Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application
Abstract
:1. Introduction
2. Mechanisms Underlying the Therapeutic Use of Ultrasound and Microbubbles
3. The Effect of Biological Barriers on the Pharmacokinetics of Ocular Drug Delivery
4. Ocular Pathologies That Could Benefit from Therapeutic Ultrasound and Microbubbles
4.1. Wet Age-Related Macular Degeneration
4.2. Glaucoma
4.3. Diabetic Retinopathy
4.4. Proliferative Vitreoretinopathy
4.5. Retinitis Pigmentosa
4.6. Retinoblastoma
4.7. Eyelid Malignant Melanoma
4.8. Corneal Opacity
Study Model | Delivered Compound | Microbubbles and In Vivo Administration Site | Ultrasound Parameters | Efficacy | Safety | Reference |
---|---|---|---|---|---|---|
In vivo, (rabbit) | Fluorescein | Definity®, intravenous | 2 MHz frequency, 0.2 and 1.7 MI, 5 min exposure time | Alteration in the diameter of uveal blood vessels observed in 20% and 80% of eyes treated al low and high MI, respectively. At high MI, vasoconstriction and extravasation of fluorescein were observed, and the mean number of altered segments in blood vessels was higher than at low MI. | No bleeding. | [79] |
In vivo, (rat) | Gd | Definity®, intravenous | 0.69 MHz frequency, 0.81, 0.88 and 1.10 MPa PNP (MI 0.98, 1.06, and 1.32, respectively), 60 s exposure time. | Immediate increase in Gd signal after treatment indicating BRB disruption. For the two lower pressures, Gd signal was lowered 3.5 h post-treatment, revealing reversibility of BRB disruption, but not at 1.10 MPa PNP. | Extravasated erythrocytes in the nuclear layers of the retina with more severe damage at 1.10 MPa. | [80] |
In vivo, (rat, mouse) | Evans blue, IgG, IgM | Definity®, intravenous | 1.1 MHz frequency, 0.36–0.84 MPa PNP (MI 0.34–0.80), 120 s exposure time. | Extravasation of Evans blue, IgG and IgM was observed in neural retina (INL and RGC) suggesting that the vascular plexi within these layers were permeabilized. No evidence for molecule transfer across the choroid and into the RPE. | Evidence for morphological damage, reactive gliosis, neuroinflammation and presence of erythroid cells. No megakaryocyte infiltration. | [81] |
In vitro (RPE, Müller glia, photoreceptors) | IgG | Custom-made NBs with shells made of DPPC/DSPE-PEG(2k)-Ome and PFP inner gaseous phase | 1 MHz frequency, 0.5 W/cm2 intensity, 30 s exposure time | Increase in the intracellular uptake of IgG after treatment with USNB was cell line-dependent. USNB efficacy is highly dependent on ultrasound intensity and exposure time. | N/A | [82] |
In vitro (RPE), in vivo (rat) | PEI/pEGFP | SonoVueTM, subretinal injection | 1 MHz frequency, 1–3 W/cm2 intensity, 1–5 min exposure time | In vitro: higher exposure time resulted in higher number of GFP-positive cells and decreased cell viability. In vivo: high density EGFP-positive cells were observed in animals treated with PEI/pEGFP + USMB, predominantly distributed in the retina. | No tissue damage. | [83] |
In vivo (rat) | pEGFP-N1 | SonoVueTM, subretinal injection | 1 MHz frequency, 2 W/cm2 intensity, 5 min exposure time | The highest EGFP-positive signal was observed in the PEI/pDNA + USMB group, distributed in neural retina and RPE cells. The same trend was observed in the quantification of EGFP gene copy number and the EGFP mRNA expression level in the RPE and neural retina. | No evidence for corneal and retinal tissue damage, no morphological alterations and no inflammatory cell infiltration. | [84] |
In vivo (rabbit) | pEGFP-N2 | Custom-made BL. Shells made by DSPC/DSPE-PEG (2k)-Ome, inner phase PFP gas. Intravitreal injection | 3 MHz frequency, 0.15 W/cm2 intensity, 60 s exposure time | Highest amount of GFP-score in the plasmid and USBL group. GFP-positive cells were colocalized with the areas exposed to ultrasound and were detected in the ONL. | No obvious tissue damage. | [85] |
In vitro (human retinal pigment epithelium cells), in vivo (rat) | rAAV-EGFP | SonoVueTM, subretinal injection | 1 MHz frequency, 0.5–2 W/cm2 intensity, 1–5 min exposure time | In vitro, combined treatment with USMB resulted in the highest transduction efficiency than treatment with ultrasound only. In vivo, quantification of EGFP signal revealed significantly elevated values for the USMB group on the first 35 days post-treatment. EGFP-positive cells USMB group were found in neural retina and RPE cells. | No evidence for tissue damage. | [86] |
In vitro (rat RPE cells), in vivo (rat) | rAAV2-EGFP | SonoVueTM, subretinal injection | 1 MHz frequency, 0.2–3 W/cm2 intensity, 15–300 s exposure time | Compared to the control group either ultrasound or microbubbles alone, but not their combination, increased rAAV-EGFP transduction of RPE-J cells in vitro. USMB-enhanced treatment resulted in a higher expression of EGFP in vivo. An increase in GFP-fluorescence was found until day 35 and reduced up to 120 days post-treatment. GFP signal was found in RPE and neural retina. | Adverse effects in cell viability in vitro observed at intensity of 3 W/cm2. In vivo, all retina cell layers were well preserved without photoreceptor loss or inflammation. | [87] |
In vivo (rat) | Lipofectamine-formulated fluorescently labelled-siRNA | SonoVueTM, intravitreal injection | 1 MHz frequency, 2 W/cm2 intensity, 300 s exposure time | The greatest quantity of transduced cells was observed in the group treated with lipofectamine-formulated siRNA combined with USMB. No fluorescence was detected in either the untreated or treated with naked siRNA + ultrasound groups. | No significant cell viability reduction observed 12 h after transfection. Retina cell layers were well preserved without photoreceptor loss, nuclear layer vacuolation, or inflammation. | [88] |
In vitro (human RPE cells) | rAAV-EGFP, PEI/pDNA and L/siRNA | SonoVueTM | 1 MHz frequency, 1–3 W/cm2 intensity, 60–120 s exposure time | Transfection efficiency of rAAV and PEI/pDNA vectors significantly improved when gene delivery was combined with USMB, in contrast to the L/siRNA efficiency that was benefited by ultrasound alone. Combined treatment with USMB did not cause structural alterations on the pDNA. | N/A | [89] |
In vitro (rat RPE cells) | Fluorescently labelled siRNA encapsulated in mPEG-PLGA-PLL nanoparticles | SonoVueTM | 1 MHz frequency, 0.5–2 W/cm2 intensity, 30–60 s exposure time | Highest nanoparticle uptake observed in cells treated with ultrasound alone. Combination with USMB did not improve the nanoparticle uptake. | At the settings with the highest nanoparticle uptake, a temperature increase of 1.9 °C was reported with no influence on cell viability. | [90] |
In vivo (rat) | Fluorescently labelled PDGF-BB siRNA encapsulated in mPEG-PLGA-PLL nanoparticles | SonoVueTM, intravitreal injection | 1 MHz frequency, 2 W/cm2 intensity, 5 min exposure time | The highest transfection efficiency in neural retina was achieved after combined treatment with USMB. | No evidence for tissue damage observed. All layers of the retina were well preserved without photoreceptor loss or inflammation. | [91] |
In vivo (rabbit, intraocular hypertension animal model) | mNGF | SonoVueTM, intravitreal | 1 MHz frequency, 0.5 W/cm2 ultrasound intensity, 60 s exposure time | Function of optic nerve myelin and axons was improved in the group that received mNGF + USMB. Retinas treated with mNGF + USMB had clear and orderly arranged cell layers. The thickness of the inner and outer plexiform layers was nearly normal. Rod and cone cells were normally aligned without degeneration, and RGC were normal in structure. | N/A | [100] |
In vitro (rat RGC) | pEGFP-N1 and bcl-xl | SonoVueTM | 0.3 MHz frequency, 0.25–1.25 W/cm2 intensity, 30–120 s exposure time | Improved transfection efficiency observed in pEGFP-N1 + USMB group. USMB-mediated bc1-xl transfection had a role in protection of RGCs from apoptosis, but not in complete apoptosis prevention. | N/A | [101] |
In vivo (rat) | rAAV2-EGFP | Custom-made lipid microbubbles (shell: DSPC, 1,2-DSPE, DSPA, inner gas: PFP), intravitreal injection | 0.3 MHz frequency, 0.5–2.5 W/cm2 intensity, 60 s exposure time | Greatest EGFP expression was observed in retinas treated with rAAV2-EGFP + USMB. The majority of GFP-positive cells were RGC. | No structural, morphological alterations, no cellular infiltration in the vitreal cavity. | [102] |
In vitro (rabbit cornea epithelial cells), in vivo (rat) | pEGFP-N2 | Custom-made BL. Shells made by DSPC/DSPE-PEG (2k)-Ome, inner gaseous phase PFP gas. Subconjunctival injection. | 1 MHz frequency, 0.8–1.2 W/cm2 intensity, 20–60 s exposure time | In vitro: The ratio of GFP-positive cells treated with USBL was about 2 times higher than the USMB group. No observed decrease in cell viability in any of the experimental groups. In vivo: GFP-positive cell density in eyes treated with USBL was significantly higher than the groups that received plasmid only, plasmid + ultrasound and plasmid + USMB. GFP-positive cells were mostly located beneath the conjunctival epithelium of the area exposed to ultrasound. No significant number of GFP-positive cells was observed in any other part of the eye. | The structure of conjunctiva was well preserved. No signs of hemorrhage, edema or inflammation. | [103] |
In vitro (human retinal vascular endothelial cells) | ES-GFP | NMB: DPPC/DSPE-PEG2000 and cationic microbubbles CMB: DPPC/DSPE-PEG2000-Biotin/DC-Chol, containing PFP gas | 1 MHz frequency, 1 W/cm2 intensity, 1 min exposure time | CMBs had higher plasmid binding compared with NMBs. In cells treated with CMBs, the level of VEGF, Bcl-2, and Bcl-xl mRNA was decreased. | N/A | [111] |
In vivo (rat) | pCMV-Gluc-1, pVAX1-LacZ, pEGFP-C1 | Artison, intra-muscle injection (ciliary muscle) | 1 MHz frequency, 0.7 MPa PNP, 120 s exposure time | One week after treatment, the group treated with pCMV-Gluc-1 plasmid + USMB had the greatest expression of luciferase. Enhanced expression of β-galactosidase in the ciliary muscle cells and sporadically around the ciliary body was observed microscopically. Similar enhancement and localization site of GFP protein observed in the pEGFP-C1 + USMB group. | No apoptotic cells detected in the conjunctiva, retina or cornea. A temperature increase of 3.7 °C in the lens and 7.3 °C in the ciliary muscle measured during ultrasound exposure. Normal temperature was immediately recovered. No alterations in the transparency of the lens for up to a month post-treatment. | [112] |
In vivo (rat, proliferative vitreoretinopathy disease model) | rAAV2-TGF-β2-siRNA and rAAV2-PDGF-B-siRNA | SonoVueTM, intravitreal injection | 1 MHz frequency, 300 s exposure time | In the group treated with siRNAs + USMB, retinal morphologic alterations progressed slower than control groups. The numbers of effector cells, such as RPE cells, glial cells, fibroblasts and macrophages, and the incidence of retinal detachment, and proliferative membrane formation were significantly less than the eyes treated without USMB. | N/A | [119] |
In vitro (human RB cells) | Doxorubicin | Artison | 1 MHz frequency, 0.3–10 W/cm2 intensity, 10 s exposure time | No significant differences in cell viability observed 24 h post-treatment between cells treated with doxorubicin alone and doxorubicin + USMB. Viability of cells exposed to doxorubicin + USMB was significantly lower compared with cells exposed to doxorubicin alone 48 and 72 h, but not 24 h post-treatment. | N/A | [133] |
In vitro (mouse melanoma cells), in vivo (mouse) | Bleomycin | OptisonTM, intratumoral injection | 1 MHz frequency, 1–2 W/cm2 intensity, 60–240 s exposure time | Combination of bleomycin and USMB in vitro resulted in a significant decrease in cell viability at all concentrations tested. In vivo, in the bleomycin + USMB group, for drug concentrations of 0.06 mg/mL, 0.25 mg/mL and 0.5 mg/mL, tumors initially increased in weight but later had a continuous decrease until day 8. Tumors treated with 0.125 mg/mL bleomycin + USMB responded immediately after the 1st treatment with a continuous reduction in size. No reduction in size was observed in the group treated with bleomycin alone. | In vivo, temperature inside the tumor increased from 34 to 37 °C. The temperature of ultrasound probe changed in similar manner. No histological abnormalities were seen in the brain, lung, liver and heart. | [137] |
In vitro, (rabbit corneal epithelial cells), in vivo (rabbit) | pEGFP-N2 | OptisonTM, intracorneal | 1 MHz frequency, 0.5–2 W/cm2 intensity, 15–120 s exposure time | In vitro: The greatest amount of GFP-positive cells ratio was significantly greater in samples treated with USMB. In vivo: The eyes that received plasmid + USMB showed the highest number of GFP-positive cells. GFP-positive cells appeared one day after treatment. Fluorescence intensity increased the first 8 days, significantly decreased on day 14, and was not measurable on day 30 after treatment. GFP was mainly located inside the corneal stroma. | Immediate corneal stroma haziness appeared at intensity >3 W/cm2, which spontaneously resolved immediately after treatment. No corneal damage, such as opacity or persistent epithelial defects, was observed. | [147] |
5. Safety and Tolerability of USMB in Ocular Therapeutic Applications
6. Future Directions
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AMD | age-related macular degeneration |
BBB | blood–brain barrier |
BLs | bubble liposomes |
BRB | blood–retina barrier |
CEUS | contrast-enhanced ultrasound |
CMB | cationic microbubbles |
DPPC | 1,2-dipalmitoyl-sn-glycero-3-phosphocholine |
DSPA | 1,2-distearoyl-snglycero-phosphoacid |
DSPC | 1,2-distearoyl-sn-glycero-phosphatidylcholine |
DSPE-PEG(2k)-OMe | 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] |
DR | diabetic retinopathy |
EGFP | enhanced green fluorescent protein |
ES | endostatin |
FDA | Food and Drug Administration |
F-VEP | flash visual evoked potential |
Gd | gadolinium |
GFAP | glial fibrillary acidic protein |
GFP | green fluorescence protein |
H&E | hematoxylin and eosin |
iBRB | inner blood–retina barrier |
IgG | immunoglobulin G |
IgM | immunoglobulin M |
ILM | inner limiting membrane |
INL | inner nuclear layer |
IOP | intraocular pressure |
L/siRNA | lipofectamine-formulated siRNA |
MFI | mean fluorescence intensity |
MI | mechanical index |
mNGF | mouse neuron growth factor |
mRNA | messenger RNA |
mPEG-PLGA-PLL | monomethoxypoly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly L-lysine |
MW | molecular weight |
NMB | neutral microbubbles |
NBs | nanobubbles |
oBRB | outer blood–retina barrier |
OLM | outer limiting membrane |
ONL | outer nuclear layer |
PDGF | platelet-derived growth factor |
pDNA | plasmid DNA |
pEGFP | plasmid enhanced green fluorescence protein |
PEI | polyethylenimine |
PFP | perfluoropropane |
PNP | peak-negative pressure |
PVR | proliferative vitreoretinopathy |
rAAV | recombinant adeno-associated virus |
RB | retinoblastoma |
RGC | retinal ganglion cells |
RP | retinitis pigmentosa |
RPE | retina pigment epithelium |
siRNA | small interfering RNA |
TGF-β2 | transforming growth factor-β2 |
UBM | ultrasound biomicroscopy |
USMB | ultrasound and microbubbles |
USNB | ultrasound and nanobubbles |
USBL | ultrasound and bubble liposomes |
VEGF | vascular endothelial growth factor |
WFUMB | World Federation of Ultrasound in Medicine and Biology |
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Rousou, C.; Schuurmans, C.C.L.; Urtti, A.; Mastrobattista, E.; Storm, G.; Moonen, C.; Kaarniranta, K.; Deckers, R. Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application. Pharmaceutics 2021, 13, 1782. https://doi.org/10.3390/pharmaceutics13111782
Rousou C, Schuurmans CCL, Urtti A, Mastrobattista E, Storm G, Moonen C, Kaarniranta K, Deckers R. Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application. Pharmaceutics. 2021; 13(11):1782. https://doi.org/10.3390/pharmaceutics13111782
Chicago/Turabian StyleRousou, Charis, Carl C. L. Schuurmans, Arto Urtti, Enrico Mastrobattista, Gert Storm, Chrit Moonen, Kai Kaarniranta, and Roel Deckers. 2021. "Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application" Pharmaceutics 13, no. 11: 1782. https://doi.org/10.3390/pharmaceutics13111782