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Theranostics 2023; 13(7):2241-2255. doi:10.7150/thno.78426 This issue Cite

Research Paper

Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy

Shivakumar K Reddy1, Abhijna R Ballal1, S Shailaja2, Raviraja N Seetharam3, Chandrashekar H Raghu4, Runali Sankhe5, Kanthilatha Pai6, Tenzin Tender4, Mary Mathew6, Annayya Aroor7, Ashok K Shetty8, Shalini Adiga9, Vasudha Devi9, Manjunatha S Muttigi3, Dinesh Upadhya1✉

1. Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India.
2. Department of Ophthalmology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India.
3. Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, 576104, India.
4. Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
5. Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
6. Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India.
7. Divison of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65211, USA.
8. Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, United States.
9. Department of Pharmacology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India.

✉ Corresponding author: Dr. Dinesh Upadhya, Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India. Email: dinesh.upadhyaedu; Phone: +91 820 2923611; Total word coun More

Citation:
Reddy SK, Ballal AR, Shailaja S, Seetharam RN, Raghu CH, Sankhe R, Pai K, Tender T, Mathew M, Aroor A, Shetty AK, Adiga S, Devi V, Muttigi MS, Upadhya D. Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy. Theranostics 2023; 13(7):2241-2255. doi:10.7150/thno.78426. https://www.thno.org/v13p2241.htm
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Abstract

Graphic abstract

Diabetic retinopathy (DR) is associated with retinal neovascularization, hard exudates, inflammation, oxidative stress and cell death, leading to vision loss. Anti-vascular endothelial growth factor (Anti-VEGF) therapy through repeated intravitreal injections is an established treatment for reducing VEGF levels in the retina for inhibiting neovascularization and leakage of hard exudates to prevent vision loss. Although anti-VEGF therapy has several clinical benefits, its monthly injection potentially causes devastating ocular complications, including trauma, intraocular hemorrhage, retinal detachment, endophthalmitis, etc.

Methods: As mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) demonstrated safety in clinical studies, we have tested the efficacy of MSC-derived small EVs (MSC-sEVs) loaded anti-VEGF drug bevacizumab in a rat model of DR.

Results: The study identified a clinically significant finding that sEV loaded with bevacizumab reduces the frequency of intravitreal injection required for treating diabetic retinopathy. The sustained effect is observed from the reduced levels of VEGF, exudates and leukostasis for more than two months following intravitreal injection of sEV loaded with bevacizumab, while bevacizumab alone could maintain reduced levels for about one month. Furthermore, retinal cell death was consistently lower in this period than only bevacizumab.

Conclusion: This study provided significant evidence for the prolonged benefits of sEVs as a drug delivery system. Also, EV-mediated drug delivery systems could be considered for clinical application of retinal diseases as they maintain vitreous clarity in the light path due to their composition being similar to cells.

Keywords: Diabetic retinopathy, extracellular vesicles, bevacizumab, intravitreal injection, neovascularization.

Citation styles

APA
Reddy, S.K., Ballal, A.R., Shailaja, S., Seetharam, R.N., Raghu, C.H., Sankhe, R., Pai, K., Tender, T., Mathew, M., Aroor, A., Shetty, A.K., Adiga, S., Devi, V., Muttigi, M.S., Upadhya, D. (2023). Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy. Theranostics, 13(7), 2241-2255. https://doi.org/10.7150/thno.78426.

ACS
Reddy, S.K.; Ballal, A.R.; Shailaja, S.; Seetharam, R.N.; Raghu, C.H.; Sankhe, R.; Pai, K.; Tender, T.; Mathew, M.; Aroor, A.; Shetty, A.K.; Adiga, S.; Devi, V.; Muttigi, M.S.; Upadhya, D. Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy. Theranostics 2023, 13 (7), 2241-2255. DOI: 10.7150/thno.78426.

NLM
Reddy SK, Ballal AR, Shailaja S, Seetharam RN, Raghu CH, Sankhe R, Pai K, Tender T, Mathew M, Aroor A, Shetty AK, Adiga S, Devi V, Muttigi MS, Upadhya D. Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy. Theranostics 2023; 13(7):2241-2255. doi:10.7150/thno.78426. https://www.thno.org/v13p2241.htm

CSE
Reddy SK, Ballal AR, Shailaja S, Seetharam RN, Raghu CH, Sankhe R, Pai K, Tender T, Mathew M, Aroor A, Shetty AK, Adiga S, Devi V, Muttigi MS, Upadhya D. 2023. Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy. Theranostics. 13(7):2241-2255.

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