Eluting combination drugs from stents

International Journal of Pharmaceutics 454 (2013) 4–10

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Mini review

Eluting combination drugs from stents Rajesh Thipparaboina a , Wahid Khan a,b,∗ , Abraham J. Domb b,∗∗ a b

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel

a r t i c l e

i n f o

Article history: Received 18 May 2013 Received in revised form 3 July 2013 Accepted 6 July 2013 Available online xxx Keywords: Coronary artery disease Dual-drug eluting stents Anti-restenotic agent Pro-healing agents Gene delivery

a b s t r a c t Cardiovascular diseases (CVD) are one of the leading causes of death across the globe. Pathogenesis of coronary artery disease (CAD) is lead by the progression of atherosclerotic lacerations in coronary arteries. Percutaneous coronary intervention (PCI) using balloon angioplasty was introduced in 1979 and was majorly used in the treatment of these lesions. Introduction of bare metal stents (BMS) has revolutionized stenting procedures overcoming elastic recoil and reducing restenosis commonly associated with balloon angioplasty, but follow up studies have shown 20–30% prevalence of in-stent restenosis (ISR), this led to the development of drug eluting stents (DES). But long-term follow up studies have shown increased liability of stent thrombosis. Boosting the development of safer and effective DES expounding for therapies like biodegradable polymer based DES, polymer free DES, bioresorbable DES and combination DES to collectively reduce neointimal hyperplasia and promote endothelial healing. In dual-DES development, a combination employing an anti-restenotic agent (for preventing VSMC’s proliferation), which is released for the first few weeks, and then the second drug a pro-healing agent (promoting re-endothelialization) released after a month would be ideal. Growing understanding in the areas of polymer therapeutics, nanoscale surface modifications and gene therapy would assist in the delivery of multiple drugs, which would further help in the design of promising therapeutic strategies for the treatment of CAD using stent based therapies. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Cardiovascular diseases (CVD) are one of the leading causes of death across the globe (accounting for 48% of all deaths in Europe alone). Stroke and coronary artery disease (CAD) are the major forms of CVD’s causing high mortality. Pathogenesis of CAD is lead by the progression of atherosclerotic lacerations in coronary arteries. Percutaneous coronary intervention (PCI) using balloon angioplasty was introduced in 1979 and is majorly used in the treatment of these lesions. In late 1980s Schatz and co-workers developed the stainless steel based Palmaz-Schatz (Johnson & Johnson) stents, the first FDA approved stent. Introduction of bare metal stents (BMS) has revolutionized stenting procedures overcoming elastic recoil and reducing restenosis commonly associated with balloon angioplasty, but follow up studies have shown 20–30% prevalence of in-stent restenosis (ISR) (Fig. 1). This made a path

∗ Corresponding author at: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Tel.: +91 4023073740; fax: +91 4023073751. ∗∗ Corresponding author. Tel.: +972 26757573; fax: +972 26757076. E-mail addresses: [email protected] (W. Khan), [email protected] (A.J. Domb). 0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.07.005

for the incorporation of anti-proliferative agents in stents leading to the development of Drug-eluting stents (DES). Since the approval of CYPHER® (Cordis) sirolimus-eluting stent in 2003 the market of DES has seen immense growth and DES became the first medical device to have returns similar to that of a “blockbuster drug”. Three million stents implanted worldwide every year generate revenue of more than $5 billion to stent manufacturers and $30 billion to hospitals and doctors for the stenting procedures. With increase in the number of aging population DES markets in India, China and Japan are set to undergo a rapid growth in the next five years, concurrent with the amelioration of the economies of these countries and the growing medical tourism. The development of DES till today is depicted as a journey of four generations as represented in Fig. 2 (Akin et al., 2011; Doostzadeh et al., 2010; Garg and Serruys, 2010; Joner et al., 2008; José and Windecker, 2012; Lange et al., 2010; Navarese et al., 2011; Sheiban et al., 2008). Long-term follow up studies have shown increased liability of stent thrombosis with DES probably due to delayed endothelialization by the currently used drugs or delayed hypersensitivity reaction caused by the degradation products for polymers currently used in DES (Grennan, 2012; Iqbal et al., 2013; Perez et al., 2013). This has boosted the development of better polymers and newer generation DES expounding for stent-based therapies employing combination of drugs like dual-drug eluting stents (dual-DES) that

R. Thipparaboina et al. / International Journal of Pharmaceutics 454 (2013) 4–10

Fig. 1. Developments in stent based therapies.

Fig. 2. Different generations of stents (pictures from www.google.com/images).

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can collectively reduce neointimal hyperplasia (NIH) and promote endothelial healing. Limited clinical data available for the delivery of multiple drugs from a DES restricts their use. The advent of new technologies and improving number of clinical trials associated with stents would help in clinical success of dual-DES. This review is centered on the literature available on dual-DES stents till today accentuating the need for further developments in stents based therapies embedding multiple therapeutic agents to enhance safety and efficacy. 2. Dual-DES based therapy The concept of dual-DES therapy is based on the inclusion of a second therapeutic agent, a pro-healing agent to the currently used drugs, which would help in further enhancing the antirestenotic performance of presently available DES. Prof. Kinam Park in his editorial comments gave new insights into the development of dual-DES stating that “the most efficient use of dual DES may come from controlling the drug release kinetics. Ideally, a drug for preventing vascular smooth muscle cells (VSMC) proliferation which is released for the first few weeks, and then the second therapeutic agent promoting re-endothelialization released after a month. Attaining such tailored release kinetics from a thin layer in the range of 5–30 m on a stent is very difficult. However, with the advent of new technologies in controlled drug delivery we are cautiously optimistic to achieve such tailored and predictable release in the near future” (Park, 2012). Hence successful performance of dual-DES is majorly based on selection of appropriate therapeutic combination and the regulation of their release kinetics (Table 1). 2.1. Antirestenotic drugs Different classes of drugs such as anti-inflammatory, antithrombogenic, antiproliferative and immunosuppressant’s are majorly explored in DES. Sirolimus, paclitaxel, zotarolimus, everolimus, tacrolimus, biolimus A9, actinomycin D, dexamethasone, antibodies, estrogen (New et al., 2002) and curcumin (Pan et al., 2006) are few of the drugs employed in DES for treating restenosis. These drugs act by inhibiting one or more biochemical pathways causing restenosis (Khan et al., 2012). 2.2. Pro-healing agents The anti-proliferative agents used in present stent based therapies are subsidiary in terms of selectivity toward the targeted cell types. Therefore, they not only inhibit proliferation of VSMCs underlying neointimal formation, but also compromise endothelial repair. Hence targeting therapeutic agents promoting endothelial repair and reducing oxidative stress using specific markers would help in development of safer DES. Many pro healing agents have been employed in stent based therapies like probucol, carvedilol, AGI1067, NADPH-oxidase inhibitors, superoxide dismutase (Watt et al., 2008), anti-CD34 antibodies (Granada et al., 2010), resveratrol and quercetin (Kleinedler et al., 2012) and succinobucol (Watt et al., 2013). 2.3. Sirolimus/rapamycin combinations Sirolimus also called rapamycin is a macrocyclic antibiotic isolated from Streptomyces hygroscopicus. It is a highly lipophilic molecule, acts by binding to specific cytosolic proteins (FK-506 binding protein-12), the complex formed on binding blocks mTOR there by inhibiting cellular proliferation. It also inhibits different phases of the restenosis cascade, such as inflammation, formation of neointimal hyperplasia and migration of smooth muscle cells (Abizaid, 2007; Kahan, 2001; Toutouzas et al., 2002). CYPHERTM

is the marketed product of DES composed of sirolimus with a concentration of 140 ␮g/cm2 coated onto parylene-C-primed stainless steel platform using polyethylene-co-vinyl acetate (PEVA) and poly (n-butyl methacrylate) (PMBA) releasing 80% of drug within 4 weeks (Biggs et al., 2012; Iqbal et al., 2013). Novel carrier free surface crystallization procedure for sirolimus coating on metallic stent was reported (Farah et al., 2013; Khan et al., 2013; Levy et al., 2012). As dual-DES, combination of estradiol and sirolimus was explored to find whether estradiol would promote reendothelialization as seen in animal models, but the former did not show any beneficial effect when used along with sirolimus (Adriaenssens et al., 2007). Shellac based dual-DES of sirolimus and probucol was prepared using sand-blasting technique on the thin strut stainless steel stent. The stent was coated employing a blend of the therapeutic agent and shellac resin (Byrne et al., 2009). ISAR-TEST-2 randomized trial demonstrated a 12-month efficacy of sirolimus and probucol dual-DES that was similar to sirolimus-eluting stents (SES) (CYPHERTM , Cordis Corporation) and predominant to zotarolimus-eluting stents (ZES) (Endeavor, Medtronic CardioVascular). At 2 years, antirestenotic efficacy of both dual-DES and ZES last enduring between 1 and 2 years, with dual-DES maintaining an advantage over the entire 2-year period (Byrne et al., 2010). A two layered dual-DES of sirolimus and triflusal was prepared by spray coating the cobalt–chromium stent with a biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) to treat restenosis and thrombosis, combining anti-proliferative and anti-thrombotic activity of drugs, respectively. The release of two drugs was modulated efficiently to curtail thrombosis and proliferation at the same time. In vivo studies performed for acute thrombosis, inflammation and restenosis at 30 days in a porcine carotid artery model have shown a significant reduction in restenosis with dual-DES compared with the controls (BMS, sirolimus coated and pure polymer-coated stent). Diminished ISR with sirolimus–triflusal combination eluting stent was coupled with reduced thrombus formation, propounding the role of dual-DES in treatment of CAD (Huang et al., 2010). Combination of sirolimus and paclitaxel was reported with both drugs completely eluted within 21 days without affecting their individual release kinetics. It was concluded that both drugs can be pharmacokinetically combined in DES for the treatment of CAD (Ma et al., 2011). Further, ‘polymer free’ Yukon stents were coated with 1% succinobucol, 2% rapamycin or 1% succinobucol plus 2% rapamycin solutions and compared with BMS. Neointimal thickening and peri-strut inflammation were studied in a porcine coronary model. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for succinobucol eluting stents (SucES), 0.19 ± 0.11 mm for rapamycin eluting stent, and 0.36 ± 0.17 mm for combination (p < 0.05 for SucES vs. BMS). Surprisingly stent based delivery of 1% succinobucol using a polymer free stent platform increased neointimal formation and inflammation following coronary stenting contrary to its reported antioxidant and anti-inflammatory properties (Watt et al., 2013). In a comparative study involving a novel combo stent (CS), polymer-free sirolimus-eluting stent coated with anti-CD34 antibody, with a composite PEVA/PMBA permanent polymer SES, a polymer free SES (PFSES) and BMS conducted for 28 days in a porcine model, at 14 days optical coherence tomography (OCT) evaluation has shown reduction in neointimal proliferation of CS and PFSES compared with SES and BMS (neointimal thickness: BMS, 0.44 ± 0.12; SES, 0.42 ± 0.03; PFSES, 0.14 ± 0.11; CS, 0.11 ± 0.06; p < 0.005; BMS/SES > CS/PFSES). At 28 days, both CS and PFSES were coupled with reduced neointimal proliferation, while SES exhibited increased neointimal thickness (BMS, 0.62 ± 0.11; SES, 0.63 ± 0.08;

Table 1 List of polymers, stent platform and drugs used in combination in DES. Drugs

Therapeutic effects

Platform

Polymers

Remarks

Reference

Recombinant-PEG–hirudin and iloprost

Anti-thrombotic agents with anti-proliferative effects Anti-proliferative and re-endothelialization promoter Anti-proliferative and anti-inflammatory Anti-inflammatory, anti-proliferative, anti-oxidant and platelet aggregation inhibitor Anti-proliferative, and anti-oxidant Anti-proliferative and anti-thrombotic

Stainless steel

PLA (biodegradable aliphatic polyester co-polymer) Polymer free

Suggested the use of local dual-drug delivery to reduce restenosis

Alt et al. (2000)

No salutary effect was seen with dual-DES eluting sirolimus and estradiol

Adriaenssens et al. (2007)

Poly(lactic-co-glycolic acid) Plasma polymerization product of 1,2 DACH

Proof of concept of a dual-DES was established showing both safety and efficacy Grafting pattern affected the loading efficiency and drug release. Dual-DES has shown improved blood compatibility.

Berg et al. (2007)

Shellac (resin based polymer) PLGA (biodegradable aliphatic polyester co-polymer) Poly (d,l-lactide coglycolide)/amorphous calcium phosphate

Dual-DES found superior to polymer based Zotarolimus eluting stents Marked decrease in restenosis was associated with reduced thrombus formation recommending the role of dual-DES Results indicated that combination of sirolimus and paclitaxel did not alter individual release kinetics suggesting that two drugs can be combined pharmacokinetically in a dual-DES In-stent restenosis rate was significantly lower in the Cilotax stent group (0% vs. 10.9%, p = 0.027) compared to Taxus Liberte stent

Byrne et al. (2009)

The in vivo and in vitro drug release from the dual drug PCL films were highly complementary indicating the scope for unidirectional and rate-tunable drug release from multi-layered PCL films for stent based therapies Stents with higher proportion of R:Q (150:75 ␮g/cm2 ) accelerated re-endothelialization by 50% compared with BMS suggesting their potential for use in dual-DES Surprisingly stent based delivery of succinobucol increased neointimal formation and inflammation With dual-DES, delayed arterial healing was minimal and no increase in inflammation was found at 28 days compared with SES suggesting the use of dual-DES VEGF/PTX nanoparticle coated stents have shown complete re-endothelialization and significantly suppressed in stent restenosis after 1 month compared to marketed DES TAXUS®

Rong et al. (2012)

Sirolimus-estradiol

Paclitaxel-pimecrolimus ␣-Lipoic acid (ALA)-abciximab

Sirolimus-triflusal

Cobalt-chromium Stainless steel

Microporous stainless steel Cobalt- chromium

Sirolimus-paclitaxel

Inhibit ISR through independent pathways

Stainless steel

Paclitaxel-cilostazol

Anti-proliferative, and platelet aggregation inhibitor

Cobalt- chromium

Paclitaxel5-fluorouracil

Inhibits tumor cell proliferation

Simple films

Resveratrol (R)-quercetin (Q)

Synergistically inhibit VSMC proliferation and macrophage activation

Stainless steel

Poly(styrene-bisobutylene-b-styrene) (polyolefin triblock polymer)

Sirolimus-succinobucol

Anti-profilerative and antioxidant, anti-inflammatory Anti-profilerative and re-endothelialization promoter

Microporous stainless steel

Polymer free

Stainless steel

Polymer free

Anti-profilerative and re-endothelialization promoter

Microporous stainless steel

PLGA (biodegradable aliphatic polyester co-polymer)

Sirolimus-anti-CD34 antibody

Paclitaxel-VEGF gene

Combination of cellulose acetate butyrate andbioabsorbable resomer PCL (biodegradable aliphatic polyester)

Song et al. (2009a)

Huang et al. (2010)

Ma et al. (2011)

Lee et al. (2011)

Kleinedler et al. (2011, 2012)

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Sirolimus-probucol

Stainless steel

Watt et al. (2013)

Zhang et al. (2013)

Yang et al. (2013a)

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PFSES, 0.18 ± 0.06; CS, 0.21 ± 0.06; p < 0.005; BMS/SES > CS/PFSES). At 14 days and 28 days, CS showed decreased fibrin and inflammation, compared with SES and PFSES. In addition, the CS was associated with increased endothelium-dependent relaxation, protected vascular endothelial function. The polymer-free dual-DES of sirolimus and anti-CD34 antibody indicated equivalent early and admirable late reduction of intimal proliferation compared with SES in a porcine model. With dual-DES, delayed arterial healing was minimal with no increase in inflammation at 28 days in contrast to SES suggesting the use of dual-DES for potential short-term benefit over traditional polymeric coated DES (Byrne et al., 2009; Zhang et al., 2013). 2.4. Paclitaxel combinations Paclitaxel (PTX) is a complex diterpenoid obtained from the Pacific yew tree, Taxus brevifolia used commonly in cancer treatment. In vitro and in vivo efficacy of paclitaxel in reducing neointimal hyperplasia after balloon and stent mediated injury have been shown (Stone et al., 2004). It acts by stabilizing microtubules through polymerization of the ␣ and ␤ units of tubulin. Paclitaxel also inhibits the proliferation and the migration of smooth muscle cells, hence used in DES to prevent restenosis. TAXUSTM Express2TM was the first marketed product of paclitaxel introduced in 2004. It is composed of stainless steel platform onto which paclitaxel (100 ␮g/cm2 ) was coated using Poly (styreneb-isobutylene-b-styrene) (SIBS). TAXUS® LiberteTM Long, TAXUS® Liberte® AtomTM , TAXUS® Liberte® , TAXUS® Express2® , IONTM are FDA approved and few of currently marketed products of paclitaxel. BMS coated with an erodible polymer containing alternate reservoirs of PTX and pimecrolimus were studied to determine the efficacy of a pimecrolimus DES and dual-DES stent as compared with BMS controls in the porcine model. At 30 days, neointimal proliferation was significantly less in the dual-DES group as compared with the BMS controls. Endothelialization was complete in both groups of stents, suggesting complete healing of the arteries. Decreased neointimal thickness (0.16 ± 0.07 mm) in the dual-DES group was significant (p = 0.01) in comparison with that for BMS (0.33 ± 0.18 mm), but it was not significant when compared to fast release pimecrolimus stents (0.22 ± 0.13 mm). The proof of concept of a dual-DES was established showing both safety and efficacy compared to BMS (Berg et al., 2007). Cilotax stent was designed to increase the antirestenotic performance of the PTX-eluting stent and decrease the risk of stent thrombosis by the incorporation of cilostazol. Investigations on the safety and efficacy of Cilotax dualDES compared their performance to that of PTX-eluting (Taxus Liberte) and results suggested that Cilotax stent was not inferior to Taxus Liberte stent as determined by in-stent late loss. In-stent restenosis rate was significantly lower in the Cilotax stent group (0% vs. 10.9%, p = 0.027). Rates of death, myocardial infarction, and any target lesion revascularization at 8 months were 0%, 0%, and 1.9%, respectively, in the Cilotax group and 1.8%, 0% and 3.6%, respectively, in the Taxus Liberte group. It was found that the Cilotax stent was safe and effective in decreasing late loss, indicating the promising future of dual-DES (Lee et al., 2011). Poly(∈-caprolactone) (PCL) based films composed of multiple layers of 5-fluorouracil (5-FU) and PTX were evaluated for a biodegradable film-based stent application. Films were prepared by employing a combination of 5-FU, PTX, PCL and polyethylene glycol, blended and extruded using HAAKE MiniLabII twinscrew extruder. The resulted blends were hot-pressed into films with assigned thickness on a compression molding machine at 100 ◦ C, subsequently cooled to room temperature. The in vitro release has shown that release rate was based on the drug loading, the ratio of 5-FU and paclitaxel, the composition of surface layer and addition of polyethylene glycol. The cytotoxicity results indicated that

the PCL-based films co-loaded with 5-FU and paclitaxel could effectively inhibit the proliferation of Eca-109 cells. The in vivo release studies were highly correlative with that of in vitro drug release showing the ability of PCL-based films co-loaded with 5-FU and PTX with for anti-tumor stent application, due to their unidirectional and rate tailored drug release characteristics and multiple drug loading capabilities (Rong et al., 2012). Incorporation of gene delivery in stent based therapies for effective inhibition of VSMC’s proliferation simultaneously promoting re-endothelialization and repair was explored by spray coating of bilayered PLGA nanoparticles containing a vascular endothelial growth factor (VEGF) 165 DNA plasmid in the external layer and paclitaxel in the inner core onto a BMS. Using Fc plasmid as a reporter gene, it was observed that Fc/paclitaxel nanoparticles successfully expressed Fc protein, but did not show cytotoxicity or anti-proliferative effect during the first 7 days in cell culture. In contrast, paclitaxel NPs showed strong anti-proliferative effect starting from day 1 in culture, suggesting succesive release of gene and paclitaxel. In vivo studies were carried out using mini-swines as animal models. VEGF nanoparticle coated stents have shown complete re-endothelialization and significantly suppressed ISR after 1 month compared to marketed DES TAXUS® (Yang et al., 2013a). 2.5. Other combinations A combination of recombinant polyethylene glycol (r-PEG)hirudin and the prostacyclin analog iloprost, both drugs with antithrombotic and potentially antiproliferative effects were coated onto Palmaz-Schatz stents using polylactic acid (PLA). Release characteristics and vascular response was evaluated in a sheep and a pig model for a period of 4 weeks. Morphometric analysis has shown a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (p, 0.02) in the standardpressure model (sheep) and by 24.8% (p, 0.02) in the overstretch pig model in coated stents compared to uncoated control stents. The results from this study demonstrated beneficial effects of a dual-DES coated with PLA releasing r-PEG–hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury (Alt et al., 2000). In a 4 week study using rat model concurrent localized delivery of a combination of dexamethasone and VEGF in PLGA microsphere/PVA hydrogel composites was evaluated. Histopathological examination of rat’s subcutaneous tissue surrounding implanted composites has shown that these composites were not only successful in controlling the inflammation and fibrosis at implant/tissue interface but were also able to facilitate neo-angiogenesis. Thus it was suggested that simultaneous elution of VEGF and dexamethasone locally could overcome the anti-angiogenic effects of the corticosteroid and can be used to develop inflammation free and well vascularized tissue in the proximity of the bio-medical devices ensuring tissue safety (Patil et al., 2007). ␣-Lipoic acid (ALA) was grafted with abciximab, which is an effective inhibitor of stent restenosis, on to a BMS primed with a polymer layer obtained by plasma polymerization of 1, 2diaminocyclohexane (DACH) to prepare a dual-drug-eluting stent. Grafting pattern affected the loading efficiency and drug release. Grafting reaction carried out in a blended solution of ALA and abciximab, produced higher loading and delayed release. Grafting reactions started with the abciximab solution, and addition of the ALA solution after a time interval has not only shown improvement in the amount of grafted abciximab but also the released amount of abciximab along with ALA. It was found that the dual-DES has shown smooth and uniform morphology with an improved blood compatibility releasing ALA and abciximab simultaneously for 3 weeks (Song et al., 2009b).

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The effects of a resveratrol (R) and quercetin (Q) eluting stent compared to that of a BMS on neointimal hyperplasia and re-endothelialization were studied in a rat model of arterial angioplasty and stenting. Nanocomposite coatings containing resveratrol and quercetin were sprayed onto BMS and deployed into the common carotid artery of rats, their impact on vascular remodeling was compared to that of BMS. Luminal stenosis in arteries stented with nanocomposite eluting stents R:Q with 150:75 ␮g/cm2 was reduced by 64.6% compared to arteries stented with BMS in addition to 59.8% reduction in macrophage infiltration. No significant differences were found between stents containing lower proportion of R:Q 50:25 ␮g/cm2 and BMS. Stents with higher proportion of R:Q (150:75 ␮g/cm2 ) accelerated re-endothelialization by 50% when compared to BMS. These data suggested that R and Q may be ideal candidates for future multi-drug stent coatings, which could potentially reduce the risk of late thrombosis associated with DES (Kleinedler et al., 2012).

3. Future perspectives Incorporation of therapeutic agents like platelet aggregation inhibitors (Alt et al., 2000; Ko et al., 2012; Lee et al., 2011; Manickavasagam et al., 2007; Parker et al., 2012), HMG-CoA reductase inhibitor (Ko et al., 2012; Tsukie et al., 2013; Zago et al., 2012), bisphosphonates (Danenberg et al., 2003a, 2003b), VSMC proliferation inhibitors like resveratrol (Kleinedler et al., 2011, 2012) and magnolol (Chen et al., 2001; Karki et al., 2013) into currently used DES may help in reducing the ISR and improving the safety and efficacy of currently available DES. Designing novel drug delivery systems like loading of presently available into albumin based nanoparticles (Margolis et al., 2007), nanoburrs (Chan et al., 2010) and targeted drug delivery using several markers like calcitonin gene-related peptide (CGRP), ␣v ␤3 integrin, vascular cell adhesion molecule-1 (VCAM-1) and sub-endothelial extracellular matrix proteins such as collagen IV or chondroitin sulfate proteoglycans (CSPGs) (Chan et al., 2011; Lanza et al., 2002; Winter et al., 2008; Yang et al., 2013b) may improve safety and efficacy of stent based therapies by promoting endothelial recovery on a stent surface and also by preventing ISR. Implementing the principles of computational fluid dynamics (CFD) to develop idealized stent geometries like thinner struts may help in decreasing the amount of wall shear stress at the arterial wall (LaDisa et al., 2004, 2005) and utilizing recently developed technologies like layer-by-layer (LbL) technology (Hossfeld et al., 2013), ultrasonic atomization, chemical vapour deposition (CVD), atom-transfer radical polymerization (ATRP), and pulsed laser deposition (PLD) as potential techniques for development of DES (Farhatnia et al., 2013), surface crystallization process for coating using drug–drug co-crystals (Farah et al., 2013; Sekhon, 2012) would help in surface deposition of drugs with improved loading and also help in effectively controlling the release kinetics. Stent coatings employing arsenic trioxide and titanium-nitricoxide were successfully evaluated in porcine coronary model and found to be effectively inhibiting local inflammatory reactions, with no significant difference in endothelial function (Shen et al., 2013; Windecker et al., 2005). Assimilating the principles gene therapy delivering VEGF gene (Hedman et al., 2003) and siRNA (Dorsett and Tuschl, 2004; Hossfeld et al., 2013; San Juan et al., 2009) delivery into current DES would also serve as better alternatives for enhancing safety and efficacy. Growing understanding in the areas of polymer therapeutics using recombinant drugs, nanoscale modifications of stent surface and gene therapy that assist in the delivery of multiple therapeutic agents using stent surfaces would help in the design of promising therapeutic strategies for the treatment of CAD.

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