Vitreous: A Barrier to Nonviral Ocular Gene Therapy
Open accessAbstract
PURPOSE: Intravitreal injection of therapeutic DNA, complexed to nonviral carriers such as cationic liposomes, may be promising in the treatment of many severe retinal eye diseases. However, after intravitreal injection, such DNA/cationic liposome complexes-called lipoplexes (LPXs)-which are typically hundreds of nanometers in size, must first diffuse through the vitreous before they can reach the retina. The aim of this study was to elucidate whether vitreous is a barrier for the LPXs and to find strategies to overcome this barrier. METHODS: Fluorescent polystyrene nanospheres and LPXs were mixed with vitreous, and their mobility was monitored by fluorescence recovery after photobleaching (FRAP), a microscopy-based technique. The stability of LPXs and naked plasmid DNA in vitreous was studied by gel electrophoresis. RESULTS: We showed that polystyrene nanospheres, in our first experiments used as a model for the LPXs, do not diffuse freely into the vitreous but adhere to fibrillar structures in the vitreous, most likely to collagen fibers. Making the surfaces of the polystyrene nanospheres hydrophilic by attaching hydrophilic polyethylene glycol (PEG) chains at their surfaces circumvented the binding to fibrillar structures in the vitreous. FRAP revealed that "pegylated" polystyrene nanospheres, as long as they are smaller than 500 nm, are indeed mobile in the vitreous. It was further demonstrated that LPXs severely aggregate in vitreous and strongly bind to biopolymers in the vitreous, which immobilizes them completely. However, as observed for the polystyrene nanospheres, coating of the LPXs with PEG averted their aggregation in the vitreous and their binding to fibrillar structures. CONCLUSIONS: Modifying the surfaces of LPXs with hydrophilic PEG chains prevents them from aggregating in vitreous. In this way, LPXs are obtained that can freely move in vitreous, an absolute criterion for reaching the retina after intravitreal injection.
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Strategies such as PEGylation, charge modification, and coating with hyaluronate or chloroquine have been shown to improve retinal transduction in animal models when administered intravitreally.
“Strategies such as PEGylation [271], charge modification [272], and coating with hyaluronate or chloroquine [273,274] have been shown to improve retinal transduction in animal models when administered intravitreally.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [271]
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“Liposomes however also present some limitations such as retinal toxicity and aggregation following administration [208].”
BackgroundMicrocapsules Ejecting Nanosized Species into the Environment
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Self-citationHyaluronan as a promising excipient for ocular drug delivery
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A review of therapeutic prospects of non-viral gene therapy in the retinal pigment epithelium
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“successful [44,45], however, results from topical treatment (for example for corneal conditions) has been more positive [46].”
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“4 Soon after, Peeters et al. found that the vitreous permits free mobility to PEGylated particles smaller than 500 nm. 5 Later, single-particle tracking technology allowed the measurement of the di ff usion coe ffi cients of nanoparticles in intact vitreous.”
Edaravone-loaded liposomes for retinal protection against oxidative stress-induced retinal damage
Hironaka, K., Inokuchi, Y., Fujisawa, T., Shimazaki, H., Akane, M., Tozuka, Y., Tsuruma, K., Shimazawa, M., Hara, H., & Takeuchi, H. (2011) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2011.01.019 · Cited by 63 · see citing works
Drug delivery to retinal photoreceptors
Himawan, E., Ekström, P. A. R., Buzgo, M., Gaillard, P. J., Stefánsson, E., Marigo, V., Loftsson, Þ., & Paquet‐Durand, F. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2019.03.004 · Cited by 62 · see citing works
Suprachoroidal Injection: A Novel Approach for Targeted Drug Delivery
Wu, K. Y., Fujioka, J. K., Gholamian, T., Zaharia, M., & Tran, S. D. (2023) · Pharmaceuticals · doi:10.3390/ph16091241 · Cited by 64 · see citing works
“aggregation and immobilization of DNA/liposome complexes [56,57].”
Sanders, N. N., Peeters, L., Lentacker, I., Demeester, J., & Smedt, S. C. D. (2007) · Journal of Controlled Release · doi:10.1016/j.jconrel.2007.05.004 · Cited by 62 · see citing works
Self-citationPhotoablation of Human Vitreous Opacities by Light-Induced Vapor Nanobubbles
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Alterations in Mucus Barrier Function and Matrix Structure Induced by Guluronate Oligomers
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“In contrast, polyethylene glycol (PEG)ylated nanoparticles, with no electrostatic charge, diffused more rapidly [63].”
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“The vitreous, a transparent gel composed of collagen fibrils filled up with hyaluronic acid, may hamper the mobility of carriers preventing them to reach the retina (Peeters et al., 2005; Le Goff & Bishop, 2008; Da Costa et al., 2016).”
BackgroundInfluentialPreventing Obstructions of Nanosized Drug Delivery Systems by the Extracellular Matrix
Tomasetti, L., & Breunig, M. (2017) · Advanced Healthcare Materials · doi:10.1002/adhm.201700739 · Cited by 58 · see citing works
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“Consequently, to enhance such interaction, protamine was incorporated in lipid formulations such as SLNs [135] or liposomes [136] but not in niosomes for retinal gene delivery.”
BackgroundProgress on ocular siRNA gene‐silencing therapy and drug delivery systems
Jiang, J., Zhang, X., Tang, Y., Li, S., & Chen, J. (2020) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12561 · Cited by 56 · see citing works
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“…the anionic system to be within physiological range (eukaryotic cell membrane zeta potentials range usually within -15 to -30 mV (Alqawlaq et al., 2014; Giannaccini et al., 2014; Koo et al., 2012; Liu et al., 2011; Peeters et al., 2005)) and for the cationic system a relatively low zeta potential.”
BackgroundInfluentialNon-viral therapeutic approaches to ocular diseases: An overview and future directions
Zulliger, R., Conley, S. M., & Naash, M. I. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.10.007 · Cited by 50 · see citing works
“It has been shown that polystyrene nanospheres are completely immobilized in the vitreous humor and DNA-compacting lipoplexes aggregate immediately upon contact with the vitreal meshwork (91).”
BackgroundPost-pegylated lipoplexes are promising vehicles for gene delivery in RPE cells
Peeters, L., Sanders, N. N., Jones, A. T., Demeester, J., & Smedt, S. C. D. (2007) · Journal of Controlled Release · doi:10.1016/j.jconrel.2007.05.033 · Cited by 50 · see citing works
Self-citationGene therapy in retinal diseases: A review
Dhurandhar, D., Sahoo, N. K., Mariappan, I., & Narayanan, R. (2021) · Indian Journal of Ophthalmology · doi:10.4103/ijo.ijo_3117_20 · Cited by 50 · see citing works
“[30] Liposomes ten to aggregate, and hence, increase the chances of retinal toxicity.[31] Due to these unresolved issues of the nonviral vectors, they do not appear to be promising for therapeutic use in retinal dystrophies.”
BackgroundBraeckmans, K., Buyens, K., Naeye, B., Vercauteren, D., Deschout, H. G., Raemdonck, K., Remaut, K., Sanders, N. N., Demeester, J., & Smedt, S. C. D. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.08.029 · Cited by 47 · see citing works
Self-citationPanatieri, L. F., Brazil, N. T., Faber, K., Medeiros-Neves, B., von Poser, G. L., Rott, M. B., Zorzi, G. K., & Teixeira, H. F. (2016) · AAPS PharmSciTech · doi:10.1208/s12249-016-0550-y · Cited by 47 · see citing works
Lee, J., Goh, U., Lee, H. J., Kim, J., Jeong, M., & Park, J. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00864 · Cited by 47 · see citing works
Lau, C. M. L., Yu, Y., Jahanmir, G., & Chau, Y. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.03.013 · Cited by 46 · see citing works
Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44 · see citing works
“It is unclear whether this adverse event is related to class effects of complement inhibition or PEGylation, as discussed in Section 7.4, or other clinical factors such as the presence and activity of macular neovascularisation in the fellow eye of study participants.”
BackgroundInfluentialShen, Y., Sun, J., & Sun, X. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-01838-x · Cited by 45 · see citing works
Gene delivery to the retina: focus on non-viral approaches
Naik, R. J., Mukhopadhyay, A., & Ganguli, M. (2008) · Drug Discovery Today · doi:10.1016/j.drudis.2008.09.012 · Cited by 45 · see citing works
FRAP in Pharmaceutical Research: Practical Guidelines and Applications in Drug Delivery
Deschout, H. G., Raemdonck, K., Demeester, J., Smedt, S. C. D., & Braeckmans, K. (2013) · Pharmaceutical Research · doi:10.1007/s11095-013-1146-9 · Cited by 45 · see citing works
“In the context of gene therapy, FRAP has been used to measure the diffusion of polystyrene nanospheres and complexes of plasmid DNA and liposomes in the vitreous of bovine eyes (84).”
Self-citationZhang, H., Rombouts, K., Raes, L., Xiong, R., Smedt, S. C. D., Braeckmans, K., & Remaut, K. (2020) · Advanced Biosystems · doi:10.1002/adbi.202000057 · Cited by 44 · see citing works
Self-citationNonviral ocular gene therapy: assessment and future directions.
Conley, S. M., Cai, X., & Naash, M. I. (2008) · PubMed · Cited by 44 · see citing works
Missel, P. J., Horner, M., & Muralikrishnan, R. (2010) · Pharmaceutical Research · doi:10.1007/s11095-010-0163-1 · Cited by 42 · see citing works
“This approach will not hold for very large molecules or for microparticles, as eventually the vitreous gel will exhibit diffusive resistance and slow the diffusivity compared to that in pure water (36).”
BackgroundPolymeric Vectors for Ocular Gene Delivery
Tamboli, V., Mishra, G. P., & Mitra, A. K. (2011) · Therapeutic Delivery · doi:10.4155/tde.11.20 · Cited by 42 · see citing works
Pharmaceutical microscale and nanoscale approaches for efficient treatment of ocular diseases
Bravo‐Osuna, I., Andrés‐Guerrero, V., Abal, P. P., Molina-Martínez, I. T., & Herrero‐Vanrell, R. (2016) · Drug Delivery and Translational Research · doi:10.1007/s13346-016-0336-5 · Cited by 41 · see citing works
“showed a decreased surface charge in comparison to nonPEGylated lipoplexes and an increased transport to the retinal pigment epithelium [102].”
Du, J., Shi, Q. S., Sun, Y., Liu, P., Zhu, M., Du, L. F., & Duan, Y. R. (2011) · The Journal of Gene Medicine · doi:10.1002/jgm.1574 · Cited by 41 · see citing works
“However, previous studies have shown that pegylation can avoid the aggregation of the vectors in the vitreous, which also keeps them mobile in the vitreous [41,42].”
BackgroundNon‐viral retinal gene therapy: a review
Issa, P. C., & MacLaren, R. E. (2011) · Clinical and Experimental Ophthalmology · doi:10.1111/j.1442-9071.2011.02649.x · Cited by 40 · see citing works
“However, ineffective gene delivery via the intravitreal route has been explained to be due to aggregation and adherence of, for example, lipoplexes to fibrillar structures in the vitreous.(45) Adherence to vitreal structures could be prevented by attaching hydrophilic polyethylene glycol chains to the lipoplexes(45,46…”
BackgroundEfficacy of topotecan nanoparticles for intravitreal chemotherapy of retinoblastoma
Delrish, E., Jabbarvand, M., Ghassemi, F., Amoli, F. A., Atyabi, F., Lashay, A., Soleimani, M., Aghajanpour, L., & Dinarvand, R. (2021) · Experimental Eye Research · doi:10.1016/j.exer.2020.108423 · Cited by 40 · see citing works
Zagato, E., Forier, K., Martens, T., Neyts, K., Demeester, J., Smedt, S. C. D., Remaut, K., & Braeckmans, K. (2014) · Nanomedicine · doi:10.2217/nnm.14.43 · Cited by 39 · see citing works
Self-citationNano and microtechnologies for ophthalmic administration, an overview
Herrero‐Vanrell, R., Vicario‐de‐la‐Torre, M., Andrés‐Guerrero, V., Barbosa-Alfaro, D., Molina-Martínez, I. T., & Bravo‐Osuna, I. (2013) · Journal of Drug Delivery Science and Technology · doi:10.1016/s1773-2247(13)50016-5 · Cited by 39 · see citing works
Toward the practical implementation of eye-related bioavailability prediction models
Pepić, I., Lovrić, J., Cetina‐Čižmek, B., Reichl, S., & Filipović‐Grčić, J. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.08.002 · Cited by 38 · see citing works
Huang, X., & Chau, Y. (2019) · Experimental Eye Research · doi:10.1016/j.exer.2019.107711 · Cited by 37 · see citing works
Retinal Dystrophies and the Road to Treatment: Clinical Requirements and Considerations
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“However, as of yet, they have not shown promising potential for safe gene delivery, due to, for example, lack of persistent transgene expression (naked DNA and nanoparticles), or the potential for retinal toxicity (liposomes).(247,248) Although gene replacement or supplementation should be sufficient in autosomal rece…”
BackgroundGene therapy for ocular diseases meditated by ultrasound and microbubbles (Review)
WAN, C., LI, F., & LI, H. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4054 · Cited by 36 · see citing works
“The negatively charged GAGs present in the vitreous humour may bind to the gene complexes, and gene materials may therefore become stuck to the gel-like materials in the vitreous humour (25).”
Rafael, D. F. D. S., Guerrero, M., Maricán, A., Arango, D., Sarmento, B. F. C. C., Ferrer, R., Durán‐Lara, E. F., Clark, S. J., & Schwartz, S. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15051484 · Cited by 37 · see citing works
“%) and water (99%), with a mesh size of about 500 nm [66,93,94].”
BackgroundMartens, T., Peynshaert, K., Nascimento, T. L., Fattal, E., Karlstetter, M., Langmann, T., Picaud, S. A., Demeester, J., Smedt, S. C. D., Remaut, K., et al. (2017) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2017.02.027 · Cited by 36 · see citing works
Self-citationOptical Fluorescence Microscopy
Diaspro, A. (2010) · Springer eBooks · doi:10.1007/978-3-642-15175-0 · Cited by 55 · see citing works
Non-viral siRNA delivery into the mouse retina in vivo
Turchinovich, A. A., Zoidl, G., & Dermietzel, R. (2010) · BMC Ophthalmology · doi:10.1186/1471-2415-10-25 · Cited by 35 · see citing works
“Additionally, negatively charged sugars of the vitreous have been shown to interact with positive DNA-transfection reagent complexes promoting their aggregation, impeding diffusion and cellular uptake [5,6].”
RES‐loaded pegylated CS NPs: for efficient ocular delivery
Pandian, S. K., Jeevanesan, V., Ponnusamy, C., & Natesan, S. (2016) · IET Nanobiotechnology · doi:10.1049/iet-nbt.2016.0069 · Cited by 35 · see citing works
- Authors
- Peeters, L., Sanders, N. N., Braeckmans, K., Boussery, K., Van de Voorde, J., De Smedt, S. C., & Demeester, J.
- Affiliations
- From the Laboratory of General Biochemistry and Physical Pharmacy and the
- Ghent University (BE)
- Department of Physiology and Pathophysiology, Ghent University, Ghent, Belgium.
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2005-10-01
- Volume
- 46
- Issue
- 10
- Pages
- 3553
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- OpenAlex
- W1964002661
- Cited by
- 189
- References
- 40
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 8 · 2023: 15 · 2022: 15 · 2021: 12 · 2020: 13 · 2019: 11 · 2018: 5 · 2017: 10 · 2016: 11 · 2015: 10 · 2014: 11 · 2013: 13 · 2012: 5
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Universiteit Gent
- Vlaamse regering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- vitreous humor, non-viral gene therapy, intravitreal injection, lipoplexes, cationic liposomes, ocular gene delivery, retinal gene therapy, diffusion barrier, PEGylation, nanoparticle aggregation, collagen fibrils, polystyrene nanospheres, FRAP
- MeSH terms
- Animals, Cattle, Dextrans, DNA, Electrophoresis, Agar Gel, Hyaluronic Acid, Microspheres, Polyethylene Glycols, Polystyrenes, Vitreous Body, Genetic Therapy, Fluorescein-5-isothiocyanate, Gene Transfer Techniques, Lipid Metabolism
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