Article Cite This: Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Amino-Functionalized Mesoporous Silica Particles for Ocular Delivery of Brimonidine Se-Na Kim,†,∇ Song Ah Ko,†,∇ Chun Gwon Park,‡ Seung Ho Lee,§ Beom Kang Huh,† Yoh Han Park,† Young Kook Kim,∥,⊥ Ahnul Ha,∥,⊥ Ki Ho Park,∥,⊥ and Young Bin Choy*,†,§,# †
Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Republic of Korea Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea § Institute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea ∥ Department of Ophthalmology, Seoul National University Hospital, Seoul 03080, Republic of Korea ⊥ Department of Ophthalmology and #Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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‡
S Supporting Information *
ABSTRACT: To treat glaucoma, conventional eye drops are often prescribed. However, the eye drops have limited effectiveness as a result of low drug bioavailability due to their rapid clearance from the preocular space. To resolve this, we proposed amino-functionalized mesoporous silica (AMS) particles as delivery carriers of the glaucoma drug, brimonidine. Because of the presence of mesopores, brimonidine (BMD) could be encapsulated in the AMS with a loading amount of 41.73 μg/mg (i.e., drug loading capacity of about 4.17%) to give the BMD−AMS, which could release the drug in a sustained manner over 8 h. BMD− AMS was also shown to be mucoadhesive due to the presence of both hydroxyl and amino groups in the surface, allowing for formation of hydrogen bonds and an ionic complex with the mucin, respectively. Therefore, when topically administered to rabbit eyes in vivo, BMD−AMS could reside in the preocular space for up to 12 h because of its adherence to the mucous layer. To assess in vivo efficacy, we examined the variance in intraocular pressure (IOP) and brimonidine concentration in the aqueous humor (AH) after applying BMD−AMS to the eye, which was compared with that induced by Alphagan P, the marketed brimonidine eye drops. For BMD−AMS, the duration in the decrease in IOP and the area under the drug concentration in the AH−time curve (AUC) were 12 h and 2.68 μg·h/mL, respectively, which were about twice as large as those obtained with Alphagan P; this finding indicated enhanced ocular bioavailability of brimonidine with BMD−AMS. KEYWORDS: brimonidine, drug delivery, glaucoma, mesoporous silica, mucosal adhesion
1. INTRODUCTION Glaucoma is a disease that damages the optic nerve in the eye to eventually result in irreparable blindness.1,2 Abnormal elevation of intraocular pressure (IOP) is considered as one of the main causes of glaucoma,3 and therefore, eye drops containing drug to lower the IOP are often administered in clinical settings.4 However, eye drops rapidly disappear from the preocular surface because of tear clearance and blinking, thereby resulting in low drug bioavailability (99.8%) and Alcaine (0.5% ophthalmic solution of proparacaine hydrochloride) were purchased from Nanjing Yuance Industry & Trade (Nanjing, China) and Seoul National University Hospital Biomedical Research Institute (Seoul, Korea), respectively. A PVA surgical sponge (PVA Spears; Network Medical Products, UK) was purchased from Medimaru (Korea). Ketamine (ketamine hydrochloride), Rompun (xylazine), and Sedaject (acepromazine maleate) were obtained from BK Pharm (Korea). Alphagan P (0.15% eye drops of briomonidine) was donated by Samil Allergan (Korea). 2.2. Particle Fabrication. The AMS particles were synthesized following the previously reported procedure.17 Briefly, 1.8 g of sodium dodecyl sulfate (SDS) was dissolved in B
DOI: 10.1021/acs.molpharmaceut.8b00215 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
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in an RPMI 1640 medium containing 10% fetal bovine serum (FBS; Gibco, CA, USA) and 1% antibiotics (penicillin− streptomycin 10 000 unit/mL, Thermo Fisher Scientific, MA, USA) at 37 °C in a humidified 5% CO2 atmosphere. Also, HCECs were cultured in a corneal epithelial cell basal medium (PCS-700−030, ATCC, USA) using a corneal epithelial cell growth kit (PCS-700−040, ATCC, USA) at 37 °C in a humidified 5% CO2 atmosphere. For cytotoxicity tests, 500 μL of the cell suspension (1.0 × 105 cells/mL) was seeded on each well of the 24-well plate. After 24 h, BMD−AMS at varying concentrations of 0.02, 0.05, 0.1, 0.2, 0.5, and 1 mg/mL were added to each well, and the plate was incubated at 37 °C for 24 h in a 5% CO2 humidified atmosphere. After that, 50 μL of EZCytox WST reagent solution was added to each well, which was incubated for 1 h at 37 °C. Then, the plate was measured using a microplate reader (SpectraMax 190 Microplate Reader; Molecular Devices, USA) at 450 and 600 nm. Cell viability was quantitatively analyzed using the following equation: cell viability (%) = (absorbance of the treated well (450 nm) − absorbance of the treated well (600 nm))/(absorbance of the untreated control (450 nm) − absorbance of the untreated control (600 nm)) × 100.28 2.7. Animal Experiments. Healthy, male New Zealand White rabbits (2.5−3.5 kg, Orient Bio, Korea) were used for in vivo evaluation of the BMD−AMS particles herein. The experimental protocol was approved by the Institutional Animal Care and Use Committee at the Biomedical Research Institute of the Seoul National University Hospital (IACUC No. 13−0101). We first assessed the preocular retention property of the BMD−AMS. For this, a 35 μL suspension containing 1.26 mg of BMD−AMS in 10 mM PBS (pH 7.4), containing 52.5 μg of brimonidine, was applied into the lower cul-de-sac of the rabbit eye. The suspension was freshly prepared at each time of in vivo experiments to avoid any possible particle aggregations (Figure S1 in the Supporting Information). At scheduled times after administration (0.5, 1, 2, 4, and 12 h after administration), the eye was locally anesthetized with a 35 μL eye drop of 0.5% proparacaine and fully wiped with a PVA surgical sponge to collect the particles.29,30 We assigned four animals (i.e., one eye for each animal) for each time of sample collection, and thus, for each animal, the BMD−AMS were collected only at the designated collection times after administration. The surgical sponge was then fully immersed in an acidic solution (HF/HNO3/H2O = 2:3:4), which was then treated by microwave digestion to quantify the amount of Si with an inductively coupled plasma mass spectrometer (ICP-MS; Agilent 7800, USA). With the measured amount of Si and its mass ratio in the BMD−AMS, we obtained the amount of the BMD−AMS remaining on the preocular surface. The remaining amount of the BMD−AMS was then calibrated in percentages based on the amount initially administered to the eye. Four eyes were tested at each time of particle collection. To evaluate the in vivo drug efficacy, we compared the profiles of the IOP change29,31,32 and drug concentration in aqueous humor (AH) of two distinct animal groups treated with either BMD−AMS or Alphagan P, the marketed eye drops of brimonidine. Six eyes were assigned for each animal group. For this, a 35 μL drop of the BMD−AMS suspension or Alphagan P, both containing 52.5 μg of brimonidine, was administrated in the lower cul-de-sac of the rabbit eye. To evaluate IOP, the rabbit eye was locally anesthetized with a 35
suspension was centrifuged at 13 500g for 10 min, and 1 mL of the supernatant was collected. The supernatant was then measured using high performance liquid chromatography (HPLC; Agilent 1260 series, Agilent Technologies, USA) with a Poroshell column (120 EC-C18, 4.6 × 100 mm, 2.7 μm pore, Agilent Technologies, USA) at a 1 mL/min feed rate of the mobile phase, which was prepared by mixing 20 mM phosphate-buffered saline at pH 2.5 and acetonitrile (v/v = 87:13). The injection volume and UV absorbance were set at 20 μL and 248 nm, respectively. 2.4. In Vitro Mucoadhesion Study. To assess the mucoadhesiveness of the particles, we first assessed the amount of mucin adsorbed to the BMD−AMS, following the previously reported protocol with modifications.23,24 In order to do this, an aqueous solution of type III mucin (1 mg/mL) was prepared and centrifuged at 13 500g for 10 min. Then, 2 mL of the supernatant was collected, in which 4 mg of the BMD−AMS was immersed. The resulting suspension was vortexed and incubated at 37 °C for periods of 0.5, 1, and 24 h. In this study, we tested the particles for a shorter period of time of mucin interaction, because the particles topically administered to the eye were expected to be under severe preocular clearance, and thus, a mucoadhesive property needed to be observed in a relatively shorter period of time. After incubation, the suspension was centrifuged at 13 500g for 10 min, and 1 mL of the supernatant that contained nonadsorbed free mucin was collected. To the collected solution, 100 μL of periodic acid diluted with acetic acid was added, which was then incubated for 2 h at 37 °C. After that, the solution was mixed with 100 μL of Schiff’s reagent at room temperature for 30 min and measured with a UV/vis spectrophotometer (UV1800 240 V, Shimadzu, Japan) at 560 nm. The mucin solutions at known concentrations (0.1, 0.25, 0.5, and 1 mg/mL) were treated and measured as described above to give a standard absorbance versus the concentration curve. The amount of mucin adsorbed to the particles was obtained by subtracting the measured amount of free mucin from the total amount of mucin in the initial solution (1 mg/mL). To examine the effect of amino groups on mucoadhesiveness, we used an aqueous solution of type III mucin (1 mg/mL) containing 0.2 M NaCl to eliminate the effect of electrostatic interaction25 and repeated the experiments described above. To further confirm the adsorption of mucin on the particles, the change in zeta potential was evaluated using a Zetasizer (Nano ZS, Malvern, UK). Before measurement, 4 mg of the BMD−AMS was incubated in 2 mL of an aqueous solution of type III mucin (0.5 mg/mL) for 0.5 h.26,27 Then, the particles were collected by centrifugation at 13 500g for 10 min and were suspended in deionized water at a concentration of 500 ppb. 2.5. In Vitro Drug Release Study. To obtain the in vitro drug release profile, the BMD−AMS (10 mg) was placed in 10 mM phosphate-buffered saline (20 mL) at pH 7.4, which was agitated at 125 rpm in a shaking incubator (SI-600R, Jeio Tech, Korea) at 37 °C. At scheduled times, 5 mL of the supernatant was taken, and the same volume of fresh buffer was returned to the mixture. The sampled supernatants were measured with HPLC as described above. 2.6. Cytotoxicity Test. The cytotoxicity of BMD−AMS was assessed with L929 mouse fibroblast cells (KCLB, Korea) and human primary corneal epithelial cells (HCECs; PCS700−010, ATCC, USA) using an EZ-Cytox cell viability assay kit (Daeillab Service, Seoul, Korea). L929 cells were cultured C
DOI: 10.1021/acs.molpharmaceut.8b00215 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
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IOPbaseline − IOPscheduled time × 100(%) IOPbaseline
To measure the drug concentrations in AH, six eyes were tested at each scheduled time after administration for each animal group. At each scheduled time, the rabbit was anesthetized with a subcutaneous injection of a cocktail of 17.5 mg/kg ketamine, 5 mg/kg xylazine, and 0.2 mg/kg acepromazine, and approximately, 100 μL of AH was aspirated using a 31 G syringe needle (Jung Rim Medical, Korea). The collected liquid was then measured using HPLC (Agilent 1260 series, Agilent Technologies, USA) with a Poroshell column (120 EC-C18, 4.6 × 100 mm, 2.7 μm pore, Agilent Technologies, USA) at a 1 mL/min feed rate of the mobile phase, which was prepared by mixing 20 mM PBS at pH 2.5 and acetonitrile (v/v = 95:5). The injection volume and UV absorbance were set at 100 μL and 248 nm, respectively.29 2.8. In Vivo Safety Evaluation. To evaluate in vivo safety, an ophthalmologist examined the rabbit eyes before and after topical administration of a 35 μL drop of the BMD−AMS suspension in a blinded manner (n = 3). The rabbit eyes were examined under a microscope to assess any possible abnormality in the sclera, cornea, conjunctiva, and anterior chamber. During this evaluation, the rabbits were anesthetized via subcutaneous injection of a mixture of ketamine (17.5 mg/ kg), xylazine (5 mg/kg), and acepromazine (0.2 mg/kg). 2.9. Statistical Analysis. IOP changes and drug concentrations in AH were statistically analyzed using the Mann−Whitney U-test, in which a p-value of 20% was still found after 4 h, which slowly disappeared over the next 12 h. The results suggest that the BMD−AMS possesses preocular retention properties originating from their mucoadhesiveness such that the BMD−AMS adhering to the mucous layer at the preocular surface had slower clearance. Comparably, the typical eye drops are known to be available at
Figure 6. Cell viability assay of BMD−AMS with (A) L929 cells and (B) human corneal epithelial cells (HCECs). Error bars = ±SD. F
DOI: 10.1021/acs.molpharmaceut.8b00215 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
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Figure 8. In vivo profiles of (A) the decrease in IOP and the (B) brimonidine concentration in the aqueous humor (AH) with topically administered BMD−AMS and Alphagan P. Asterisk indicates statistically significant difference between BMD−AMS and Alphagan P (p < 0.05). Error bars = ±SD.
the eye surface only for 3−7 min.42 We also sought to examine the in vivo efficacy of brimonidine after topical administration of the BMD−AMS suspension to the eye. In order to do this, we used the change in IOP and drug concentration in AH as the pharmacodynamic and pharmacokinetic parameters, respectively, which were then compared with those of Alphagan P. As shown in Figure 8A, the IOP decreased for all of the tested animal groups because of brimonidine’s effects.31 For Alphagan P, the IOP decreased to 30%, which then returned to the initial level by 6 h. Notably, when the same dose of brimonidine was administered with BMD−AMS, the IOP decreased further to about 40%, and the period of IOP decrease was prolonged up to 12 h, which was twice longer than that of Alphagan P. The drug concentration profile in AH further confirmed enhanced ocular bioavailability of brimonidine with BMD−AMS as shown in Figure 8B. The peak drug concentration was observed at 1 h for both BMD−AMS and Alphagan P. However, with BMD−AMS, the area under the drug concentration in AH−time curve (AUC) increased (2.68 μg·h/mL) when compared with that of Alphagan P (1.6 μg·h/ mL). The drug concentrations with the BMD−AMS were statistically significantly higher than those with Alphagan P from 2 to 6 h (p < 0.05). To evaluate the safety of the BMD−AMS, the rabbit eye was examined by an ophthalmologist. In a 24 h follow-up experiment after topical administration of BMD−AMS, the rabbits’ eyes did not show any apparent complications or tissue damages other than minimal conjunctivitis (Figure 9 and Figure S5 in the Supporting Information), which could be explained by dehydration of the eyes often observed with general anesthesia. The degree of conjunctivitis after the
BMD−AMS administration was not apparently different from that of untreated rabbit eyes.
4. DISCUSSION Since the discovery of mesoporous materials in the early 1990s,43−45 they have drawn a great deal of interest because of many advantages originating from their high surface area, versatility in surface modification, and other factors.46−48 Among them, mesoporous silica has been extensively studied for various applications such as catalysts, adsorbents for separation, and/or molecular sieving and sensing materials.49−51 In particular, mesoporous silica has been widely studied for drug delivery due to the outstanding capacities in high drug loading, controlled drug delivery, multifunctionalization, and biocompatibility.47,52−54 Therefore, for the first time to our knowledge, we proposed the AMS, a type of the mesoporous silica particle as an ocular drug delivery carrier in this study. Unlike rapidly disappearing, conventional eye drops,42 the AMS used in this study possessed a preocular retention property, which appeared to originate from their mucoadhesiveness (Figure 4). Similar to other silica particles, there are many hydroxyl groups in the AMS, allowing for formation of a hydrogen bond with the mucin.14 As a result of the presence of amino groups, the AMS appeared to adhere better to the mucin compared with the mesoporous silica particles without the amino groups (Figure S6), which implied that the amino groups in the AMS form an ionic complex with the negatively charged mucin (Figure 4A).15 This mucoadhesive property was shown to be comparable to that of chitosan micropaticles (Figure 4A).23,24 While microparticles made of hydrogel, such as chitosan, would be better suited for hydrophilic drugs,55−57 a variety of drugs could be encapsulated via simple absorption because of the presence of abundant mesopores in the AMS. Therefore, when topically administered to the eye, the AMS would better adhere to the mucin at the eye surface, slowing down the particle clearance from the preocular space (Figure 7). In addition, the AMS could serve as a suitable carrier of an ocular drug, brimonidine. As a result of the mesopores with large specific surface area as well as the positively charged amino groups, the negatively charged brimonidine could be entrapped in the AMS via physical adsorption and electrostatic attraction, respectively, from which the drug was released in a sustained manner for 8 h (Figure 5). In comparison, the mesoporous silica particles without amino groups exhibited a
Figure 9. Representative images of rabbit eyes observed (A) before administration and (B) 3 and (C) 24 h after administration of the BMD−AMS. G
DOI: 10.1021/acs.molpharmaceut.8b00215 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
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Molecular Pharmaceutics lower drug loading amount (17.58 μg/mg) as well as more rapid drug release (Figure S6 in the Supporting Information). Thus, when topically administered to the eye, the brimonidineloaded AMS would stay longer in the eye surface, releasing the drug in a sustained manner, to eventually improve drug bioavailability in the eye. Our in vivo findings revealed that the BMD−AMS in this study exhibited enhanced ocular brimonidine bioavailability (Figure 8). Brimonidine is an ocular hypotensive agent known to effectively treat glaucoma by decreasing aqueous humor production and increasing uveoscleral outflow.40 Therefore, the conventional eye drops of brimonidine, although almost completely disappearing in 3−7 min after administration, still showed an effective pharmacodymanic profile (i.e., decrease in IOP) for 6 h (Figure 8). Meanwhile, the BMD−AMS particles herein could stay much longer in the eye surface (Figure 7), and during this period, drug was continuously released, being expected to improve drug bioavailability in tears.58 Therefore, the BMD−AMS were shown to more efficiently decrease IOP for twice as long of a duration of drug action when compared with the same dose used in clinical settings, i.e., a drop of Alphagan P59 (Figure 8A). According to the pharmacokinetic analysis, the AUC value indeed increased compared with that of Alphagan P, further confirming improved ocular bioavailability of brimonidine with the delivery carrier, AMS (Figure 8B). In our previous study,29 to extend the period of the decrease in IOP to 12 h, as done with the BMD−AMS herein, a 4-fold higher dose was needed with Alphagan P. In an aspect of the dosing frequency, Alphagan P of the same dose needed to be administered twice with an interval of 5 h; however, the IOP was not maintained satisfactorily. For this reason, it is recommended to administer Alphagan P three times per day in clinical settings.59 The silica-based particles, including mesoporous silica particles, have long been sought for biomedical applications because of their high biocompatibility.60,61 Therefore, the BMD−AMS in this study, when incubated for 24 h, did not exhibit cytotoxicity up to 1 mg/mL, which was about 0.25 mg/ cm2 of particle density in a microwell of 2 cm2 area. The particle density used for cytotoxicity tests was higher than that for in vivo examinations, which was about 0.16 mg/cm2, considering 1.26 mg of BMD−AMS particles administered to the frontal eye surface of about 7.6 cm2.62,63 Moreover, after administration, the particles would continuously disappear from the preocular surface as a result of clearance (Figure 7). For this reason, the BMD−AMS also exhibited no apparent complications when applied topically to the eye (Figure 9).
decrease and higher AUC values when compared with Alphagan P. Therefore, we conclude that AMS particles are promising carriers for enhanced bioavailability of a topically delivered ocular drug.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.8b00215. Schematic procedure for synthesis of AMS; particle size distribution of the BMD−AMS; drug loading amounts in the AMS with varied times of particle immersion; TEM images and EDS maps for AMS and BMD−AMS particles; fluorescent images of rabbit eyes after staining with a fluorescein solution; results from the mesoporous silica particles without amino groups (SBA15) (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]; Tel: +82-2-740-8592; Fax: +82-2741-6303 (Y.B.C) ORCID
Young Bin Choy: 0000-0001-6300-9377 Author Contributions ∇
S.-N.K. and S.A.K. contributed equally as the first author to the work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (2017R1A2B3004830) and the Technology Innovation Program (10060067, Technical Development of Nanosystem-Based Technology for Drug Therapy Preventing Side Effects after Cataract Surgery), funded by the Ministry of Trade, Industry and Energy (MI, Korea).
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ABBREVIATIONS AMS,amino-functionalized mesoporous silica; BMD,brimonidine; IOP,intraocular pressure; AH,aqueous humor; AUC,area under the drug concentration in the AH−time curve; XRD,Xray powder diffraction; FTIR,Fourier transform infrared spectroscopy; SEM,scanning electron microscopy; TEM,transmission electron microscopy; APTES,(3-aminopropyl)triethoxysilane; TEOS,tetraethyl orthosilicate; SDS,sodium dodecyl sulfate; BET,Brunauer−Emmett−Teller; BJH,Barrett−Joyner−Halenda; HCECs,human primary corneal epithelial cells; FBS,fetal bovine serum
5. CONCLUSION We suggest the AMS particles as a potential carrier of a glaucoma drug, brimonidine, for topical delivery to the eye. The AMS particles can be successfully fabricated by a simple one-step synthesis procedure to obtain the amino-functionalized surface with an evident mesoporous structure. Therefore, when loaded with brimonidine, AMS can release the drug slowly via the mesopores. As a result of the presence of hydroxyl and amine groups, the AMS particles can be adhesive to the mucous layer lining the eye surface to allow for a high preocular retention property. Therefore, after topical administration to the eye, the AMS can remain in the preocular space longer and concurrently release the drug in a sustained manner; hence, it enhanced ocular drug bioavailability. In this work, BMD−AMS produced a longer duration of IOP
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