The Open Ophthalmology Journal




ISSN: 1874-3641 ― Volume 13, 2019

Controlled Release of Bevacizumab Through Nanospheres for Extended Treatment of Age-Related Macular Degeneration



Fengfu Li*, 1, 2, Bernard Hurley 1, 2, Yun Liu 3, Brian Leonard 1, 2, May Griffith 1, 2, 4
1 Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H8L6, Canada
2 University of Ottawa Eye Institute, 501 Smyth Road, Ottawa, Ontario K1H8L6, Canada
3 Centre for Catalysis Research and Innovation, and Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
4 Integrative Regenerative Medicine Centre, and Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden

Abstract

Bevacizumab (Avastin®) has been used by ophthalmologists in many countries as an off-label drug for the treatment of wet age-related macular degeneration (AMD). Due to its short half-life necessitating frequent intravitreal injection, a method for sustained delivery is in need. We demonstrated that bevacizumab could be released in a sustained fashion over 90 days from nano- and microspheres fabricated from poly(DL-lactide-co-glycolide) and poly(ethylene glycol)-b-poly(D,L-lactic acid), respectively. The drug release rate could be adjusted by alteration of the drug/polymer ratio. The use of such nano- and microspheres as bevacizumab delivery vehicles may improve the treatment of wet AMD.

Keywords: Bevacizumab, age-related macular degeneration, nanospheres, microspheres, and controlled release.


Article Information


Identifiers and Pagination:

Year: 2012
Volume: 6
First Page: 54
Last Page: 58
Publisher Id: TOOPHTJ-6-54
DOI: 10.2174/1874364101206010054

Article History:

Received Date: 6/6/2012
Revision Received Date: 11/6/2012
Acceptance Date: 11/6/2012
Electronic publication date: 25/6/2012
Collection year: 2012

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© Li et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada; Tel: (613) 798-5555, Ext. 19776; Fax: (613) 761-4929; E-mail: fengfuli99@gmail.com




1. INTRODUCTION

In the past few years, intravitreal injection of an anti-cancer drug, bevacizumab (Avastin®, Genetech) [1Ferrara N, Hillan K, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy Biochem Biophys Res Commun 2005; 333: 328-5.] has been found to be a very effective treatment for the wet form of age-related macular degeneration (AMD) [2Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study Ophthalmology 2006; 112: 1035-47.], proliferative diabetic retinopathy [3Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (avastin) in the treatment of proliferative diabetic retinopathy Ophthalmology 2006; 113 (10): 1695-705.] and choroidal neovascularization [4Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration Retina 2006; 26: 383-90.]. Short-term results suggested that intravitreal bevacizumab (1.25mg) was well tolerated and associated with improvement in visual acuity, decreased retinal thickness and reduction in angiographic leakage in most patients [5Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir AA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration Ophthalmology 2006; 113: 363-72.]. Bevacizumab is thought to be as safe as ranibizumab (Lucentis®, Genetech), a prescription medication approved for the treatment of wet AMD [6Kernt M, Neubauer AS, Kampik A. Intravitreal bevacizumab (Avastin) treatment is safe in terms of intraocular and blood pressure Acta Opthalmol Scand 2007; 85(1): 119-20.]. It has been increasingly used in many countries as an off-label treatment for AMD and is evolving into the standard of care for wet AMD. However, to achieve and maintain the improvement in vision, repetitive injection and follow-up visits are required. Intravitreal injection is a currently accepted therapy for many posterior segment ocular disorders. However, when repeated injections are required, there is a high risk of complications such as endophthalmitis [7Yenerel NM, Dinc UA, Gorgun E. A case of sterile endophthalmitis after repeated intravitreal bevacizumab injection J Ocul Pharmacol Ther 2008; 24(3): 362-.], as well as repetitive pain, apprehension and distress associated with inserting needles into eyes. Moreover, the intravitreal half-life of 1.25mg injected bevacizumab is approximately only 3 days [8Beer PM, Wong SJ, Hammad AM, Falk NS, O'Malley MR. Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients Retina 2006; 26: 871-6.]. Therefore an effective drug delivery method needs to be developed to render bevacizumab delivery less invasive and long-lasting.

Recently, nanospheres, microspheres and liposomes have been extensively studied as drug carriers in the pharmaceutical and medical fields [9Xia Y. Nanomaterials at work in biomedical research Nat Mater 2008; 7(10): 758-60.-14Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic)acid microspheres Invest Ophthalmol Vis Sci 2003 ; 44(1): 290-9.]. They have shown promise as drug delivery systems due to their controlled and sustained release properties, subcellular size and biocompatibility with tissue and cells. Very recently, studies have shown the beneficial effects of liposomes in prolonging the residency of bevacizumab in the vitreous in animal model during 42 days [15Abrishami M, Zarei-Ghanavati S, Soroush D, Rouhbakhsh M, Jaafari MR, Malaekeh-Nikouei B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration Retina 2009; 29(5): 699-703.]. Hao et al. [16Hao Y, Patel A, Liu W, Krishna R, Sabates NR, Mitra AK. PPreparation and characterization of bevacizumab (avastin) nanoparticles for the treatment of age related macular degeneration American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, Los Angeles, California, USA. 2009 November; Available from http://www.aapsj.org/abstracts/AM_2009/AAPS2009-002539.PDF] encapsulated bevacizumab within Poly(DL-lactide-co-glycolide) (PLGA) nanoparticles with an entrapment rate of 45%. The release of the entrapped bevacizumab from the nanoparticles could last 4 weeks. Pan et al. [17Pan CK, Durairaj C, Kompella UB. Comparison of long-acting bevacizumab formulations in the treatment of choroidal neovascularization in a rat model J Ocul Pharmacol Ther 2011; 27: 219-4.] also created long-lasting formulations (8 weeks) of bevacizumab through poly(ethylene glycol) (PEG) conjugation or encapsulation within PLGA nanoparticles. In this study, we encapsulated bevacizumab within particles of PLGA and poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA), and studied the profiles of drug release from these different polymers.

2. MATERIALS AND METHODS

2.1. Materials

Bevacizumab (25mg/ml, Avastin®, Genentech Inc) was purchased from the Ottawa Hospital Pharmacy (Ottawa, Canada). Poly (DL-lactide-co-glycolide) (50:50) (PLGA, Mw=17,000-22,000Da), PEG(1000)-b-PLA(5000) (PEGLA 15) and PEG(5000)-b-PLA(5000) (PEGLA55) were purchased from PolySciences Inc. (PA, USA).

2.2. Preparation of Bevacizumab-Loaded PLGA Nanoparticles (PLGA-A)

305.2mg PLGA was dissolved in 5ml of dichloro-methane. To this solution, 0.2ml of bevacizumab (25mg/ml) was added. The resulting mixture was sonicated for 30 seconds using a probe sonicator (Model VC50, Sonics & Materials Inc, Danbury, CT, USA). Then, the mixture was poured into 40ml of polyvinylpyrrolidone solution (2.5% w/v) and was sonicated for another 30 seconds. After evaporation of dichloromethane through stirring the mixture overnight in fume hood, nanoparticles were collected through centrifugation and washed with 25ml x 2 MiliQ water. Finally, nanoparticles were freeze-dried overnight, in 74% yield. Bevacizumab loading efficiency (LE) is 95.4% as determined by UV spectrometry based on the following equation:

LE= C/Co x 100%

where, C is the quantity of encapsulated bevacizumab - calculated by subtracting the quantity of bevacizumab in the supernatant and the washing solutions from the initial feeding quantity of bevacizumab, Co.

All other bevacizumab-loaded particles were prepared as described above. For size comparison, bevacizumab-loaded PLGA particles were also prepared by homogenization of the corresponding mixture using a homogenizer (ULTRA-TURRAX, IKA T10 Basic, IKA Works Inc, USA).

2.3. Bevacizumab Release Study

Between 30-50mg of bevacizumab-loaded particles were placed into centrifuge tubes, followed by addition of 1ml of 10mM phosphate buffered saline (PBS). The tubes were capped and maintained in a 37oC incubator. At certain intervals, the tubes were centrifuged and 0.5ml of the supernatant was removed followed by addition of an equal volume of fresh PBS. The concentration of bevacizumab in the supernatant was determined using a UV spectrophotometer (Beckman 640B) at 270nm against a calibration curve.

3. RESULTS

3.1. Bevacizumab-Loaded Nano- and Microparticles

For equivalent bevacizumab/PLGA ratios (1.6%), the particle size range obtained was dependent upon the method of preparation. PLGA spheres were both obtained but the particle sizes were heterogenous both when a probe sonicator was used (Fig. 1), and when a homogenizer was used (Fig. 2). Sonication resulted in particles with diameters mainly within the 0.2 to 1.0µm range. Particles prepared using a homogenizer, however, were more polydispersed, with the majority of particle diameters ranging from 0.5 to 3µm. When the loading of the drug was increased to bevacizumab/PLGA = 13%, the particles no longer showed shape uniformity, although some spheres were still present (Fig. 3). The particles fabricated from PEGLA15 appeared spherical and porous (Fig. 4), with the diameters of the particles ranging from 2 to 10µm. When PEGLA55 polymer was used, the diameter of particles was under 1µm, but the particles were no longer spherical (Fig. 5).

Fig. (1)

SEM image of bevacizumab-loaded PLGA nanoparticles (bevacizumab/PLGA= 1.6 %) prepared through sonication using probe sonicator.



Fig. (2)

SEM image of bevacizumab-loaded PLGA particles (bevacizumab/PLGA= 1.6 %) prepared through homogenization using homogenizer.



Fig. (3)

SEM image of bevacizumab-loaded PLGA nanoparticles (bevacizumab/PLGA= 13 %) prepared through sonication using probe sonicator.



Fig. (4)

SEM image of bevacizumab-loaded PEGLA15 particles (bevacizumab /PEGLA15=1.9%) prepared through sonication using probe sonicator.



Fig. (5)

SEM image of bevacizumab-loaded PEGLA55 particles (bevacizumab/PEGLA55= 2.0 %) prepared through sonication using probe sonicator.



Fig. (6)

Profile of bevacizumab release from PLGA nanoparticles (bevacizumab/PLGA=1.6%).



Fig. (7)

Profile of bevacizumab release from PLGA nanoparticles (bevacizumab/PLGA=13.0%).



Fig. (8)

Profile of bevacizumab release from PEGLA15 particles (bevacizumab/PLGA=1.9%).



Within our experimental range, the drug encapsulation (loading) efficiency was above 90% (Table 1) when PLGA and PEGLA15 polymers were used. The yield of the particles was greater than 70% with these two polymers. However, when PEGLA55 was used, the yield dropped to 24%.

Table 1

Drug Encapsulation (Load) Efficiency




3.2. Bevacizumab Release Profiles

For the particles with an initial bevacizumab/ PLGA=1.6% loading ratio (PLGA-A, Table 1), approximately 0.5mg of bevacizumab was relatively steadily released over 55 days (Fig. 6). Beyond this time until day 91, only an insignificant amount of release was detected. However, when the bevacizumab/PLGA ratio was increased to 13% (PLGA-HiA, Table 1), a steady release of 1.9mg of bevacizumab was observed throughout the experimental period of 91 days. There was a plateau in the release profile around 30 days for both of the release curves (Figs. 6, 7). Over the 91-day release period, we calculated that approximately 47% and 64% bevacizumab were released from particles with 1.6% and 13% drug loading respectively. Bevacizumab release from the PEGLA15 particles showed a similar plateau in the release profile (Fig. 8) as those in Figs. (6) and (7), but starting at about day 20. Approximately 62% of encapsulated bevacizumab was released from this system during the 91-day period.

4. DISCUSSION

PLGA is an FDA-approved biodegradable polymer, and has been extensively studied for its biocompatibility, toxicology and degradation kinetics [18Gopferich A, Langer R. Modeling monomer release from bioerodible polymers J Control Release 1995; 33: 55-69., 19Batycky RP, Hanes J, Langer R, Edwards DA. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres J Pharm Sci 1997; 86: 1464-77.]. It has been used clinically as a suture material since the 1970s [20Frazza EJ, Schmitt EE. A new absorbable suture J Biomed Mater Res 1971; 1: 43-58.] and it has been recently used as scaffolds in tissue engineering [21Hasirci V, Berthiaume F, Bondre SP. Expression of liver-specific functions by rat hepatocytes seeded in treated poly(lactic-co-glycolic) acid biodegradable foams Tissue Eng 2001; 7: 385-94.,22Ma PX, Choi JW. Biodegradable polymer scaffolds with well-defined interconnected spherical pore network Tissue Eng 2001; 7: 23-33.]. More importantly, the degradation rate of PLGA is in the range of months to years [23Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres Adv Drug Deliv Re 1997; 28: 5-24.]. This is dependent upon the ratio of lactide to glycolide units in the polymer [24Jain RA, Rhodes CT, Railkar AM, Malick AW, Shah NH. Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: Effect of various formulation variables Eur J Pharm Biopharm 2000; 50(2): 257-62.,25Duvvuri S, Janoria KG, Mitra AK. Development of a novel formulation containing poly(D,L-lactide-co-glycolide) microspheres dispersed in PLGA-PEG-PLGA gel for sustained delivery of ganciclovir J Control Release 2005; 108: 282-93.], which is favorable for regulating the release rate of encapsulated drugs. PLGA nanospheres or microspheres have been studied as vehicles for intravitreal delivery of various types of drugs such as dexamethasone acetate [26Xu J, Wang Y, Li Y. Inhibitory Efficacy of Intravitreal Dexamethasone Acetate-Loaded PLGA Nanoparticles on Choroidal Neovascularization in a Laser-Induced Rat Model J Ocul Pharmacol Ther 2007; 23(6): 527-39.], ganciclovir [27Duvvuri S, Janoria KG, Pal D, Mitra AK. Controlled delivery of ganciclovir to the retina with drug-loaded Poly(D,L-lactide-co-glycolide) (PLGA) microspheres dispersed in PLGA-PEG-PLGA gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis J Ocul Pharmacol Ther 2007; 23(3): 264-74.], 5-fluorouracil [28Moritera T, Ogura Y, Honda Y, Wada R, Hyon SH, Ikada Y. Microspheres of biodegradable polymers as a drug-delivery system in the vitreous Invest Ophthalmol Vis Sci 1991; 32: 1785-90.] and glial cell line-derived neurotrophic factor [29Jiang C , Moore MJ , Zhang X , Klassen H , Langer R , Young M . Intravitreal injections of GDNF-loaded biodegradable microspheres are neuroprotective in a rat model of glaucoma Mol Vis 2007; 13: 1783-92.], as well as for transscleral delivery of Macugen® (pegaptanib sodium), the first anti-VEGF inhibitor that was approved for wet AMD treatment [30Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic)acid microspheres Invest Ophthalmol Vis Sci 2003; 44(1): 290-9.]. These in vivo studies for treatment of various ocular diseases have reported no sign of retinal toxicity nor significant inflammatory responses for periods of up to 2 months [28Moritera T, Ogura Y, Honda Y, Wada R, Hyon SH, Ikada Y. Microspheres of biodegradable polymers as a drug-delivery system in the vitreous Invest Ophthalmol Vis Sci 1991; 32: 1785-90.,31Giordano GG, Chevez-Barrios P, Refojo MF, Garcia CA. Biodegradation and tissue reaction to intravitreous biodegradable poly(DL-lactic-co-glycolic)acid microspheres Curr Eye Res 1995; 14(9): 761-8.]. Therefore, in this work we selected PLGA for encapsulating bevacizumab to achieve sustained release of this drug.

We noted that with a higher loading of bevacizumab, the PLGA particles lost uniformity, this was most likely due to partial phase separation of PLGA polymer and bevacizumab. PEG-b-PLA has two polymer blocks. The PEG block is water-soluble and has anti-fouling properties. As a result, it is believed that the particles prepared from this polymer are long-circulating within the in vivo environment. Unlike PLGA, PEGLA15 is hydrophilic and retains water. Water could be removed via freeze-drying, which was why the particles from this polymer appeared porous after loss of absorbed water. The hydrophilicity of PEGLA15 also facilitated dispensing the particles compared to PLGA. The PEGLA55 polymer was even more hydrophilic than PEGLA15. This resulted in a lower yield of the particles as the majority of the polymer was dissolved in the water phase during particle preparation.

It is noted that the use of liposomes was reported for enhancing the in vivo residence of bevacizumab in animal model [15Abrishami M, Zarei-Ghanavati S, Soroush D, Rouhbakhsh M, Jaafari MR, Malaekeh-Nikouei B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration Retina 2009; 29(5): 699-703.]. However, the reported drug encapsulation efficiency was only about 45%. Hao et al. [16Hao Y, Patel A, Liu W, Krishna R, Sabates NR, Mitra AK. PPreparation and characterization of bevacizumab (avastin) nanoparticles for the treatment of age related macular degeneration American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, Los Angeles, California, USA. 2009 November; Available from http://www.aapsj.org/abstracts/AM_2009/AAPS2009-002539.PDF] also reported a similar drug encapsulation efficiency using ethyl acetate and phosphate buffer as oil and aqueous phases respectively. However, in our approach, more than 90% drug encapsulation efficiency was achieved via double emulsion methods using PLGA and PEGLA15 polymers.

The plateaus in the release profiles at around 30 days for both of the release curves as shown in Figs. (6) and (7), suggested that the release of the surface absorbed bevacizumab was completed after about 30 days of incubation of the particles. After that, the PLGA began degrading and released additional drug entrapped within the polymeric core [32Cao X, Schoichet MS. Delivering neuroactive molecules from biodegradable microspheres for application in central nervous system disorders Biomaterials 1999; 20(4): 329-9.].

5. CONCLUSION

Our results indicated that bevacizumab can be released from nano- and microparticles of PLGA and PEGLA in a sustained fashion for over 91 days. The release rate could be adjusted by altering the drug/polymer ratio. However, bevacizumab activity still needs to be tested in vivo using animal models. Nevertheless, these results may offer improvements for the treatment of wet AMD using bevacizumab and may also improve cancer treatment using the same carriers for sustained release of the drug.

ACKNOWLEDGEMENT

Declared none.

CONFLICT OF INTEREST

Declared none.

REFERENCES

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[2] Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study Ophthalmology 2006; 112: 1035-47.
[3] Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (avastin) in the treatment of proliferative diabetic retinopathy Ophthalmology 2006; 113 (10): 1695-705.
[4] Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration Retina 2006; 26: 383-90.
[5] Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir AA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration Ophthalmology 2006; 113: 363-72.
[6] Kernt M, Neubauer AS, Kampik A. Intravitreal bevacizumab (Avastin) treatment is safe in terms of intraocular and blood pressure Acta Opthalmol Scand 2007; 85(1): 119-20.
[7] Yenerel NM, Dinc UA, Gorgun E. A case of sterile endophthalmitis after repeated intravitreal bevacizumab injection J Ocul Pharmacol Ther 2008; 24(3): 362-.
[8] Beer PM, Wong SJ, Hammad AM, Falk NS, O'Malley MR. Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients Retina 2006; 26: 871-6.
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[15] Abrishami M, Zarei-Ghanavati S, Soroush D, Rouhbakhsh M, Jaafari MR, Malaekeh-Nikouei B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration Retina 2009; 29(5): 699-703.
[16] Hao Y, Patel A, Liu W, Krishna R, Sabates NR, Mitra AK. PPreparation and characterization of bevacizumab (avastin) nanoparticles for the treatment of age related macular degeneration American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, Los Angeles, California, USA. 2009 November; Available from http://www.aapsj.org/abstracts/AM_2009/AAPS2009-002539.PDF
[17] Pan CK, Durairaj C, Kompella UB. Comparison of long-acting bevacizumab formulations in the treatment of choroidal neovascularization in a rat model J Ocul Pharmacol Ther 2011; 27: 219-4.
[18] Gopferich A, Langer R. Modeling monomer release from bioerodible polymers J Control Release 1995; 33: 55-69.
[19] Batycky RP, Hanes J, Langer R, Edwards DA. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres J Pharm Sci 1997; 86: 1464-77.
[20] Frazza EJ, Schmitt EE. A new absorbable suture J Biomed Mater Res 1971; 1: 43-58.
[21] Hasirci V, Berthiaume F, Bondre SP. Expression of liver-specific functions by rat hepatocytes seeded in treated poly(lactic-co-glycolic) acid biodegradable foams Tissue Eng 2001; 7: 385-94.
[22] Ma PX, Choi JW. Biodegradable polymer scaffolds with well-defined interconnected spherical pore network Tissue Eng 2001; 7: 23-33.
[23] Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres Adv Drug Deliv Re 1997; 28: 5-24.
[24] Jain RA, Rhodes CT, Railkar AM, Malick AW, Shah NH. Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: Effect of various formulation variables Eur J Pharm Biopharm 2000; 50(2): 257-62.
[25] Duvvuri S, Janoria KG, Mitra AK. Development of a novel formulation containing poly(D,L-lactide-co-glycolide) microspheres dispersed in PLGA-PEG-PLGA gel for sustained delivery of ganciclovir J Control Release 2005; 108: 282-93.
[26] Xu J, Wang Y, Li Y. Inhibitory Efficacy of Intravitreal Dexamethasone Acetate-Loaded PLGA Nanoparticles on Choroidal Neovascularization in a Laser-Induced Rat Model J Ocul Pharmacol Ther 2007; 23(6): 527-39.
[27] Duvvuri S, Janoria KG, Pal D, Mitra AK. Controlled delivery of ganciclovir to the retina with drug-loaded Poly(D,L-lactide-co-glycolide) (PLGA) microspheres dispersed in PLGA-PEG-PLGA gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis J Ocul Pharmacol Ther 2007; 23(3): 264-74.
[28] Moritera T, Ogura Y, Honda Y, Wada R, Hyon SH, Ikada Y. Microspheres of biodegradable polymers as a drug-delivery system in the vitreous Invest Ophthalmol Vis Sci 1991; 32: 1785-90.
[29] Jiang C , Moore MJ , Zhang X , Klassen H , Langer R , Young M . Intravitreal injections of GDNF-loaded biodegradable microspheres are neuroprotective in a rat model of glaucoma Mol Vis 2007; 13: 1783-92.
[30] Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic)acid microspheres Invest Ophthalmol Vis Sci 2003; 44(1): 290-9.
[31] Giordano GG, Chevez-Barrios P, Refojo MF, Garcia CA. Biodegradation and tissue reaction to intravitreous biodegradable poly(DL-lactic-co-glycolic)acid microspheres Curr Eye Res 1995; 14(9): 761-8.
[32] Cao X, Schoichet MS. Delivering neuroactive molecules from biodegradable microspheres for application in central nervous system disorders Biomaterials 1999; 20(4): 329-9.

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"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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