these findings, the lowest evaluated effective dose of 100 μg/cm2 everolimus was chosen for XIENCE V. The in vivo cumulative percentage of everolimus released during the first 28 days was approximately 71%, with 29% released during the first 24 h. Everolimus release reached ~ 92% by 90 days and was nearly complete (95.3 ± 4.5%) by 120 days after stent implantation, as shown in Fig. 3(a). The peak everolimus concentration in stented arterial segments occurred at 3 h after implantation with a mean of 6.6 ng/mg. Subsequently, everolimus levels were maintained from 2.6 to 0.8 ng/mg from 6 h to 28 days and gradually decreased to 0.2 ng/mg by 120 days post-implantation, as shown in Fig. 3(b).

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coating (fast release) vs. PC coating with topcoat PC (moderate release), and the platform: cobalt–chromium vs. stainless steel–tantalum. In terms of elution profile, 98% of zotarolimus elutes within 14 days in Endeavor, 90% elutes within 30 days in ZoMaxx, and 85% of the drug elutes within 60 days for Resolute. A comparison between ZESs is summarized in Table 1.

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Table 1 Comparison between ZESs.

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Endeavor Resolute

Cobalt–chromium Cobalt–chromium

10 μg/mm 10 μg/mm

Stainless steel–tantalum

10 μg/mm

95% zotarolimus released in 15 days 85% of the drug elutes within 60 days and continue to elute up to 180 days. 90% of zotarolimus released in 30 days

TLR = 5.1% TLR = 1.1%

ZoMaxx

Phosphorylcholine (PC) BioLinx (hydrophobic C10, hydrophilic C19, and polyvinyl pyrrolidone) PC drug layer + PC topcoat as control layer

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3.1.2. Everolimus-eluting stent (EES) Everolimus is a 40-O-hydroxy ethyl derivative of sirolimus, and not very different from sirolimus except for a slightly lower halflife. The XIENCE V stent (Boston Scientific, Massachusetts, USA) consists of a 81 μm strut, cobalt chromium platform that elutes everolimus from a nonerodible two-polymer (polyvinylidene fluoride co-hexafluoropropylene and poly-n-butylmethacrylate) combination. It contains 100 μg/cm2 of everolimus, 71% of everolimus being released at 28 days, and complete release at 120 days.

TLR = 9.4%

TLR, target lesion revascularization at one year, p b 0.001 [13].

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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3.1.3. Biolimus A9 eluting stent (BES) Biolimus A9, developed by Biosensors International, appears to be also a modification of sirolimus at the 40-Oxygen position, rendering it much more lipophilic than sirolimus, and longer-lived in tissue. The BioMatrix Flex (Biosensors) stent consists of a 112 μm strut, stainless steel stent platform that delivers biolimus A9 (15.6 μg/mm) from a polylactic acid (PLA) biodegradable polymer applied to the abluminal surface, which allows direct release of biolimus A9 into the vessel wall and, enhanced by its high lipophilicity, fast uptake by the surrounding tissue. A minimal amount of drug is expected to be released into peripheral circulation. The in vitro cumulative amount of biolimus A9 released profile was shown in Fig. 4 [25], about 15 μg (5.9%) was released during the first 24 h, and about 80 μg (31.7%) was released during the first 34 days. In addition to the BioMatrix FleX (Biosensors Inc.; Singapore), Nobori (Terumo Europe, Leuven, Belgium) and Axxess (Biosensors Inc.) also use biolimus A9 in a biodegradable coating. In one study [26], 20 patients were treated with single 14 mm (n = 10) and 28 mm (n = 10) long Nobori stents, and blood samples were drawn at 16 time points to determine the pharmacokinetics of biolimus A9, as shown in Fig. 5. The median maximum concentration (C max) was 17.7 pg/mL with concentrations ranging from below the lower limit of quantitation (LLOQ) to 32.2 pg/mL. Nine months after stent implantation, biolimus A9 concentrations were below the LLOQ in all samples. In comparison with sirolimus-eluting stent [27], C max of Sirolimus after implantation of a single sirolimus-eluting stent was 570 ± 120 pg/mL and after implantation of two stents, 1005 ± 390 pg/mL. After 7 days, 17 of 19 subjects still had sirolimus blood concentrations higher than 200 pg/mL. So the Cmax of biolimus A9 was 17.7 ± 10.2 pg/mL and 33-58 fold lower than sirolimus, consistent with abluminal release into the tissue than into the lumen.

376

Long term follow-up studies of drug-eluting stents have shown increased incidence of (sometimes fatal) stent thrombosis probably due to delayed endothelialization by the currently used drugs or delayed hypersensitivity reaction caused by the durable polymer, or by degraded polymer products currently used in DES [30–32]. A dual

377

O

F

4. Dual drug eluting stent (DDES)

R O

309 310

P

307 308

D

305 306

E

303 304

T

301 302

C

299 300

E

297 298

R

296

354

R

294 295

superiority = 0.18), rates of cardiac death (3.2% vs. 3.9%, HR: 0.81, 95% CI: 0.49 to 1.35, p = 0.42), and myocardial infarction (6.3% vs. 5.6%, HR: 1.12, 95% CI: 0.76 to 1.65, p = 0.56). The rate of definite stent thrombosis through 2 years was 2.2% for BES and 2.5% for SES (p = 0.73). For the period between 1 and 2 years, event rates for definite stent thrombosis were 0.2% for BES and 0.5% for SES (p = 0.42). The NEXT trial (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BES with EES in terms of target lesion revascularization (TLR) at 1 year [29]. Between May and October 2011, 3235 patients were randomly assigned to receive either BES (n = 1617) or EES (n = 1618). The primary efficacy endpoint of TLR was 4.2% for the BES group, and 4.2% for the EES group, demonstrating noninferiority of BES relative to EES (p for noninferiority b 0.0001, and p for superiority = 0.93). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.25% vs. 0.06%, p = 0.18). An angiographic substudy enrolling 528 patients (BES: n = 263, and EES: n = 265) demonstrated noninferiority of BES relative to EES regarding the primary angiographic endpoint of in-segment late loss (0.03 ± 0.39 mm vs. 0.06 ± 0.45 mm, p for noninferiority b 0.0001, and p for superiority = 0.52) at 266 ± 43 days after stent implantation.

N C O

292 293

(1.9% vs. 1.9%, p = 0.96). In another comparison study of 1704 patients monitored over 12 months, the unadjusted major adverse event rate was significantly lower in the PROMUS EES group versus the ZES group (3.1% vs. 8.7%; p = 0.001), and the SES group (5.2% vs. 9.6%; p = 0.01). This was mainly driven by lower TVR rates (EES: 2.6% vs. ZES: 8.2%; p b 0.001) and 4.1% with EES vs. 7.0% with SES (p = 0.05) [23]. However, with a modified scaffold designed to provide improved deliverability, vessel conformability, side-branch access, radio-opacity, radial strength, and fracture resistance, the PtCr platform was used in the biodegradable polymer coated SYNERGY stent. The SYNERGY EES (Boston Scientific; Natick, Massachusetts, USA) consists of a 74 μm thin strut, PtCr platform that delivers everolimus from a poly-lactide-co-glycolide (PLGA) polymer applied to the abluminal surface. In the randomized, EVOLVE trial [24], the safety and efficacy of 2 dose formulations (5.6 μg/mm, and half dose (HD) 2.8 μg/mm) of the SYNERGY stent were compared to the durablepolymer PROMUS EES. A total of 291 patients were randomly assigned in a 1:1:1 ratio to SYNERGY, SYNERGY HD, and PROMUS EES. The TLR occurred in 3.1%, 1.1% and 0% of patients at 30 days in the SYNERGY, SYNERGY HD, and PROMUS EES groups, respectively. At 6 months, late lumen loss was 0.10 mm, 0.13 mm and 0.15 mm for SYNERGY, SYNERGY HD, and EES groups, respectively (p b 0.001). Recently, the SYNERGY stent acquired CE mark approval, and a pivotal EVOLVE II trail aiming a head-to-head comparison of 12-month TLF with SYNERGY (842 patients) and EES (842 patients) is currently ongoing, estimated completion date is December 2014 (Clinical Trials. gov NCT01787799).

U

290 291

5

3.1.3.1. Human data. 2-year follow-up clinical safety and effectiveness [28] have been demonstrated for BES with biodegradable polymer compared to a durable polymer-based Cypher SES in a noninferiority randomized trial which included 1707 patients (BES, n = 857; SES, n = 850): target vessel revascularization (BES 12.8% vs. SES 15.2%, HR: 0.84, 95% CI: 0.65 to 1.08, p for noninferiority b 0.0001, p for

Fig. 3. (a) In vivo cumulative percent drug-release profile of XIENCE V. (b) Everolimus concentration in stented artery following XIENCE V implantation [17].

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375

378 379 380 381

6

Y. Huang et al. / Journal of Controlled Release xxx (2014) xxx–xxx

382 383

413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443

4.1.2. Sirolimus and triflusal The authors of this review have developed a DDES consisting of a closed cell design cobalt–chromium stent with strut dimensions 0.075 × 0.080 mm (W × T), and a two-layered coating including the biodegradable PLGA drug layer and the drug-free top layer (total coating thickness 10 μm); this DDES elutes sirolimus and triflusal to treat both restenosis and thrombosis [34]. Triflusal, an aspirin derivative, has been used both prophylactically and following MI, as an anti-coagulant via oral dosing [35]. The cumulative release profile shows an initial burst of about 30% for sirolimus, and a subsequent release of 60% by day 14, and more than 70% cumulative sirolimus release after 30 days. In contrast, approximately 60% of triflusal was released as a burst and almost all of it is released in about 5 days, as shown in Fig. 6. In a pig study (Expanded stent/artery = 1.1:1) we saw significantly less percentage stenosis for DDES, compared with SES and BMS (DDES 22 ± 4% vs. SES 37 ± 12%, p b 0.036; vs. BMS 30 ± 4%, p b 0.034). We attributed the significant restenosis reduction to the prevention of thrombus formation due to the early burst release of triflusal: this may contribute significantly to lowered thrombus formation since it is accepted that the thrombus formed initially (1–3 days) acts as a scaffold for neointimal proliferation of SMCs. 4.1.3. Paclitaxel and cilostazol (Cilotax stent) Cilostazol is a quinolinone derivative, used orally to treat clauditation in peripheral vascular disease. The Cilotax® stent platform consists of a thin-strut tube stent (77 μm) made of L605 cobalt chromium, coated with drug-carrying polymers (a blend of hydrophilic biocompatible cellulose acetate butyrate and a bioabsorbable resomer; coating thickness 10 μm). Most of the incorporated paclitaxel (1 μg/mm2) is released within 1 month and most of the cilostazol (6 μg/mm 2) within 3 months. Slow release of cilostazol may hinder local thrombus formation around the stent strut, helping to prevent stent thrombosis during the early hazard period. The 8-month clinical results from 2 centers in Korea showed that in-stent late loss was significantly lower

R O

444 445 446 447 Q14 448 Q15 449 450 451 452 453 454 455 456

4.2. Anti-proliferative + re-endothelialization promoter

457

4.2.1. Sirolimus and estradiol Estradiol has been shown to promote rapid re-endothelialization of the stent and to reduce the restenosis after PCI. Sirolimus (rapamycin) plus 17-β-estradiol-eluting stent (ERES®), is a rough surface stainless steel stent which allows coating without the need of a polymer. There was a markedly slower release of rapamycin from ERES compared to sirolimus eluting stent (SES): at 1 month, the total release of rapamycin was 95% from SES and 60% from ERES, as shown in Fig. 7 [37]. Disappointingly, in the single center ISAR-PEACE trial (ClinicalTrials.gov, number NCT00402636), no apparent beneficial effect was seen by adding estradiol to a polymer-free rapamycineluting stent during the first year after the procedure. Late lumen loss (0.52 ± 0.58 mm vs. 0.51 ± 0.58 mm, p = 0.83), the incidence

458 459

pg/mL

411 412

C

410

E

408 409

R

407

R

405 406

O

403 404

C

401 402

in the Cilotax stent than in the PES (0.22 ± 0.31 vs. 0.50 ± 0.55 mm, p = 0.002), as well as, in-stent restenosis rate was significantly lower in the Cilotax stent group compared with PES (0% vs. 10.9%, p = 0.027) [36]. In general, DDES with an anti-thrombotic and anti-proliferative do not report thrombotic event prevention because acute (definite) thrombosis is rarely observed; on the other hand, prevention of a thrombus is usually reflected in reduced restenosis, due to the scaffolding effect mentioned above. Larger clinical trials are ongoing with the Cilotax®: a multi-center trial in Korea was started in April 2012 (ClinicalTrials.gov, number NCT01612819), and a comparison of Cilotax stent and EES with diabetes mellitus (ESSENCE-DM III) was started in January 2012 (ClinicalTrials. gov, number NCT01515228).

N

399 400

U

397 398

Fig. 4. The in vitro cumulative biolimus A9 release profile from the BioMatrix Flex stent (total amount of drug = 252 μg) [25].

P

4.1.1. Polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost The first DDES was reported by Alt et al. in 2000 [33]. Palmaz-Schatz stents were coated with a 10 μm layer of polylactic acid (PLA, MW = 30 kDa) releasing a combination of polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost, drugs with anti-thrombotic and potentially anti-proliferative effects, respectively. About 60% of the antithrombotic r-PEG-hirudin was eluted during the first 24 h, but Iloprost had a prolonged action profile. The morphometric analysis demonstrated that the DDES was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (p b 0.02) in the standard-pressure sheep model and by 24.8% (p b 0.02) in the overstretch pig model for coated stents compared with uncoated control stents at 28 days. However, there was no report of reduced thrombosis in this work.

D

396

E

4.1. Anti-proliferative + anti-thrombotic

T

395

O

F

drug eluting stent (DDES) would include two therapeutic agents, antiproliferative agents and pro-healing agents, which would help in 384 further enhancing the anti-restenotic performance of current available 385 DES, and would promote healing (either anti-thrombotic or enhanced 386 endothelialization) performance. The successful performance of DDES 387 is mainly based on the selection of appropriate therapeutic combination 388 Q12 and the regulation of their release kinetics (Table 2). 389 The mechanism of anti-proliferative agents — limus family or 390 Q13 paclitaxel has been discussed in earlier Section 2.1. Both cytostatic 391 (limus type) and cytotoxic (paclitaxel) drugs do not exhibit selectivity 392 toward the targeted cell types; thus they not only inhibit proliferation 393 of VSMCs underlying neointimal formation, but also compromise 394 endothelial repair.

26 24 22 20 18 16 14 12 10 8 6

28mm 14mm

Minutes

Hours

Days

Months

Time points Fig. 5. Mean (±standard deviation) biolimus A9 concentrations after implantation of 14 mm (n = 10) and 28 mm (n = 10) Nobori stents [26].

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

460 461 462 463 464 465 466 467 468 469 470

Table 2 Drug eluting stent.

t2:3

Drug(s)

t2:4 t2:5

Limus-type elution from biostable coating Sirolimus (140 μg/cm2) Cypher™ (Cordis)

t2:6

Zotarolimus (10 μg/mm)

t2:7

Stent name (manufacturer)

Polymer(s)

Stent platform

Descriptions

Status [reference]

SS

Zotarolimus (10 μg/mm)

ZoMaxx ZES (Abbott Vascular)

PC drug layer and PC topcoat

SS–tantalum

Zotarolimus (10 μg/mm)

Resolute (Medtronic)

80% of the sirolimus released within 30 days, complete release is about 90 days Approximately 95% of zotarolimus released within 15 days About 90% of zotarolimus released within 30 days About 85% of the drug elutes within 60 days and continue to elute up to 180 days 71% of everolimus released at 28 days, and completed release at 120 days 71% of everolimus released at 28 days, and completed release at 120 days

FDA approved

Endeavor (Medtronic)

Polyethylene-co-vinyl acetate (PEVA) and poly n-butyl methacrylate(PBMA) Phosphorylcholine (PC)

t2:8 t2:9

Everolimus (100 μg/cm )

t2:10

Everolimus (100 μg/cm2)

t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25

2

U

N

Co–Cr

C

BioLinx (hydrophobic C10, hydrophilic Co–Cr C19 and polyvinyl pyrrolidone(PVP)) XIENCE V (Boston Scientific) Polyvinylidene fluoride co-hexafluoropropylene Co–Cr and poly-n-butylmethacrylate PROMUS PREMIER (Boston Scientific) Polyvinylidene fluoride co-hexafluoropropylene Pt-Cr and poly-n-butylmethacrylate

O

Non-limus drug elution from biostable coating Paclitaxel (15 μg) Taxus (Boston Scientific) Limus-type elution from biodegradable coating Sirolimus (6.6 μg/mm) Supralimus (Sahajan and Medical) BioMime (Meril Life Science) Sirolimus (125 μg/cm2) Sirolimus (140 μg/cm2) Orsiro (Biotronik) Novolimus (4.6 μg/mm) DESyne BD (Elixir Medical) Everolimus (5.6 μg/mm and SYNERGY (Boston Scientific) 2.8 μg/mm) Biolimus A9 (15.6 μg/mm) BioMatrix Flex (Biosensors) Biolimus A9 (15.6 μg/mm) Nobori (Terumo) Biolimus A9 (15.6 μg/mm) Axxess (Biosensors) Anti-proliferative in combination with another drug (dual-drug eluting stent) r-PEG-hirudin and iloprost N.A.

R

R

Poly(styrene-b-isobutylene-b-styrene)

E

PLLA-PLGA-PCL-PVP PLLA + PLGA PLLA + silicon carbide layer PLA PLGA PLA PLA PLA

C

t2:28 t2:29 t2:30 t2:31

Sirolimus (7.7 μg/mm) and N.A. triflusal (3.2 μg/mm) 2 Cilotax stent Paclitaxel (1 μg/mm ) and cilostazol (6 μg/mm2) Rapamycin and estradiol N.A. Sirolimus and anti CD-34 antibody Combo stent Paclitaxel (15 μg) and N.A. pimecrolimus (162 μg)

t2:32

Sirolimus and paclitaxel (90 μg)

t2:33 t2:34 t2:35

t2:36

t2:37 t2:38 t2:39

t2:40 t2:41

N.A.

Abbott drops ZoMaxx FDA-approved for patients with diabetes, CE approved FDA approved FDA approved

100% of paclitaxel released within 30 days

FDA approved

SS Co–Cr Co–Cr Co–Cr Pt–Cr

Almost 100% of sirolimus released in 48 days Almost 100% of sirolimus released in 30 days about 50% of sirolimus released in 30 days about 90% of Novolimus released in 90 days 50% in 60 days

CE approved CE approved CE approved CE approved CE approved

45% in 30 days 45% in 30 days 45% in 30 days

CE approved CE approved CE approved

60% of r-PEG-hirudin eluted in the first 24 h, but Iloprost with a prolonged action profile About 70% of sirolimus released in 30 days, and almost 100% of triflusal released in 5 days Almost 100% of paclitaxel released in 1 month and most of the cilostazol within 3 months 60% rapamycin released at 1 month Total release in 30 days ∼50% of pimecrolimus released in the first 48 h, complete release in 10 weeks and 100% paclitaxel released in 30 days Approximately 60% of paclitaxel and 50% of sirolimus released at first week, followed about 80% of paclitaxel and 70% of sirolimus were released at 21 days.

Pre-clinical (Kuchulakanti PK et al. [2]) Pre-clinical (Huang YY et al. [34]) Clinical Trial (NCT01612819 & NCT01515228) Clinical Trial (NCT00402636) Clinical Trial (NCT00967902) Pre-clinical

Controlled release in 3 months, both paclitaxel release and magnesium degradation completed in 6 months No updated information 75% of loaded everolimus within 30 days

Clinical trial (NCT01168830)

SS SS Nitinol

E

PLA

SS

PLGA

Co–Cr

Hydrophilic biocompatible cellulose acetate butyrate and bioabsorbable resomer Polymer free Biodegradable matrix PLGA

Co–Cr

t2:26 t2:27

CE approved

SS

T

SS SS Co–Cr

PLGA and amorphous calcium phosphate nanoparticles (ACP, b150 nm)

SS

Erodible stents with erodible coating DREAMS I (Biotronik) Paclitaxel (70 μg/cm2)

PLGA

Mg

Sirolimus Everolimus (100 μg/cm2)

DREAMS II (Biotronik) BVS 1.0 (Abbott Vascular)

PLLA PDLLA

Mg PLLA

Sirolimus Novolimus (5 mg per mm of stent length) Mitomycin C (100 μg per stent) Cisplatin

ReZolve2 (REVA Medical) DESolve (Elixir Medical)

N.A. PLLA

N.A. N.A.

N.A. PLGA

D P

R O

O

F

Q2

Y. Huang et al. / Journal of Controlled Release xxx (2014) xxx–xxx

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

t2:1 t2:2

Research stage (Ma X et al. [43])

Clinical trial (NCT01960504) Clinical trial (NCT00300131 and NCT00856856) Poly-tyrosine-derived and polycarbonate Majority of loaded sirolimus released within 90 days Clinical trial (NCT01845311) PLLA 100% of loaded novolimus released between 6 and Clinical trial (NCT02013349) 9 months 33% of loaded MMC released over 12 weeks Pre-clinical (Zhu et al. [73]) poly(L-lactide-co-ε-caprolactone) (PLC) PCL Cisplatin released in 4 weeks through linear Pre-clinical (Chao et. al. [75]) diffusion-control

7

8

505 Q16

As discussed in Section 2.1, the mechanism of action for paclitaxel is different from pimecrolimus and sirolimus. Some researchers expect to obtain synergistic effects (improved safety and/or efficacy, for example) by combining two agents with differing modes of action, as is often the case with dual agent cancer chemotherapy.

499 500 501

506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531

C

497 498

E

495 496

R

493 494

R

491 492

4.3.1. Paclitaxel and pimecrolimus Dual pimecrolimus–paclitaxel eluting stent consists of cobalt– chromium coronary stents with 590 “individual reservoirs” (Conor Medsystems); the total dose of pimecrolimus was 162 μg, and the total dose of paclitaxel used was 15 μg, loaded in different PLGA copolymers (50:50 and 85:15), resulting in different release kinetics. For pimecrolimus, the faster release stent was designed for ∼ 50% release in the first 48 h, with the majority of the drug completely released over ∼ 10 weeks. For paclitaxel, the same polymer formulation was used as in the “30-day release group” (i.e., complete release of paclitaxel in 30 days) in the PISCES study, as this group showed the best efficacy in follow-up analyses of the PISCES study [16]. The 30-day pig study results showed that neointimal proliferation and inflammation were both significantly less in the single pimecrolimus fast release group as compared with the bare metal controls, and neointimal proliferation was significantly less in the DDES as compared with the bare metal controls. However, while there was a trend toward decreased neointimal thickness (0.16 ± 0.07 in DDES compared with 0.22 ± 0.13 in the fast release pimecrolimus group), this was not statistically significant [42].

O

489 490

C

487 488

N

485 486

U

483 484

F

4.3. Dual anti-proliferative agents (independent pathways)

481 482

O

504

479 480

Fig. 6. The triflusal and sirolimus release from stent w/dual sirolimus–triflusal, and the corresponding periods of thrombus deposition and proliferation [34].

(ACP, b150 nm) as a drug carrier layer, with drug-free PLGA as the top layer, the total thickness of coating being 30 ± 10 μm. The total drug loading for both sirolimus and paclitaxel is 90 μg. Both drugs have similar release behavior in vitro as shown in Fig. 9, with approximately 60% of paclitaxel and 50% of sirolimus being released in one week, and about 80% of paclitaxel and 70% of sirolimus being released at 21 days (in vivo release was found to be similar to in vitro release). However, the burst release effect occurred significantly earlier in vivo, over 70% of sirolimus, and over 30% of paclitaxel being released by 3 days. Disappointingly, no angiographic or histology results of efficacy were reported. Most available DESs are coated with anti-proliferative drugs on both the abluminal and luminal surfaces for treating neointimal hyperplasia. These anti-proliferative drugs (as illustrated in Section 2.1) are not cell specific; they not only inhibit the growth of smooth muscle cells but also endothelial cells. Hence, incomplete endothelial cell coverage observed on DES has led to late stent thrombosis (LST) [44–46]. Normal endothelial cells produce different anticoagulant factors to inhibit adhesion, aggregation, and activation of blood platelets, thereby preventing thrombosis. However, when these cells are damaged, it initiates the coagulation cascade that results in stent thrombosis [44–46]. Hence, the strategy of development of DDES is to promote endothelialization while inhibiting neointimal hyperplasia. Clearly, this can be achieved by co-delivering two different therapeutic agents, such as anti-thrombotic/ anti-proliferative, anti-proliferative/re-endothelialization promoter. It would be more advantageous if the DDES elutes an anti-proliferative drug from the abluminal stent surface to inhibit the growth of smooth muscle cells, and elutes (or has attached) the re-endothelialization promoter from the luminal stent surface to promote the growth of endothelial cells. The difficulty of developing such DDES is attaining the tailored release kinetics of both drugs from a thin layer in the range of 5–30 μm coating. Implementing the principles of an analytical model could provide insights into the required drug release profiles [47,48]; however, no such model has been developed and used in designing DDES systems.

532

4.3.3. Peptide/protein — eluting stent Other than DDES, researchers have been hunting for more selective drugs that inhibit smooth muscle cells without affecting endothelial cells, but until recently, these efforts have not been met with much success. In 2008, researchers at Mayo Clinic reported on a novel chimeric peptide that has interesting vasodilating properties without renal effects; this peptide was termed CD-NP or cenderitide [49]. This peptide was tested in human trials using IV infusion, and found to successfully moderate ventricular remodeling post-MI. Our collaborative efforts

567

T

502 503

4.2.2. Sirolimus and anti CD-34 antibody (Combo stent) Another interesting concept to enhance endothelialization rates is via the use of an antibody (CD-34) that specifically targets circulating endothelial cells or their progenitors [38]. A stent incorporating this antibody on its surface (both luminal and abluminal) was developed (Genous™) and tested in humans (HEALING IIA and B); unfortunately, increased restenosis was seen, although endothelialization appeared to be accelerated [39]. A newer improved concept using two bioactive molecules is the Combo® stent: the Combo stent consists of an abluminal biodegradable matrix incorporating sirolimus and a luminal CD-34 antibody layer, as shown in Fig. 8. The porcine model study showed that the Combo stent promotes endothelialisation, and reduces neointimal formation and inflammation compared with SES. In human trials (First-in-Man) the mean angiographic late luminal loss was 0.63 ± 0.52 mm, and the percent stent volume obstruction was 27.2 ± 20.9%, at 6 months [40]. The Combo stent is currently being evaluated at the Randomized Evaluation an Abluminal Sirolimus Coated Bio-engineered Stent (REMEDEE) Study (ClinicalTrials.gov, number NCT00967902), which is a prospective, multicenter, randomized clinical trial to compare the Combo stent with PES in 183 patients. The primary endpoint results at 9 months were presented at the Transcatheter Cardiovascular Therapeutics 2011 [41]. In-stent late lumen loss at 9 months for the Combo stent and PES were 0.39 ± 0.45 mm and 0.44 ± 0.56 mm, respectively. The rate of major adverse cardiac events at 9 months was 8.7% in the Combo stent group and 11.0% in the PES group. Both groups had 0% stent thrombosis at 9 month follow-up.

R O

477 478

P

475 476

D

473 474

of binary angiographic restenosis (17.6% vs. 16.9%, p = 0.85), the incidence of target lesion revascularization (14.3% vs. 13.2%, p = 0.72), the combined incidence of death and myocardial infarction (7.9% vs. 8.0%, p = 0.98), and the incidence of stent thrombosis (0.8% vs. 1.2%, p = 0.99) were not significantly different between the ERES and the SES groups.

E

471 472

Y. Huang et al. / Journal of Controlled Release xxx (2014) xxx–xxx

4.3.2. Sirolimus and paclitaxel This DDES consists of a stainless steel stent (VasoTech, Inc., Lowell, MA), PLGA and amorphous calcium phosphate nanoparticles

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

533 534 535 536 537 538 539 540 541 542 543 544 545 Q17 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566

568 569 570 571 572 573 574 575 576

Y. Huang et al. / Journal of Controlled Release xxx (2014) xxx–xxx

9

599

Amidst the on-going debates on polymer coating-associated hypersensitivity and inflammatory reactions, some researchers have developed strategies that eliminate the use of polymer in the coating. This section describes some interesting work in polymer freeDES where the drug could be loaded by (1) micro- and nano-fabricated reservoirs and (2) other novel methodologies.

600 601

5.1. Micro- and nano-fabricated reservoirs on stent surface

606

The creation of micro- and nano-pores on stent or strut surfaces is one of the polymer-free strategies used to house therapeutic agents. Prunotto et al. made use of micro-troughs created on the external surfaces of the stent struts so that drugs can reside in them [50]. Using this technique, they evaluated tacrolimus-loaded stents in porcine coronary artery models and found that complete re-endothelialization was achieved by 15 days. They attribute this relatively rapid and favorable re-endothelialization due to the absence of polymer. However, the true value of this stent needs to be further evaluated since no sustained long-term neointimal suppression was observed in this study. In another study, Tada and co-workers evaluated Biofreedom® stents (Biosensors) in comparison to Cypher® stents in reduction of neointimal proliferation in a porcine overstretch coronary model [51]. In the Biofreedom® stents, the stainless steel surface is mechanically modified to effectively load the drug biolimus. The study showed that apart from early and superior late reduction of proliferation equivalent to the Cypher® stents, the Biofreedom® stent also demonstrated superior absence of inflammation at 180 days. MIV Therapeutics have gone beyond animal studies to a human trial using the VESTAsync stent which provides a non-mechanical example of creating microparticulate structures with the use of hydroxyapatite surface coating impregnated with sirolimus [52,53]. In the VESTAsyn I trial, the stent was evaluated in 15 single de novo artery lesion patients [52] and the VESTAsyn stents showed an effective reduction of lumen loss and neointimal hyperplasia up to 9 months. In more recent VESTAsyn II trial, they carried out a randomized study to compare VESTAsyn stents against BMS [53]. The results indicated that VESTAsyn stents significantly reduced in-stent late loss and neointimal hyperplasia compared to BMS. Moreover, no stent thrombosis was observed in the 1 year follow-up.

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5. Polymer free drug eluting stent (PFDES)

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resulted in a demonstration of SMC inhibition by CD-NP formulations in vitro without affecting endothelial cells, which is not surprising given their endothelial cell origins. Based on these in vitro work, we designed a peptide-eluting stent (or cenderitide-eluting stent, CES) that could deliver cenderitide in a controlled fashion from Co–Cr stent coating matrix composed substantially of a biodegradable polymer. CD-NP was encapsulated in biodegradable poly( -caprolactone) and spraycoated on the Cr–Co metallic stent. Controlled release of CDNP from stents was achieved for 30 days, and an array of slow, moderate and fast release profiles was also attained from the addition of PEG and its copolymers in formulations (Fig. 10). The retention of bioactivity of released CD-NP was verified from the elevated production of intracellular second messenger, cGMP. Moreover, the released CD-NP up to 7 days has showed an effective inhibition of human coronary smooth muscle (HCaSMC) proliferation. More significantly, it was demonstrated that CD-NP inhibited HCaSMCs but did not hamper human umbilical vein endothelial cell (HUVEC) proliferation (Fig. 10). Thus, the CES has the potential to reduce restenosis without retarding the endothelialization and possibly replace currently-used drug-eluting stents in the near future. An animal study of CES is currently underway to investigate the effect of sustained released CD-NP on the SMCs and ECs in vivo.

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Fig. 7. Release kinetics of rapamycin (sirolimus) from ERES and RES [37].

Fig. 8. The Combo stent [41].

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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5.2. Novel methodologies

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Substitute materials and novel methodologies have also been employed to achieve polymer-free stents. Steigerwald and co-workers used the “material substitution” method to develop the R-PROS stent, where rapamycin is encapsulated by blending with probucol and shellac [56]. Probucol is a complementary anti-restenotic drug while shellac is a natural resin material secreted from female lac bugs. Apart from acting as a concurrent treatment, the addition of lipophilic probucol actually regulates the release of rapamycin. In fact, it managed to prolong the release of rapamycin for 28 days (approximately 80% release) compared to 1 week in formulation with only rapamycin and shellac. Levi and coworkers developed a novel crystallization methodology [57], which utilizes a temperature gradient between the drug solution and the stent surface to directly deposit crystallized drug of interest onto the stent surface. They demonstrated that crystallized rapamycin spray coated on Transluminia® stainless steel stents could achieve a 64% release over 16 days in vitro. Moreover, the release profile could be tailored by varying the degree of crystallinity of the agent, because the more crystalline form results in more gradual release profiles. The added advantage of this method is that drugs in the crystalline phase are highly stable against physiological degradation associated with amorphous phase of drugs.

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5.2.1. Summary and prognosis: DES and DDES

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679 Q18 Currently, no DDES have been approved for commercial use, 680 although several are in clinical trials; it is clear that combinations of cy681 682 683

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6.1. Commercially-available

712

So far, there has only been a single fully-erodible drug-eluting stent approved for commercial use in coronary patients. Building upon the early successful feasibility and safety results from the Igaki-Tamai stent [58,59] made of poly-L-lactic acid (PLLA) implanted in humans, Abbott Vascular (Santa Clara, California, USA) embarked on an ambitious plan to develop and market a fully-erodible drug-eluting vascular stent. The stent has a PLLA backbone with a poly-DL-lactic acid coating that releases the anti-proliferative drug, everolimus, with a coating-to-drug ratio of 1:1 [60,61]. This erodible everolimus-eluting stent (called BVS™) system underwent a series of clinical trials, with results in 30 patients at 2 and 4 years indicating that the stent was fully absorbed, had vasomotion restored and restenosis prevented (ClinicalTrials.gov, numbers NCT00300131 and NCT00856856). This suggested clinical safety and freedom from late-stage thrombosis [62,63]. Following this, in the late 2012, Abbott launched a secondgeneration Absorb™ as the world's first drug-eluting fully-erodible vascular scaffold [64], that claims to elute 75% of loaded everolimus within 30 days and with the same dose density (100 μg/cm2 ) as

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combinations show much promise, although showing superiority in clinical would be both difficult and expensive. In the meantime, it appears that limus-derivatives will slowly take over market share from SES and PES. In this context, both everolimuseluting stents (EES ) and biolimus-eluting stents (BES) are the front-runners, but likely to be approved (or already approved) as non-inferior products. It also appears as though erodible coatings (mostly PLGA) are preferred to biostable ones in ensuring complete and rapid release of drugs, thus not delaying endothelialization as much as biostable coatings appear to do. Additionally, the polymerfree, controlled-release stent designs may become the substrate of choice in the longer-term, especially if they exhibit non-inferiority in terms of restenosis reduction. It also appears that the limusfamily will dominate the market, with concerns regarding cardiac toxicity of paclitaxel being one of the reasons for its slow eclipse. With successful clinical trials, we envisage a slow return to high market share for drug-eluting stents against bare metal stents, perhaps back to the 2004–2005 levels. The key to this would be demonstration of cessation of anti-platelet therapy for DES/DDES at times that are comparable to BMS. In this context, of delayed endothelialization and late-stage thrombosis, considerable attention has been paid to fully-erodible stents, as these appear to be ideal in prevention or even elimination of late stage thrombosis, with consequences for earlier cessation of anti-platelet therapy and thus for costs. It is likely that erodible stents will also slowly garner more market share, at the expense of both BMS and DES.

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The idea to house drugs in nano-porous structure has resulted in the development of BICARE stents (Lepu Medical) by a group of researches in China [54]. BICARE stents underwent surface modulation in the creation of nanoporous cavities, followed by coating of sirolimus and probucol (a cholesterol-lowering drug). In their in vivo preclinical study, they reported that BICARE stents can provide differential release of sirolimus (80%) and probucol (20%) by 28 days. In the BICARE FIM feasibility study [54], the stents demonstrated the absence of early adverse clinical events and favorable suppression of neointimal hyperplasia for 4 months. At the 3 month time-point, they also reported improved strut coverage compared to Cypher® stents, which they believe resulted in accelerated healing process attributable to the absence of polymer. In a separate study (the ISAR-TEST 5 trial), a sirolimus and probucol dual-eluting drug was evaluated against the efficacy of Endeavor® [55]. The polymer-free stents demonstrated non-inferiority in terms of combined incidence of cardiac death, target vessel related myocardial infarction and target lesion revascularization at 1 year follow-up.

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Fig. 9. The in vitro (a) and in vivo (b) release profiles from dual-sirolimus–paclitaxel eluting stents [43].

totoxic and cytostatic drugs are not beneficial, and will not enter largescale clinical. However, both the anti-thrombotic/anti-proliferative as well as the anti-proliferative (abluminal)/CD34 antibody (luminal)

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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the cobalt–chromium everolimus-coated Xience V™ coronary (Fig. 3(A)) The release kinetics for everolimus in Absorb™ therefore suggests that it is purely diffusion-controlled instead of erosion-controlled (as there is very little erosion of PLLA in 30 days), an inherently Fickian first-order release behavior proportional to square-root of time, following the well-known relationship from Higuchi:

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Fig. 10. (a) CD-NP release profiles, (b) cyclic 3′5′ guanosine monophosphate (cGMP) generation in smooth muscle cells (SMCs) induced by CD-NP released from different CD-NP loaded formulations, (c) CD-NP on the relative proliferation in SMCs and endothelial cells (ECs) and (d) relative proliferation of SMCs treated with CD-NP released from different CD-NP loaded formulations (released in 1 day, 3 days and 7 days) via colorimetric bromodeoxyuridine (BrdU), *p b 0.05.

1=2

Mt ¼ Að2DtCS C0 Þ 739 740 741 742 743 744 745 746 747

for C0 ≫CS

India, Malaysia and New Zealand [64]. In the early-2013, Abbott announced the initiation of the ABSORB III clinical trial (ClinicalTrials. gov, number NCT01751906) in around 2250 patients in the United States. This trial is designed to compare the Absorb™ BVS device to the company's Xience™ family of drug-eluting stents. Data from the ABSORB III trial will support US FDA regulatory filings for Absorb™ [65].

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ð1Þ

where Mt is the amount of drug released at time t, C0 is the starting concentration, CS is the solubility of drug in the matrix (polymer), A is the surface area of the matrix, and D is the diffusion coefficient. With a coating-to-drug ratio of 1:1 (50% everolimus loading), it can be assumed that C0 ≫ CS as solubility limits for drugs in hydrocarbonbased polymers are rarely above 5%, therefore validating the use of this expression. Absorb™ is currently not approved for sale in the United States by the US FDA, but authorized for sale in Europe (CE Mark countries), Middle East, parts of Latin America, and in Singapore, Hong Kong,

Although there has been a considerable effort in the general area of 755 fully-erodible stents, few have reported incorporation of drug elution 756 for their platforms. Some of these are reviewed below. 757 6.2.1. Coronary stents Reva Medical, Inc. (San Diego, California, USA) has been developing fully-biodegradable sirolimus-eluting coronary stents, under their ReZolve™ range of stents. A pilot, safety study for the ReZolve™ stent in the RESTORE clinical trial (ClinicalTrials.gov, number NCT01262703) recruited 26 patients in Brazil and Europe till July 2012, and will be followed for 5 years [66]. A second-generation ReZolve2™ scaffold has

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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6.2.2. Tracheal/bronchial stents Research and development into fully-biodegradable drug-eluting stents for the treatment of airway diseases have been confined to pre-clinical animal work in recent years. Pioneering work in this aspect was conducted by Zhu et al. who evaluated both drug-free and mitomycin C (MMC) loaded fully-biodegradable tubular tracheal stents in 25 rabbits, and compared their results with commercial silicone stents as controls [73]. Differentiated from Absorb™, ReZolve™ and DREAMS, the drug was distributed homogeneously within a poly(L -lactide-co-ε-caprolactone) (PLC) polymer matrix which also served as the main scaffold, instead of as an abluminal drug-loaded coating. All fabricated stents had 0.25 mm wall thickness and MMC dosage was optimized to 0.1 mg/stent (Fig. 12). In vitro MMC release studies were conducted to correlate with the in vivo results from the rabbit study. Fig. 12(b) shows the drug release kinetics for a 12-week study. The release kinetics for MMC in PLC mirrors that for Absorb™ and Xience V™, in that the release mechanism appears to be purely diffusional in nature. However, due to MMC degradation in aqueous media over time, only about 33% of intact (efficacious) MMC was detected to be eluted via high performance liquid chromatography (HPLC) over the 12-week study period. A simplified equation of (1) was used in this instance:

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n

Mt =M∞ ¼ kt

808 809 810 811 812 813 814 815

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ð2Þ

where Mt /M ∞ is the fraction or percentage of total drug (M∞ ) 839 released at time t, k is a constant depending on the conditions of the system, and n is the exponent that describes the diffusional 840 release kinetic mechanism [73]. 841

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alloy as the main scaffold. BIOSOLVE-II is expected to enroll around 120 patients from Germany, Belgium, Denmark, The Netherlands, Switzerland, Spain, Brazil and Singapore; and patients to be followed up to 3 years with in-segment late lumen loss as the primary endpoint [71]. This study will be used for regulatory approval of the device. Amaranth Medical (Singapore) is another company that has reported the development of fully-erodible stents [72], from technology that was first developed in Singapore by the authors. However, the reported FIM trials of the FORTITUDE™ stent did not have drug-eluting capability.

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been developed as a lower profile and sheathless version of the original ReZolve™ scaffold. ReZolve2™ incorporates a proprietary desaminotyrosine polycarbonate polymer that provides for biodegradability and adequate strength over time. A unique feature of the polymer is that it is visible under X-ray, allowing the entire scaffold to be visualized during the implant procedure and at follow-up. Both scaffold and coating for sirolimus use the same polymer, and allow for controlled release of the drug over 30 days, with the majority of the drug released within 90 days. ReZolve2™ is being evaluated in the RESTORE II trial (ClinicalTrials.gov, number NCT01845311), where up to 125 patients will be enrolled (since March 2013) in several countries to apply for European CE Marking [66]. Biotronik AG (Berlin, Germany) has plans to develop and market the world's first Drug Eluting Absorbable Metal Scaffold (DREAMS). Based on a proprietary magnesium-based alloy as the main scaffold and coated with an anti-proliferative paclitaxel-containing polylactic-co-glycolic acid (PLGA) layer (1 μm), the nominal drug content of DREAMS is 0.07 μg/mm2, with a maximum amount of 8.5 μg of paclitaxel on the largest scaffold size of 3.5 × 16 mm [67,68]. It is claimed that tailormade magnesium alloys provide the best balance for coronary stents in terms of biocompatibility, mechanical properties and absorption characteristics. Controlled paclitaxel release occurs within the first 3 months, together with magnesium degradation, while the polymer layer remains stable. After 6 months, both paclitaxel release and magnesium degradation would have been completed, leaving only the polymer layer to be completely absorbed by 9–12 months (see Fig. 11). Similar to Absorb™, drug-elution for DREAMS is driven primarily by diffusion, with delayed polymer erosion having no or negligible influence over drug release kinetics. DREAMS was tested in a first-in-man trial (BIOSOLVE-I, ClinicalTrials. gov number NCT01168830) in 46 patients at five European centers from July to December 2010, and 12-month results indicated feasibility, good safety profile and promising clinical and angiographic performance [67,69]. Two-year clinical trial data for BIOSOLVE-I revealed no cardiac deaths and no scaffold thrombosis for 44 patients who were followed up [70]. Encouraged by the success of the initial trial, an announcement was made in October 2013 to commence BIOSOLVE-II (ClinicalTrials. gov, number NCT01960504) to evaluate the safety and efficacy of DREAMS with an improved design [71]. This second-generation DREAMS replaces paclitaxel with a limus drug (not made public) eluted from a biodegradable polymer matrix, with a similar magnesium

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Fig. 11. Degradation and paclitaxel-elution processes for DREAMS (image provided Biotronik AG).

Please cite this article as: Y. Huang, et al., Drug-eluting biostable and erodible stents, J. Control. Release (2014), http://dx.doi.org/10.1016/ j.jconrel.2014.05.011

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7. Summary

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As is evident from the above discussion, although fully-erodible, drug-eluting stents appear to be the “ideal” stent of the future, the safety aspects dictate lengthy clinical trials, and considerable R&D expense before approval. This represents a formidable barrier for entry of companies to this marketplace. This is reflected in the relatively small number of players in this arena. Nevertheless, both polymeric and metallic erodible stents are expected to enter the market in significant numbers by 2015 or 2016. It is anticipated that most if not all of them will have drug-containing coatings of a limus-type drug (for coronary stents) or a different type of anti-proliferative/anti-inflammatory (mitomycin or dexamethasone) for tracheal stents. The latter will almost necessarily have drug incorporated into the stent body, by virtue of the relatively higher doses needed.

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drug-eluting tracheal stent and also the first study on the delivery of anti-mitotic MMC in a controlled-release method via a stent. Another interesting research has been described by Chao et al. in 2013. Biodegradable tracheal stents injection-molded from polycaprolactone (PCL) had a polylactide-co-glycolide (PLGA) copolymer spray-coated onto the surfaces with the anti-tumor drug, cisplatin, used for lung cancers [75]. Different cisplatin:PLGA ratios were evaluated for in vitro drug-elution and cisplatin levels were also investigated in rabbits' tissue and blood (Fig. 13). Fig. 13(a) suggested that cisplatin (as a coat within PLGA) release from PCL stents showed biphasic drug release, as can be seen from a mild initial burst followed by an almost linear diffusion-controlled phase. High concentrations of cisplatin were shown to be released up to 4 weeks. Perhaps more importantly, cisplatin levels in the rabbits' tracheas were measureable from the first week and maintained at high levels up to 5 weeks (Fig. 13(b)), whereas the serum levels were about 100 times lower throughout the experiment [75]. These results hold promise for the use of fully-erodible drug-eluting stents for the sustained delivery of cisplatin to the trachea for management of malignant airway obstruction.

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This was not entirely unexpected as PLC is known to be completely biodegrade only after a year. As the structure of the trachea is unique and assuming MMC elution from the stent to the tracheal wall was unidirectional, a low dosage of 0.0165 mg/stent was calculated to have been sufficient during the 12-week in vivo study to prevent tracheal stenosis (disease induced in all 25 rabbits) [73]. A concurrent study was conducted to develop a physical model to simulate the heterogeneous environment of the trachea, and pseudo “surfaceeroding” profiles were elucidated for some biodegradable polymers depending on different plasticizers added; and such data could be significant to tailor drug release kinetics in the trachea [74]. This was the first study to evaluate a novel fully-biodegradable

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Fig. 12. (a) Two designs of tracheal stent; and (b) graph of 0.1 mg MMC release profile over 12 weeks [73].

Fig. 13. (a) In vitro release of cisplatin from PCL stents, and (b) cisplatin levels in the tissue and blood [75].

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Drug-eluting biostable and erodible stents.

This paper reviews the latest research and development of drug-eluting stents. The emphasis is on coronary stenting, and both biostable and bioerodibl...
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