Multiple-drug Delivery from Mesoporous Coating Realizing

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Interface Components: Nanoparticles, Colloids, Emulsions, Surfactants, Proteins, Polymers

Multiple-drug Delivery from Mesoporous Coating Realizing Combination Therapy for Bare Metal Stents Qi Wang, Shuang Long Hu, Yingben Wu, Qian Niu, Yang Yang Huang, Fan Wu, Xiao Tan Zhu, Jin Fan, Guo Yong Yin, Mimi Wan, Chun Mao, and Min Zhou Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b04080 • Publication Date (Web): 30 Jan 2019 Downloaded from http://pubs.acs.org on January 31, 2019

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Multiple-drug

Delivery

from

Mesoporous

Coating

Realizing

Combination Therapy for Bare Metal Stents Qi Wanga†, Shuang Long Huc†, Ying Ben Wua, Qian Niua, Yang Yang Huanga, Fan Wua, Xiao Tan Zhua, Jin Fanb, Guo Yong Yinb, Mi Mi Wan a*, Chun Maoa, Min Zhouc*

aNational

and Local Joint Engineering Research Center of Biomedical Functional Materials,

School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, Jiangsu, China

bDepartment

of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University,

Nanjing, Jiangsu, China.

cDepartment

of Vascular Surgery, Nanjing Drum Tower Hospital, The Affliated Hospital of

Nanjing University Medical School, Nanjing, Jiangsu, China

†These

authors contribute equally to the article.

ACS Paragon Plus Environment

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Abstract: The simultaneous loading of multi-functional drugs has been regarded as one of the major challenges in drug delivery system. Herein, a mesoporous silica coating

was

constructed

on

the

bare

metal

stent

(BMS)

surface

by

evaporation-induced self-assembly method, in which both hydrophilic and hydrophobic drugs (heparin and rapamycin) were encapsulated by one pot method for the first time, and the release behaviours of these drugs were studied. Releasing mechanisms of these drugs were investigated in detail. Rapid release of heparin can achieve anticoagulation and endothelialization, while slow release of rapamycin can realize antiproliferative therapy for long term. In vitro hemocompatibility and promotion for proliferation of vein endothelial cells and the inhibition of smooth muscle cells were conducted. In vivo stent implantation results verify that the mesoporous silica coating with both heparin and rapamycin can successfully accelerate the endothelialization process and realize antiproliferative therapy for as long as three months. These results indicate that this multifunctional mesoporous coating containing both hydrophilic and hydrophobic drugs might be promising stent coating in the future.


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1. Introduction The use of bare metal stents (BMS) as a milestone in coronary intervention, particularly the application of drug-eluting stents (DES), successfully inhibited stenosis rates1-4. Yet, poor endothelialization and late thrombosis have become the most serious complications of DES5,6, causing high rate of restenosis. For example, the traditional rapamycin-loaded DES can inhibit neointimal proliferation and stent stenosis7,8. However, late coronary thrombosis, slow healing of the arteries and delayed endothelialization still exist in the operative rehabilitation patient owing to the limitation of single drug loading9. Hence, combination therapy is a global strategy for treating diseases that requires a multi-functional drug load release system to encapsulate multiple drugs with different properties and functions. Heparin is a commonly used anticoagulant10, which may solve the problem of late thrombosis in DES. And VEGF is a member of a gene family consisting of placental growth factor that can promote the proliferation of vascular endothelial cells (ECs)11. Therefore, it is of great significance to construct multifunctional drug-coated stents to meet above clinical requirements. Some inorganic coating strategies have been applied because of the disadvantages of polymer coatings such as the failure of long-term drug release, low biocompatibility, and low drug-loaded amount. The appearance of mesoporous silica can potentially conquer the above difficulties. Mesoporous silica has many unique characteristics, such as large surface area, high pore volume, tunable nanometer-scale pore sizes, abundant inner/outer surface chemistries and intrinsic biocompatibility12. However, in many studies, only one kind of drug was entrapped into the mesoporous silica coatings and the preparation procedures were somewhat complicated13-15. Up to date, the co-delivery of multiple drugs with different molecular properties by one-pot synthetic method were rarely reported 16,17. In this study, we develop a mesoporous silica coating with hydrophilic (heparin) and hydrophobic (rapamycin) drugs for rapid anticoagulation, and long-term anti-tissue proliferation/endothelialization (Figure 1). Heparin and rapamycin can


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form micelle during the self-assembly process of P123, in which rapamycin was located at the inner core and heparin was situated at the outer shell of P123. Mesoporous

silica/heparin/VEGF/rapamycin

(M/H/V/R)

synthesized

by

evaporation-induced self-assembly method was directly anchored on bare metal stents (BMS) based on the mussel-inspired adhesion technique. In vitro platelet adhesion and aggregation, whole blood contact test, hemolysis and related morphology test of red blood cells and in vitro clotting time tests were performed to evaluate the hemocompatibility and anticoagulant effect of S/M/H/V/R. In vivo stent implantation was conducted to detect the endothelialization process and antiproliferative performance of the coating.

Figure 1. A Schematic illustration for the formation of mesoporous silica coating on BMS and its anti-fouling and promotion of endothelial cell adhesive properties (Fast release of heparin to realize anticoagulation and endothelialization and slow release of rapamycin to realize antiproliferative therapy for long term).

2. Experimental Section Materials Pluronic P123 (Mw=5800) was obtained from Sigma (USA). Tetraethoxysilane (TEOS), sodium chloride, potassium phosphate monobasic, disodium hydrogen phosphate, potassium chloride, ethanol, glutaraldehyde and hydrochloric acid (37%) were obtained from Sinopharm Chemical reagent. Heparin was purchased from


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Aladdin. Dopamine and rapamycin were obtained from Energy Chemical. 6-Diamidino-2-phenylindole (DAPI) was purchased from Beyotime Biotechnology (Shanghai, China). Bare metal stents (BMS) were purchased from Yinyi Co. (Dalian, China). Synthesis of S/M, S/M/H, S/M/R, S/M/H/R For the preparation of S/M/H/R, dopamine solution was prepared by dissolving dopamine hydrochloride (2 mg mL-1) in Tris-HCl buffer (10 mM, pH = 8.5). BMS were immersed in the above solution at 20 ℃ for 24 h under dark condition. The obtained samples were washed with double distilled water for three times. 0.5 g of P123 was dissolved in 10 mL of water with 1 g of 2 M hydrochloric acid at 20 ℃. Then 0.15 g of heparin and 0.05 g of rapamycin were added. Under constant stirring, 1.0 g of TEOS was added dropwise to the mixed solution. After 10 minutes, the mixed solution was put into a culture dish containing polydopamine-modified BMS. The mixture was kept in an oven at 37 ℃ for 5 h. The obtained sample was named as S/M/H/R, where S representing BMS, M representing mesoporous silica, H representing heparin and R representing rapamycin. For comparison, S/M, S/M/H and S/M/R were also prepared by a similar procedure. Characterizations,

heparin

and

rapamycin

release

performance,

blood

compatibility tests, cell culture procedure and in vivo stent implantation were included in supporting information.

3. Results

Figure 2. SEM images of (a) S, (b) S/M, (c) S/M/H, (d) S/M/R, (e) S/M/H/R, and (f) TEM image of S/M/H/R.


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In order to investigate the influence of mesoporous silica coating on the morphology of BMS surface, SEM images of S, S/M, S/M/H, S/M/R and S/M/H/R were detected. Porous structure with diameter about 1 μm could be observed on the BMS (S) surface (Figure 2a). After the construction of mesoporous silica coating, S/M (Figure 2b), S/M/H (Figure 2c), S/M/R (Figure 2d) and S/M/H/R (Figure 2e) samples display similar flat surface morphology, indicating that mesoporous silica coating had very little influence on morphology of S surface. TEM images of S/M/H/R verifies the ordered mesoporous structure of the mesoporous silica coating (Figure 2f). FT-IR spectra of the samples were used to verify the successful encapsulation of the drugs in mesoporous silica coating. As shown in Figure S1, S/M, S/M/H, S/M/R and S/M/H/R all show peaks around 1095, 1630 and 3400 cm-1, which can be ascribed to stretching vibrations of Si-O-Si and O-H group18. Absorption peak of the group C=O in heparin and rapamycin located at 1730 cm-1 was observed on S/M/H, S/M/R, and S/M/H/R samples (Figure S2)19. For S/M/H/R sample, the intensity of peak at 1730 cm-1 was increased compared with that of S/M/H and S/M/R samples, indicating that two kinds of drugs (heparin and rapamycin) were introduced in S/M/H/R sample. Moreover, the existence of mesoporous silica and the drugs on the surface of BMS were also proved by the SEM-mapping results. The existing elements on the bare BMS sample were Cr, Ni and Fe (Figure S3). As shown in Figure S4, the SEM-mapping of S/M/H/R confirms the existence and uniform distribution of Si, O, Na, C, S, N, Fe elements. The Na, S and N element mappings indicate the successful encapsulation of heparin and rapamycin. Also, results from EDS spectra are in accordance with that of SEM-mapping. The hydrophilicity of the surface of biological materials has a great relationship with its biocompatibility20. Figure S5 displays the static water contact angle (CA) of different coatings deposited into BMS substrate. The CA of S, S/M, S/M/H, S/M/R and S/M/H/R were 72.4±1.6°, 58.1±3.1°, 41.7±1.5°, 64.5±0.9°, 48.0±0.4°, respectively. It can be seen that the CA of S/M decreased with the coated mesoporous silica owing to the existence of Si-OH and P123. Meantime, the CA of S/M/H further


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decreases with the addition of heparin due to the fact that heparin contained a lot of hydrophilic organic groups such as carboxylic and sulfate groups21. Owing to the hydrophobic nature of rapamycin22, the coating containing rapamycin shows increased value of CA (S/M/R). The mesoporous silica coating containing two drugs (S/M/H/R) shows much lower contact angle compared with that of BMS surface. The enhanced hydrophilic surfaces can resist protein adsorption23. To check the influence of the added drugs to the pore structure of the mesoporous silica coatings, the template free samples were tested with nitrogen adsorption-desorption at -196 ℃. Figure S6 and Table S1 illustrate how the specific surface areas, pore volumes, and pore sizes of the composites vary along with the addition of drugs. It can be observed in Figure S6a that pure mesoporous silica coating (S/M-c) displays a typical IV isotherm according to the IUPAC classification, indicating uniform mesopores. When heparin and rapamycin were added, S/M/H, S/M/R-c and S/M/H/R-c also show typical IV isotherms, implying uniform mesopores in these coatings. The pore size distributions (Figure S6b) display that S/M-c, S/M/H-c, S/M/R-c and S/M/H/R-c exhibit a sharp peak centered at about 3.7 nm, indicating that the added drugs showed few effects on pore size. When rapamycin was added to the synthetic gel, the final mesoporous coating shows a slightly decreased surface area, which decreased from 533 to 414 m2 g-1. The BET surface area of S/M/H/R-c shows a sharply decreased trend, which may be attributed to the fact that the excess amount of drugs can cause salt effect which would exert negative effect on the formation of mesoporous structure. 120

Release percentage (%)

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Heparin Rapamycin

100 80 60 40 20 0 0

10

20

Time (d)

30

40

50

Figure 3. The release profiles of heparin and rapamycin from S/M/H/R.


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The release behaviours of different drug from the S/M/H, S/M/R and S/M/H/R were investigated in PBS solution (pH=7.4). As shown in Figure S7A, the release of heparin is fast at the first day, which can be attributed to the easily diffusion of heparin located on the outer surface of the coating. Then, a lower releasing rate was observed. The release study of rapamycin (Figure S7B) was performed in mixed solution of PBS and ethanol (VPBS/Vethanol=9/1)24. Different from burst release phenomenon of heparin, rapamycin shows a stable release rate for as long as 35 days. The final release amount of rapamycin is about 350 μg, which is much higher than many other reports25,26. Different release rate of heparin and rapamycin was suitable for the clinical application. Rapid release of heparin can achieve anticoagulation and endothelialization, while slow release of rapamycin can realize antiproliferative therapy for long term. Meanwhile, the drugs release profiles of S/M/H/R were detected (Figure 3). Results display that no obvious change was observed on the release profile of rapamycin. Since the existence of heparin can facilitate the immobilization of VEGF, part of heparin can interact with VEGF. Hence VEGF will be released with the release of heparin. In order to detect the release performance of VEGF, ELISA Kit for VEGF was used and the release profile of VEGF was shown in Figure S8, which displays that the release of VEGF can last for one week. The rate of hemolysis can be used to measure the damage of red blood cells (RBCs) when materials contact blood. The hemolysis rates of S, S/M, S/M/H, S/M/R, and S/M/H/R were shown in Figure S9. The hemolysis rates of materials without heparin are more than 1.2%, which decrease to about 0.6% for S/M/H and S/M/H/R materials. When samples confronted with red blood cells, aggregation, crenation and hemolysis are indicators to illustrate interactions and incompatibility of samples with RBCs27. Figure S10 shows the pictures of RBCs treated with different samples. The morphology of untreated RBCs in PBS (as negative control) is normal biconcave shape. Some of RBCs treated with S, S/M and S/M/R display deformation but most of the RBCs remain normal biconcave shape. The RBCs treated with samples containing heparin retain similar circular morphology of the negative control group. These results


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reveal that S/M/H and S/M/H/R had no destruction to RBCs, which is consistent with the results of the hemolysis analysis. The APTT, TT, PT results of S, S/M, S/M/H, S/M/R and S/M/H/R were summarized in Figure S11. The APTT values of S, S/M and S/M/R are between 12 s and 17 s, but that of S/M/H and S/M/H/R are significantly longer than 17 s, timeout occur on the samples with heparin, indicating that heparin has favorable anticoagulant property. The PT and TT values of S/M/H and S/M/H/R also exceed the measuring range of the instrument, which is in consistent with the APTT results. MTT assay has been applied to study the cell viability on the samples. The cell viability of ECs cultured with S/M/H and S/M/H/R is similar with each other, and more than 95% of the cells maintain their viability, indicating low cytotoxicity and good cell compatibility of S/M/H and S/M/H/R samples (Figure S12)28,29.

Figure 4. (A) SEM images of (a) S, (b) S/M, (c) S/M/H, (d) S/M/R, and (e) S/M/H/R exposed to rabbit whole blood for 1 h; and (B) SEM images of (a) S, (b) S/M, (c) S/M/H, (d) S/M/R, and (e) S/M/H/R exposed to platelet-rich plasma of rabbit for 1 h, respectively.


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To further investigate the overall blood compatibility of the samples, the whole blood test was carried out (Figure 4A)30. Clearly, there are a lot of blood cells adhere on the S, S/M and S/M/R. However, it is obvious that almost no blood cell attach on the S/M/H and S/M/H/R because of the existence of heparin. Figure 4B shows the SEM images of platelets adherent on the different samples. It can be clearly seen that large amounts of platelets aggregate on the S, S/M and S/M/R surfaces, while almost no adhered platelets are observed on S/M/H and S/M/H/R surfaces. These results indicate that adding heparin can effectively prevent the adhesion of platelets.

Figure 5. The images of immunofluorescence staining of (a-e) ECs and (f-j) smooth muscle cells cultured on the S, S/M, S/M/H, S/M/R and S/M/H/R (Scale bar: 100 μm).

Moreover, rapamycin has been regarded as an effective drug inhibiting intimal thickening

after

transplantation.

Smooth muscle cells

(SMCs)

proliferation

performance was detected by seeding SMCs on the surface of different samples. As shown in Figure 5a-e, cell densities on S, S/M and S/M/H surfaces are much higher than that on S/M/R and S/M/H/R surface, indicating that cell proliferation phenomenon is obvious when there is no rapamycin and the cell proliferation can be greatly suppressed by the released rapamycin31. ECs proliferation performance was also detected by seeding ECs on the surface of different samples. As shown in Figure 5f-j, cell densities on S/M/H and S/M/H/R surfaces are much higher than that on S, S/M and S/M/R surface, indicating that heparin combined with VEGF can attenuate the inhibitory effect of rapamycin on endothelial cells32.


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Figure 6. (A) Endothelialization assessed by SEM images of stainless-steel stent surface and (B) Representative images of hematoxylin and eosin staining of cross sections after implantation for (a) S for one month, (b) S/M/H/R for one month, (c) S for three months, and (d) S/M/H/R for three months.

In order to examine the endothelialization performance in vivo for S and the S/M/H/R, these stents were implanted in the one side of carotid artery of New Zealand rabbits (Figure S13). Images of the blood flow detected by digital subtraction angiography were summarized in Figure S14, which displays that the blood flow is good and all the stents are in place33. SEM images of the implanted stents surface after one and three months of implantation were shown in Figure 6A. It is obvious that S displays almost complete endothelialization for one month, while endothelialization of S/M/H/R is incomplete, suggesting that drug-coated stent inhibited initial hyperplasia a little. Meanwhile, complete endothelialization for the S and S/M/H/R stents was realized after three months, indicating that early anti-tissue proliferation did not affect the following endothelialization. At the same time, images of hematoxylin and eosin staining of cross sections after one and three months


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implantation of the inserted coronary stent verify that tissue proliferation can be effectively avoided for S/M/H/R implantation, illustrating that the introduced rapamycin can realize antiproliferative therapy (Figure 6B).

4. Discussion Among current drug releasers, micelles of linear amphiphilic block copolymers are promising candidates34. Yet, low stability of micelles leads to fast release of the drugs. To get rid of this drawback, evaporation-induced self-assembly method was used to encapsulate both hydrophilic and hydrophobic drugs during synthesis of the materials. P123 is a kind of triblock copolymer containing the hydrophilic part PEO (located in the outside of the micelle) and hydrophobic part PPO (the inner core of the micelle). As shown in Figure 1, hydrophobic rapamycin will interact with the hydrophobic part of P123 (PPO, the inner core of the micelle), and heparin will interact with the hydrophilic part of P123 (PEO, the outside of the micelle). As a result, heparin located in the outer surface of the mesoporous coating displays release burst while rapamycin doesn’t. The sample well controls the dual release of hydrophilic and hydrophobic drugs.

Figure 7. (A) DLS curves of P123 and P123 with heparin or rapamycin, and summary of (B) particle size and (C) zeta potential of different samples.

DLS (dynamic light scattering particle size analyzer) of P123 micelle, P123 micelle with heparin (P123-H), P123 micelle with rapamycin (P123-R), P123 micelle with heparin and rapamycin (P123-H-R) was detected and results were shown in Figure 7A. It can be seen clearly that the size of P123 micelle is about 17.3 nm, which


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increases to 19.3 nm with the addition of heparin because heparin can interact with the hydrophilic PEO groups in P123 to increase the particle size. With the addition of rapamycin, the micelle size increases to 20.5 nm, owing to the fact that hydrophobic rapamycin can interact with the hydrophobic PPO group in P123 to increase the micelle size. When heparin and rapamycin were added, the micelle size further increases to 25.7 nm, illustrating that both heparin and rapamycin interact with P123 to increase the micelle size. Furthermore, zeta potentials of different composites were also detected to further verify the proposed interaction between heparin/rapamycin and P123 (Figure 7B). Zeta potential of P123 micelle is about 0.939 mV which is reasonable since P123 is non-ionic surfactant, which decreases to -2.44 mV with the addition of negative charged hydrophilic heparin, proving that heparin located at the outside of the micelle interacting with PEO groups (Figure 1B). The zeta potential of P123-R is about 0.0659 mV, which is similar with that of P123 micelle, while the micelle size (20.5 nm) is larger than that of P123 micelle (17.3 nm), demonstrating that hydrophobic rapamycin locates in the P123 micelle interacting with the hydrophobic groups PPO of P123. Besides, zeta potential of P123-H-R is about -1.36 mV, revealing that heparin locates at the outside of the micelle. These results verify the possible interaction between drugs and P123 micelle proposed in Figure 1. In order to find the difference of heparin and rapamycin release from mesoporous silica coatings, Higuchi (1961) model, Mt /M∞ = a × t1/2, and Peppas (1987) model, Mt /M∞ = a × tb, were used to investigate release mechanisms35,36. Experimental profiles of heparin and rapamycin release from S/M/H/R were fitted to theoretical models. In the formula, “a” is a kinetic constant, Mt and M∞ are cumulative release amount of drugs at time t and infinite time. “b” from Peppas model is an exponent identifying the diffusion mechanism. Peppas model and Higuchi model are the same when the value of b equals to 0.5. If we take logarithm of Peppas equation, we can get the formula: ln Mt / M∞ =ln a + b ln t. If we plot ln Mt / M∞ against ln t, a line is obtained, of which the slope and intercept are b and ln a. When b is approximately equals to 0.5, the release model of drugs on the sample belongs to Higuchi model, which displays relatively unique pore property37. Heparin from S/M/H and rapamycin from S/M/R were fitted to Peppas models (Figure S15 and Figure S16). As shown in Tables S2 and Tables S3, the value of R2 for rapamycin was larger than that of heparin, demonstrating that the location of rapamycin was similar


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to the uniform pores. We further used First-order (ln (Q0-Qt)=ln Q0-K1t) and Zero-order (Qt=K0t) release models to deeply investigate the release behavior of heparin and rapamycin from mesoporous silica coatings38. Here, the release profiles of heparin and rapamycin were fitted with these three models (First order release models (Figure S17A), Zero order release models (Figure S17B) and Peppas model (Figure S18)), and the fitted results were summarized in Table S4 and Table S5. As shown in Table S4 and Table S5, the values of R2 for the above three release models of heparin were 0.9780, 0.3896 and 0.9975, and that of rapamycin were 0.8920, 0.5539 and 0.9912. It can be deduced from these results that the release mechanism of heparin and rapamycin on this sample was more consistent with Peppas model than First order release and Zero order release model, which indicated the location of heparin and rapamycin was uniform pores. Especially, the R2 value for both heparin and rapamycin model are larger than 0.99, indicating a good relative correlation. As has been proposed that Higuchi model requires the relatively uniform pore property, these results imply that location of heparin exhibited little heterogeneous pores, which was in accordance with the proposed possible interaction between heparin and PEO groups shown in Figure 1B. Some of the heparin located at the outside of the coatings, which is the reason to explain that the release model of heparin is not as uniform as that of rapamycin, further confirming the proposed interaction between drugs and P123 (Figure 1B).

5. Conclusions In summary, we present a simple strategy to construct mesoporous silica coating on the BMS surface by evaporation-induced self-assembly method. The process of surface modification is simple, time-saving and energy-saving. Both heparin and rapamycin drugs can be successfully encapsulated into the mesoporous silica coating to inhibit thrombus formation and promote ECs proliferation, which shows that the release of heparin and rapamycin can last for more than 30 days. At the same time, this multi-functional interface also has good blood compatibility. In addition, improved BMS greatly enhances the proliferation of ECs. In vivo results reveal that the mesoporous silica coating with both hydrophilic and hydrophobic can successfully realize rapid endothelialization and antiproliferative therapy. All of these results


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indicate that mesoporous silica coatings have the potential to be applied to the surface modification of bare metal stents. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications. Additional information including the detailed experimental sections, physicochemical properties of the calcined mesoporous coatings (Tables S1), parameters and coefficients obtained for Peppas release model fitted to the heparin release profiles from S/M/H sample (Tables S2) and the rapamycin release profiles from S/M/R sample (Tables S3), parameters and coefficients obtained for First order release kinetic model and Zero order release kinetic model (Tables S4) fitted to the heparin and rapamycin release profiles from S/M/H/R sample, parameters and coefficients obtained for Peppas release kinetic model to the heparin and rapamycin release profiles from S/M/H/R sample (Tables S5). FT-IR spectra of S, S/M, S/M/H, S/M/R and S/M/H/R (Figure S1), the chemical structures of heparin and rapamycin (Figure S2), SEM and EDX spectrum mapping of S (Figure S3) and S/M/H/R (Figureure S4), the static water contact angle (Figure S5), N2 adsorption-desorption isotherms of different samples (Figure S6), the release profiles of heparin from S/M/H and rapamycin from S/M/R. (Figure S7), release profile of VEGF by S/M/H/V/R after combining with VEGF (Figure S8), hemolysis ratio (Figure S9), optical images of RBCs treated (Figure S10), in vitro coagulation time (Figure S11), MTT assay results (Figure S12) of ECs treated with different samples, schematic illustration of the surgical procedure for stent implantation (Figure S13), digital subtraction angiography of the implanted stents (Figure S14), release data fits to Peppas model for heparin from S/M/H (Figure S15) and for rapamycin from S/M/R (Figure S16), release data fits to First order and Zero order release model for heparin and rapamycin from S/M/H/R (Figure S17), release data fits to Peppas model for heparin and rapamycin from S/M/H/R (Figure S18) (PDF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. E-mail: [email protected].


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Acknowledgement The work was supported by Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, National Natural Science Foundation of China (21603105, 21571104, 31771049), Chinese Postdoctoral Science Foundation (2015M580446), Jiangsu Province (1601240C), Jiangsu Key Technology RD Program (BE2016010), the Priority Academic Program Development of Jiangsu Higher Education Institution, and State Key Laboratory of Materials-Oriented Chemical Engineering (ZK201806, KL17-07).

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Table of contents

Multiple-drug Delivery from Mesoporous Coating Realizing Combination Therapy for Bare Metal Stents Qi Wanga†, Shuang Long Huc†, Ying Ben Wua, Qian Niua, Yang Yang Huanga, Fan Wua, Xiao Tan Zhua, Jin Fanb, Guo Yong Yinb, Mi Mi Wan a*, Chun Maoa, Min Zhouc*

Keywords: multifunctional mesoporous silica, anticoagulant, endothelialization, antiproliferative, bare metal stent


Multiple-drug Delivery from Mesoporous Coating Realizing

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