TW202320887A - Radionuclide brachytherapy source systems for ocular radiotherapy of chronic serous chorioretinopathy - Google Patents

Abstract

Radionuclide brachytherapy sources (RBS) for applying radiation to a target area, for example for treating chronic serous chorioretinopathy (CSCR). The RBSs provided herein are useful for decreasing vascular permeability while minimizing adverse effects associated with radiotherapy, thereby providing advantages over existing brachytherapy sources.

Description

Radionuclide brachytherapy radiation source system for ocular radiation therapy of chronic serous chorioretinopathy (CHORIORETINOPATHY)

Related applications

This application claims the benefit of U.S. Provisional Application No. 63/273,593, filed October 29, 2021, the description of which is incorporated herein by reference in its entirety. field of invention

The present invention relates to the field of radiation therapy, and more particularly to the subfield of brachytherapy, and to radionuclear brachytherapy for the treatment of ocular conditions, such as the treatment of chronic serous chorioretinopathy (CSCR) Radiation source (radionuclide brachytherapy source, RBS).

Background of the invention Background of the Invention on Central Serous Chorioretinopathy

Central serous chorioretinopathy (CSCR) is a condition affecting the eye that causes visual disturbances that are usually unilateral in one eye, but can be bilateral in up to 40% of cases. CSCR often causes blurred or distorted vision, for example, metamorphopsia. Patients may also report poor vision (objects appear smaller than they really are) and/or color vision disturbances. Temporary farsightedness is usually present. CSCR can also cause blurred or gray dots in the central visual field, which usually occur with retinal detachment. Vision loss may resolve after resolution of CSCR, or may persist after fluid accumulation associated with CSCR dissipates and CSCR resolves.

CSCR is generally considered to be of unknown etiology and primarily affects Caucasian males between the ages of 20 and 50. It is believed that CSCR is associated with exogenous corticosteroid use. In addition, CSCR is also thought to be associated with psychological stress, which in turn is associated with increased endogenous Cortisol levels. In addition, other conditions associated with increased endogenous cortisol production, such as Cushing syndrome and pregnancy, are also associated with an increased risk of CSCR. Cortisol is an endogenous glucocorticoid corticosteroid produced by the adrenal cortex, more specifically the fascicularis. Therefore, it is believed that there is a general correlation between increased levels of corticosteroids (whether from exogenous or endogenous sources) and the development of CSCR. Pathophysiology of central serous chorioretinopathy

CSCR is characterized by fluid accumulation beneath the retina. Specifically, fluid tends to accumulate under the macula, an oval-shaped area surrounding the fovea, a small depression in the retina where cones are particularly concentrated and where visual acuity is highest. The source of this fluid is usually the hyperpermeable large blood vessels of the choroid, such as the large choroidal vessels. Serous fluid leaking from the choroid accumulates beneath the retina, causing a minor, localized detachment of the neurosensory layer of the macula (part of the retina), with or without concomitant retinal pigment epithelium (RPE) detachment, eg With or without pigment epithelial detachment (pigment epithelial detachment, PED). Detachment of the neurosensory layer results in acute or chronic symptoms of metamorphopsia and other visual changes associated with CSCR.

The choroid is the vascular layer of the eye, located between the retina (the deepest part of the choroid) and the sclera (the superficial part of the choroid). The choroid provides blood flow to most of the retina. The choroid is divided into four layers. From the most superficial (farthest from the retina) to the deepest (closest to the retina), the layers are: Haller's layer, Sattler's layer, choriocapillary layer, and Bruch's membrane (Bruch's membrane) membrane). The Haller's layer is the outermost (most superficial) layer of the choroid and contains the largest choroidal vessels. Sattler's stratum is as deep as Haller's stratum and contains medium-sized choroidal vessels. The choriocapillary layer is as deep as Sadtler's layer and contains capillaries, such as small blood vessels. Bruch's membrane is the innermost (eg, deepest) layer of the choroid, contains small blood vessels, and contains the basement membrane of the choroid capillary layer (at its outermost side) and the retinal pigment epithelium (at its innermost side).

The primary disease process involved in CSCR is serous fluid leakage from the large choroidal vessels with subsequent submacular fluid accumulation and resulting detachment of the neurosensory layer of the macula with or without PED. However, the pathophysiology of CSCR is multifactorial. Inflammation of the choroid leads to vascular stasis, hyperosmolarity, and choroidal thickening. Thus, the characteristic intermediate elements of CSCR pathology are choroidal hyperpermeability and choroidal thickening. This then results in increased tissue pressure on the RPE, which leads to damage to the RPE and possibly PED. Damage to the RPE reduces its effectiveness as a barrier, and choroidal fluid can thus pass through the RPE, causing detachment of the neurosensory layer.

In addition, it was hypothesized that CSCR could lead to a loss of polarity of the RPE. In a healthy eye, the RPE pumps fluid from the subretinal space into the choroid, keeping the retina relatively "dry". However, if there is a loss of polarity, the RPE can reverse its pumping direction, pumping fluid from the choroid into the subretinal space. This can lead to accumulation of fluid under the retina. Furthermore, attenuation and hypoperfusion of the choriocapillary layer can lead to increased hydrostatic pressure and to decreased resorption by the capillaries of the choriocapillary layer. Also, this can contribute to subretinal fluid accumulation.

It is believed that the mineralocorticoid receptor may also play a role, although its potential role is currently unknown. Experimental results demonstrate that intravitreal aldosterone injection causes choroidal vein dilation and choroidal hyperemia, which leads to subretinal fluid accumulation. Prior Art Therapy for Central Serous Chorioretinopathy

CSCR resolves spontaneously and restores normal vision in most cases, however, recurrent retinal detachment is common. Because symptoms usually resolve spontaneously, most clinicians observe patients for three to six months while attempting to correct for any predisposing factors (eg, tapering and stopping exogenous steroids, reducing patient stress, etc.). CSCR may be classified as chronic CSCR if CSCR and associated symptoms persist for more than three to six months, or if disengagement recurs. Chronic CSCR causes permanent pathophysiological changes such as foveal atrophy and retinal pigment epithelial changes. Chronic cases can lead to permanent vision loss if left untreated. Therefore, the treatment of chronic CSCR is targeted. The most widely used prior art treatments with the highest level of evidence are laser photocoagulation and photodynamic therapy (PDT). laser photocoagulation

Laser photocoagulation uses a laser to emit light that is absorbed by the target tissue, raising the temperature of the tissue and causing subsequent denaturation of proteins. Leaky sites on the retinal pigment epithelium were visualized angiographically and indicated by hyperfluorescent sites, and these sites were then targeted with lasers. The leak is thus sealed, which reduces the time for subretinal fluid to be cleared. However, laser photocoagulation has several disadvantages. If the RPE detachment involves the fovea, laser photocoagulation is not an option because permanent vision loss can result if the laser is used on the fovea. Laser photocoagulation has not been demonstrated to reduce the chance of CSCR recurrence. Laser photocoagulation results in the destruction of surrounding healthy retinal tissue and can thus lead to the appearance of blind spots (spots of complete or partial blindness in otherwise normal visual field). Laser photocoagulation can also lead to choroidal neovascularization and further vision loss, especially if Bruch's membrane is damaged by the laser. Due to the potential development of these adverse effects, frequent ophthalmic follow-up of patients undergoing laser photocoagulation is required. Laser photocoagulation is considered an outdated treatment by many clinicians. photodynamic therapy

Photodynamic therapy (PDT) is another option for treating CSCR. PDT is particularly preferred over laser photocoagulation in the presence of a leak on or near the fovea, in the presence of multiple leaks, and in cases of diffuse RPE decompensation. Verteporfin (photosensitizer) is given intravenously. Verteporfin reaches the eye via the bloodstream and is activated by light at a wavelength of 689 nm, generating short-lived reactive oxygen species and causing localized damage and blockage of blood vessels in the area targeted by the light source. PDT thus seals the source of choroidal leak and causes choroidal vascular remodeling and choroidal hypoperfusion, further reducing choroidal hyperpermeability. PDT is generally considered more effective and safer than laser photocoagulation. Low-flux or half-flux PDT, or low-dose or half-dose PDT (using low- or half-dose verteporfin) has been found to be as effective as standard-flux or standard-dose PDT with a more favorable adverse effect profile. However, PDT still has deficiencies, such as the need to minimize UV exposure and photosensitivity after treatment. Standard-flux PDT is also associated with significant damage to the choriocapillary layer, although reduced-flux PDT has reduced the incidence of this complication. other treatments

Other treatments for CSCR have been tested with mixed results. Due to the potential role of mineralocorticoids in the development of CSCR, the use of eplerenone, a mineralocorticoid antagonist, has been explored. Eplerenone was found not to be superior to placebo in chronic CSCR (Lotery, A et al. (2020) Lancet 395(10220), 294-303). Other attempts to use anti-corticosteroid therapy have included finasteride (a 5α-reductase inhibitor with antiandrogenic properties), mifepristone (an antiprogesterone abortion drug), and diazepam. Forin (rifampin, an anti-tuberculosis antibiotic that accelerates the metabolism of corticosteroids in the liver by acting as a potent inducer of CYP3A4 (the main enzyme responsible for steroid breakdown)). However, studies on these agents are generally small, results are often inconclusive, and none of these agents are currently considered standard of care. The same was true for tested anti-adrenergic agents such as the selective beta-blocker metoprolol. Anti-VEGF therapy, including intravitreal injection of anti-VEGF agents such as bevacizumab, has shown lack of benefit in CSCR. The rationale for the use of anti-VEGF agents in CSCR has been widely questioned because there is no known overexpression of VEGF in CSCR and CSCR is generally not associated with angiogenesis or neovascularization. Thus, it is generally believed that the pharmacological rationale for the use of anti-VEGF in CSCR is lacking. Consequently, conflicting evidence or a general lack of clear efficacy limits the treatment of most CSCR to either laser photocoagulation (a more limited treatment approach considered obsolete by some clinicians) or PDT (which is often superior to laser photocoagulation). condensation).

Summary of the invention

The object of the present invention is to provide a device and a composition allowing to irradiate the choroidal target in the eye, as specified in the scope of the independent application. Embodiments of the invention are given in the appended claims. If the embodiments of the invention are not mutually exclusive, they can be freely combined with each other.

The present invention is useful for treating chronic serous chorioretinopathy (CSCR). For example, the invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of the eye, wherein the RBS is present in a cannula of a delivery device, the method comprising inserting the cannula Into the potential space below the Tenon's capsule of the eye, whereby the RBS is positioned over the choroidal target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the choroidal target, wherein the radiotherapy portion of the RBS is in the process Medium consumption.

Without wishing to limit the invention to any theory or mechanism, the therapeutic dose is generally selected to result in increased proliferation of the intima of the large choroidal vessels with concomitant damage to the vessels of the choroidal capillary layer and other radiation-sensitive structures of the eye such as the lens minimized.

In some embodiments, the therapeutic dose is 6 to 18 Gy. In some embodiments, the therapeutic dose is 6 to 8 Gy. In some embodiments, the therapeutic dose is 6 to 10 Gy. In some embodiments, the therapeutic dose is 6 to 12 Gy. In some embodiments, the therapeutic dose is 6 to 16 Gy. In some embodiments, the therapeutic dose is 8 to 10 Gy. In some embodiments, the therapeutic dose is 8 to 12 Gy. In some embodiments, the therapeutic dose is 8 to 16 Gy. In some embodiments, the therapeutic dose is 8 to 18 Gy. In some embodiments, the therapeutic dose is 10 to 12 Gy. In some embodiments, the therapeutic dose is 10 to 14 Gy. In some embodiments, the therapeutic dose is 10 to 18 Gy. In some embodiments, the therapeutic dose is 12 to 16 Gy. In some embodiments, the therapeutic dose is 12 to 18 Gy. In some embodiments, the therapeutic dose is 14 to 18 Gy.

The therapeutic dose is delivered to a particular depth or range of depths, eg, as measured from the interface of the sclera with the delivery device. For example, in some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 12 Gy.

As disclosed herein, the RBS is configured to deliver a therapeutic dose to a target, such as a target tissue. Target tissue may refer to a volume or region of tissue having a depth and a width or diameter. For example, a target is defined as occupying between 0.5 mm and 2.0 mm of the interface of the sclera and the delivery device (or between 0.75 mm and 2.0 mm of the interface of the sclera and the delivery device, or between 0.5 mm and 1.5 mm, or between between 0.5 mm and 1.25 mm, or between 1.0 mm and 2.0 mm, etc.) Referring to the aforementioned methods, in some embodiments, the RBS is configured such that a portion of the target tissue located at a depth of 0.5 mm (eg, as measured from the interface of the sclera and the delivery device) receives a therapeutic dose of 10 to 18 Gy. In some embodiments, the RBS is configured such that a portion of the target tissue located at a depth of 0.5 mm (eg, as measured from the interface of the sclera and the delivery device) receives a therapeutic dose of 12 to 18 Gy. In some embodiments, the RBS is configured such that a portion of the target tissue located at a depth of 1 mm (eg, as measured from the interface of the sclera and the delivery device) receives a therapeutic dose of 8 to 14 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1 mm receives a therapeutic dose of 10 to 14 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1 mm receives a therapeutic dose of 11 to 13 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1 mm receives a therapeutic dose of 12 to 13 Gy. In some embodiments, the RBS is configured such that the target tissue portion located at a depth of 1.25 mm receives a therapeutic dose of 6 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion located at a depth of 1.25 mm receives a therapeutic dose of 8 to 11 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1.25 mm receives a therapeutic dose of 9 to 11 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1.5 mm receives a therapeutic dose of 6 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1.5 mm receives a therapeutic dose of 6 to 11 Gy. In some embodiments, the RBS is configured such that the target tissue portion located at a depth of 1.5 mm receives a therapeutic dose of 8 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 2.0 mm receives a therapeutic dose of 6 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 2.0 mm receives a therapeutic dose of 6 to 10 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 2.0 mm receives a therapeutic dose of 6 to 8 Gy.

In some embodiments, the therapeutic dose is calculated based on the thickness of the choroidal target. In some embodiments, the thickness of the choroidal target is measured using imaging.

In some embodiments, the retina is exposed to less than 8 Gy. In some embodiments, the choriocapillary layer is exposed to less than 10 Gy. In some embodiments, the interface of the large choroidal vessels and the choriocapillary layer is exposed to less than 12 Gy. In some embodiments, the retina is exposed to less radiation than the choroidal target. In some embodiments, the choriocapillary layer is exposed to less radiation than the choroidal target.

As will be described herein, in some embodiments, the therapeutic dose is fractionated in multiple stages. For example, therapeutic doses can be graded in at least two stages.

The dose is delivered to the choroidal target over a period of time such as the dwell time. In some embodiments, the dwell time is from 5 seconds to 10 minutes. In some embodiments, the dwell time is from 5 seconds to 15 seconds. In some embodiments, the residence time is from 5 seconds to 30 seconds. In some embodiments, the dwell time is from 5 seconds to 45 seconds. In some embodiments, the dwell time is from 5 seconds to 1 minute. In some embodiments, the dwell time is from 5 seconds to 2 minutes. In some embodiments, the dwell time is from 15 seconds to 30 seconds. In some embodiments, the dwell time is from 15 seconds to 1 minute. In some embodiments, the dwell time is from 15 seconds to 90 seconds. In some embodiments, the dwell time is from 15 seconds to 2 minutes. In some embodiments, the dwell time is from 30 seconds to 1 minute. In some embodiments, the residence time is from 1 minute to 90 seconds. In some embodiments, the residence time is from 1 minute to 2 minutes. In some embodiments, the dwell time is from 90 seconds to 2 minutes. In some embodiments, the residence time is 2 to 4 minutes. In some embodiments, the residence time is 4 to 6 minutes. In some embodiments, the residence time is 6 to 8 minutes. In some embodiments, the residence time is 8 to 10 minutes. In some embodiments, the residence time is 5 to 10 minutes. In some embodiments, the residence time is greater than 10 minutes.

In some embodiments, the RBS delivers radiation to, for example, an irradiated area having a diameter. In some embodiments, the diameter of the illuminated area is at most 6 millimeters. In some embodiments, the diameter of the illuminated area is at most 8 millimeters. In some embodiments, the diameter of the illuminated area is at most 10 millimeters. In some embodiments, the diameter of the illuminated area is at most 12 millimeters. In some embodiments, the diameter of the illuminated area is 3 to 5 mm. The invention is not limited to the aforementioned diameters.

In some embodiments, the RBS delivers radiation to the treatment area, wherein the treatment area is at most 8 millimeters in diameter. In some embodiments, the RBS is a source of particle radiation. In some embodiments, the RBS is a source of ionizing radiation. In some embodiments, the RBS is a beta radiation source. In some embodiments, the RBS is a source of X-ray radiation. In some embodiments, RBSs are multiple types of radiation sources.

In some embodiments, the RBS is contained within the cannula. In some embodiments, the cannula is part of the delivery device. In some embodiments, the delivery device comprises: a cannula comprising a curved distal portion adapted to be placed around a portion of the eyeball; The inflection points of the direction change symbols are connected to each other; and the proximal part of the straight line. In some embodiments, the distal portion has a radius of curvature between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and the proximal portion has a radius between about 25 mm and 35 mm; a radius of curvature between the inner cross-sectional radius and about 1 meter; and an angle θ between a line ℓ ₃ tangent to the distal portion and the curved proximal portion at the point of inflection and the straight proximal portion is greater than about ₀ degrees to about 180 degrees. The present invention is not limited to the aforementioned delivery devices or cannulas.

The invention features a method of reducing hyperpermeability of large choroidal vessels in the eye of a patient with central serous chorioretinopathy in need thereof. In some embodiments, the method comprises inserting a cannula into the potential space below the Tenon's capsule of the patient's eye, the cannula having a radionuclide brachytherapy source (RBS) at the treatment site, whereby the RBS is positioned at above the choroidal target, and wherein a therapeutic dose of radiation is delivered to the choroidal target.

The invention features a method of increasing collagen deposition associated with large choroidal vessels in the eye of a patient with central serous chorioretinopathy in need thereof. In some embodiments, the method comprises inserting a cannula into the potential space below the Tenon's capsule of the patient's eye, the cannula having a radionuclide brachytherapy source (RBS) at the treatment site, whereby the RBS is positioned at above the choroidal target, and wherein a therapeutic dose of radiation is delivered to the choroidal target.

The invention features a method of treating central serous chorioretinopathy in a patient in need thereof. In some embodiments, the method comprises inserting a cannula into the potential space below the Tenon's capsule of the patient's eye, the cannula having a radionuclide brachytherapy source (RBS) at the treatment site, whereby the RBS is positioned at above the choroidal target, and wherein a therapeutic dose of radiation is delivered to the choroidal target.

Referring to the aforementioned methods, in some embodiments, the therapeutic dose is 6 to 18 Gy. In some embodiments, the therapeutic dose is 6 to 8 Gy. In some embodiments, the therapeutic dose is 6 to 10 Gy. In some embodiments, the therapeutic dose is 6 to 12 Gy. In some embodiments, the therapeutic dose is 6 to 16 Gy. In some embodiments, the therapeutic dose is 8 to 10 Gy. In some embodiments, the therapeutic dose is 8 to 12 Gy. In some embodiments, the therapeutic dose is 8 to 16 Gy. In some embodiments, the therapeutic dose is 8 to 18 Gy. In some embodiments, the therapeutic dose is 10 to 12 Gy. In some embodiments, the therapeutic dose is 10 to 14 Gy. In some embodiments, the therapeutic dose is 10 to 18 Gy. In some embodiments, the therapeutic dose is 12 to 16 Gy. In some embodiments, the therapeutic dose is 12 to 18 Gy. In some embodiments, the therapeutic dose is 14 to 18 Gy.

Referring to the aforementioned methods, in some embodiments, the RBS is configured such that a portion of the target tissue located at a depth of 0.5 mm (eg, as measured from the interface of the sclera and the delivery device) receives a therapeutic dose of 10 to 18 Gy. In some embodiments, the RBS is configured such that a portion of the target tissue located at a depth of 0.5 mm (eg, as measured from the interface of the sclera and the delivery device) receives a therapeutic dose of 12 to 18 Gy. In some embodiments, the RBS is configured such that a portion of the target tissue located at a depth of 1 mm (eg, as measured from the interface of the sclera and the delivery device) receives a therapeutic dose of 8 to 14 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1 mm receives a therapeutic dose of 10 to 14 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1 mm receives a therapeutic dose of 11 to 13 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1 mm receives a therapeutic dose of 12 to 13 Gy. In some embodiments, the RBS is configured such that the target tissue portion located at a depth of 1.25 mm receives a therapeutic dose of 6 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion located at a depth of 1.25 mm receives a therapeutic dose of 8 to 11 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1.25 mm receives a therapeutic dose of 9 to 11 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1.5 mm receives a therapeutic dose of 6 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 1.5 mm receives a therapeutic dose of 6 to 11 Gy. In some embodiments, the RBS is configured such that the target tissue portion located at a depth of 1.5 mm receives a therapeutic dose of 8 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 2.0 mm receives a therapeutic dose of 6 to 12 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 2.0 mm receives a therapeutic dose of 6 to 10 Gy. In some embodiments, the RBS is configured such that the target tissue portion at a depth of 2.0 mm receives a therapeutic dose of 6 to 8 Gy.

In some embodiments, the retina is exposed to less than 8 Gy. In some embodiments, the choriocapillary layer is exposed to less than 10 Gy.

In some embodiments, the interface of the large choroidal vessels and the choriocapillary layer is exposed to less than 12 Gy. In some embodiments, the retina is exposed to less radiation than the choroidal target. In some embodiments, the choriocapillary layer is exposed to less radiation than the choroidal target.

As will be described herein, in some embodiments, the therapeutic dose is fractionated in multiple stages. For example, therapeutic doses can be graded in at least two stages.

The dose is delivered to the choroidal target over a period of time such as the dwell time. In some embodiments, the dwell time is from 5 seconds to 10 minutes. In some embodiments, the dwell time is from 5 seconds to 15 seconds. In some embodiments, the residence time is from 5 seconds to 30 seconds. In some embodiments, the dwell time is from 5 seconds to 45 seconds. In some embodiments, the dwell time is from 5 seconds to 1 minute. In some embodiments, the dwell time is from 5 seconds to 2 minutes. In some embodiments, the dwell time is from 15 seconds to 30 seconds. In some embodiments, the dwell time is from 15 seconds to 1 minute. In some embodiments, the dwell time is from 15 seconds to 90 seconds. In some embodiments, the dwell time is from 15 seconds to 2 minutes. In some embodiments, the dwell time is from 30 seconds to 1 minute. In some embodiments, the residence time is from 1 minute to 90 seconds. In some embodiments, the residence time is from 1 minute to 2 minutes. In some embodiments, the dwell time is from 90 seconds to 2 minutes. In some embodiments, the residence time is 2 to 4 minutes. In some embodiments, the residence time is 4 to 6 minutes. In some embodiments, the residence time is 6 to 8 minutes. In some embodiments, the residence time is 8 to 10 minutes. In some embodiments, the residence time is 5 to 10 minutes. In some embodiments, the residence time is greater than 10 minutes.

In some embodiments, the RBS delivers radiation to the treatment area, wherein the treatment area is at most 8 millimeters in diameter. In some embodiments, the RBS is a source of particle radiation. In some embodiments, the RBS is a source of ionizing radiation. In some embodiments, the RBS is a beta radiation source. In some embodiments, the RBS is a source of X-ray radiation. In some embodiments, RBSs are multiple types of radiation sources.

In some embodiments, the RBS is contained within the cannula. In some embodiments, the cannula is part of the delivery device. In some embodiments, the delivery device comprises: a cannula comprising a curved distal portion adapted to be placed around a portion of the eyeball; The inflection points of the direction change symbols are connected to each other; and the proximal part of the straight line. In some embodiments, the distal portion has a radius of curvature between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and the proximal portion has a radius between about 25 mm and 35 mm; a radius of curvature between the inner cross-sectional radius and about 1 meter; and an angle θ between a line ℓ ₃ tangent to the distal portion and the curved proximal portion at the point of inflection and the straight proximal portion is greater than about ₀ degrees to about 180 degrees. The present invention is not limited to the aforementioned delivery devices or cannulas.

In some embodiments, the dose delivered is such that radiation retinopathy is avoided. In some embodiments, the dose delivered is such that radiation-induced choroidopathy is avoided. In some embodiments, the dose delivered is such that radiation maculopathy is avoided. In some embodiments, the dose delivered is such that radiation neuropathy is avoided. In some embodiments, the dose delivered is such that cataracts are avoided. In some embodiments, the dose delivered is such that choroidal neovascularization is avoided.

One of the unique and inventive technical features of the present invention is the ability to deliver a therapeutically effective dose to the choroidal target while avoiding or minimizing damage to other structures of the eye, such as the retina and choriocapillary layer. Without wishing to limit the present invention to any theory or mechanism, it is believed that the technical features of the present invention advantageously provide therapeutic efficacy while avoiding or minimizing adverse effects of treatment, for example, radiation retinopathy, radiation choroidopathy, Radiation maculopathy, radiation neuropathy, cataract and/or choroidal neovascularization. None of the prior references or works are presently known to possess the unique inventive features of this invention.

The present invention represents an unexpected advance in the field of brachytherapy. As will be described herein, previous use of brachytherapy, and radiation therapy more generally, has moved away from the use of brachytherapy to treat CSCR as embodied in the present invention.

Radiation therapy (and brachytherapy, which is a subfield of radiation therapy) is generally believed to increase vascular permeability, rather than decrease it. Thus, the fact that the present invention reduces vascular permeability through the use of radiation is an unexpected result. Radiation has been taught for decades to increase vascular permeability: "Studies in the 1940s and 1950s suggested that multiple mechanisms are responsible for the increased permeability of the endothelial barrier following radiation exposure." (Bouten et al., (2021 ) Tissue Barriers in Disease, Injury and Regeneration (pp. 43-94). Elsevier). Furthermore, radiation exposure has been taught by prior art to "destabilize the endothelial barrier, increase vascular permeability, and alter vesicle migration." (Bouten et al., 2021). These effects of radiation have been observed both in vivo in "various animal models" and in vitro. (Bouten et al., 2021). Radiation has been taught to increase "capillary permeability" in a localized fashion in an in vivo rabbit model. (Bouten et al., 2021).

Furthermore, this phenomenon has previously been recognized for multiple types of radiation at multiple intensities, exposures or dose levels. "A comparison of different types of radiation shows that the effects of radiation on blood vessels respond consistently to the effects of different energies in the direction of increasing vascular permeability." (Bouten et al., 2021).

Furthermore, even at relatively low levels of radiation exposure, a relationship between radiation exposure and increased vascular permeability has been reported. "Several studies have shown an immediate increase in vascular permeability following irradiation as low as 2 Gy" (Lee, C. G. et al., (2021), Journal of Radiation Research, 62(5), 856-860). Thus, the fact that even though the low and controlled radiation dose delivered by the present invention does not increase vascular permeability, it actually decreases vascular permeability is surprising. In other words, the present invention's use of radiation, even at low doses, to reduce vascular permeability is an unexpected and unexpected result not taught by the prior art. Indeed, the prior art teaches away from using even low doses of radiation to reduce vascular permeability because the prior art teaches that even low doses of radiation increase vascular permeability. In contrast, the present invention surprisingly produces a reduction in vascular permeability through the use of low and well-controlled radiation doses.

Recent studies have elucidated the molecular mechanisms behind the general tendency of radiation to increase vascular permeability. "A common finding of radiation in vitro studies of endothelial barriers is the reduction in the level of proteins required for endothelial cell-cell contact." (Bouten et al., 2021) "Our results suggest a mechanism for the irradiation-induced increase in permeability. ...is dominated by activation of ADAM10 and subsequent alteration of endothelial permeability via degradation and internalization of VE-cadherin.” (Kouam, P. N. et al., (2019). BMC Cancer, 19(1) , 958). Furthermore, studies have confirmed that even as low as 5 Gy of gamma or photon-based radiation induces a decrease in PECAM-1, an endothelial cell adhesion molecule essential for endothelial cell-cell adhesion. (Bouten et al., 2021) Other studies have found "an immediate increase in vascular permeability following irradiation at doses as low as 2 Gy." (Lee et al., 2021).

Human blood vessels have been found to exhibit increased permeability following exposure of the endothelial cell layer to ionizing radiation. Furthermore, this relationship has been found to hold for macromolecules of different sizes, and to be true in a dose-dependent manner. This has been associated with reduced amounts of two junction proteins, one of which is VE-cadherin. VE-cadherin is cleaved by ADAM10 in a radiation dose-dependent manner, which appears to be mediated at least in part by intracellular calcium release. Inhibition of ADAM10 rescues radiation-induced permeability (Kabacik, S. et al., (2017). Oncotarget, 8(47), 82049-82063).

Other studies have identified "at least two mechanisms" responsible for "radiation-induced endothelial cell permeability," which are "(1) modulation of cell-cell contact protein levels and (2) increased contractility of endothelial cells )” (Bouten et al., 2021). Other mechanisms of radiation-induced permeability changes can be attributed to changes in non-paracellular pathways, including changes in the following: permeation-dominant passive transporters (such as reduced expression of aquaporin 1), tissue fibrinolytic Zymogen activator (which converts plasminogen to plasmin, which then breaks down blood clots) and vascular cell adhesion protein 1 (VCAM1, a protein involved in leukocyte extravasation). Generally, these changes constitute changes in gene expression, which often involve "reduced adhesion and altered molecular transport." (Bouten et al., 2021)

Clinical use of coronary brachytherapy directly teaches away from the use of brachytherapy as used in the present invention. Coronary brachytherapy, used in conjunction with coronary angioplasty, works on the principle that, in simple terms, delivering radiation to a blood vessel will prevent thickening of the vessel wall.

Atherosclerosis is the formation of fatty plaques in the lumen of arteries, which reduces the area of the lumen, inhibiting blood flow and oxygen delivery to tissues (Nath, R et al., Phys., 26: 119-152). Plaque formation culminates in smooth muscle cell proliferation with concomitant collagen and elastin proliferation. In turn, fibrous plaques begin to form, which contain lipids, necrotic cells, and collagen. These lesions calcify, causing platelet aggregation, decreased blood flow, and thrombosis, which can cause myocardial ischemia or myocardial infarction, especially if located in the heart. (Nath, R. et al., (1999))

Percutaneous transvascular angioplasty ("angioplasty") is a procedure intended to disrupt these plaques, thereby restoring blood flow and preventing myocardial ischemia and/or myocardial infarction. The primary goal of angioplasty is to re-establish a stable lumen with a diameter similar to that of a normal, healthy artery. Angioplasty is a practice well known in the art that can be accomplished using a variety of devices and techniques. Described in detail herein as an exemplary form of angioplasty is balloon angioplasty. The catheter over a guide wire is introduced into an artery (typically the femoral or brachial artery) and advanced with the aid of imaging to the target artery, usually the coronary artery. An angioplasty device, such as a balloon angioplasty device, is then inserted and guided via the guidewire to the target lesion to be treated. An angioplasty device, such as a balloon angioplasty device, is then used to treat the target lesion by, for example, inflating the balloon within the lumen of the artery. Use of the device (eg, inflation of the balloon) is intended to increase the diameter of the artery and break up plaque in the target lesion. Physical inflation of the balloon ruptures the plaque and stretches (and often ruptures) the tissue of the vessel lumen, typically the inner elastic layer. Tissue fissures may extend into the medial layer of blood vessels. (Nath, R. et al., (1999))

Restenosis (eg, restenosis) of blood vessels is a common and therapeutically undesirable occurrence following angioplasty procedures. Restenosis is believed to involve three independent mechanisms: early recoil, neovascular intimal hyperplasia, and late constriction. Early recoil is simply the elastic recoil that occurs after overstretching of the artery due to the stretch produced by the angioplasty procedure itself (e.g., as by intraluminal angioplasty balloon) caused by inflation). Intimal proliferation is the result of new tissue growth that fills the gaps in the vessel wall created by the stretch trauma of the angioplasty procedure. Typically, this tissue proliferation can occur to the point of severe reocclusion of the blood vessel. Late contraction is similar to wound contraction and is sometimes called remodeling. It basically involves the healing tissue becoming contracted so that the periphery of the vessel after surgery is smaller than it was before surgery.

Intimal hyperplasia, a secondary mechanism of restenosis, is particularly problematic, with excessive neovascular intimal hyperplasia leading to clinically symptomatic restenosis within three to six months in approximately 40% of patients. (Nath, R. et al., (1999))

Therefore, there is a strong need to minimize intimal hyperplasia following angioplasty. This is the main goal of coronary brachytherapy. Following angioplasty, a radioactive source (usually a beta or gamma emitter) is introduced into the blood vessel and used to irradiate the treatment site. (Nath, R. et al., (1999)) Studies, both in clinical and animal models, have demonstrated that coronary brachytherapy reduces neovascular intimal hyperplasia after angioplasty. (Nath, R. et al., (1999)) The findings in "Intracoronary irradiation can reduce vascular smooth muscle proliferation and neovascular intima proliferation after balloon overstretch surgery, thereby preventing or reducing in-stent restenosis" derived from the hypothesis. (Ohri, N. et al., (2015). Advances in radiation oncology, 1(1), 4-9). Indeed, studies in a porcine model found that "intracoronary radiation primarily inhibited the first wave of cell proliferation in the vessel wall and showed a beneficial effect on later remodeling by preventing adventitial fibrosis at the site of injury." (Waksman, R. et al., (1997). Circulation, 96(6), 1944-1952).

In contrast, the present invention uses radiation to increase the proliferation of certain cells in the walls of blood vessels, thereby reducing the permeability of those blood vessels. This is in contrast to prior art, which taught that radiation, even at low doses, reduces cell proliferation, including by reducing cell proliferation in vessel walls (eg, including by reducing intimal hyperplasia).

Contrary to this established understanding of the effect of radiation on cell proliferation, the present invention utilizes radiation to increase cell proliferation of cells in the walls of choroidal vessels, thereby reducing the permeability of these vessels. The choroidal vessels in patients with chronic serous chorioretinopathy are thereby rendered impermeable, reducing the amount of fluid they leak. Thus, less fluid accumulates under the retina, which addresses the underlying pathophysiological etiology of CSCR, thereby treating CSCR by arresting the disease process that leads to CSCR.

Without wishing to limit the present invention to any theory or mechanism, it is believed that the present invention has advantages over previous methods in that it increases intimal proliferation of large choroidal vessels while minimizing damage to small vessels, especially the choriocapillary layer. Other approaches have been shown to cause damage to smaller, more delicate vessels, perhaps most importantly those of the choriocapillary layer. Attenuation of the choriocapillary layer is generally an intrinsic part of the pathophysiological process of CSCR. Thus, while there is always a need to avoid unnecessary damage to the choriocapillary layer, it is especially important to do so in CSCR, considering that the choriocapillary layer is often damaged by the disease state itself.

Smaller blood vessels are generally more sensitive to radiation than larger blood vessels. For example, Amoaku et al. studied the effect of brachytherapy on the structure of choroidal vessels in the treatment of choroidal melanoma and found that the vessels that had undergone radiation-induced atrophy were first those of the choriocapillary layer. (Amoaku, W. M. K. et al., (1995). Eye, 9(6), 738-744). Initial changes are concentrated in smaller vessels, with larger vessels undergoing changes later. Since the treatment of CSCR may involve reducing the permeability of the large choroidal vessels without occluding the small vessels of the choriocapillary layer, radiation therapy previously known in the art would present challenges if used for the treatment of CSCR.

However, the present invention solves this problem by allowing radiation therapy to be delivered to the eye, resulting in increased intimal proliferation of large choroidal vessels, thereby reducing their permeability, while minimizing damage to smaller vessels of the choriocapillary layer or to the retina. to minimum. In some embodiments, this is achieved in part by delivering appropriate doses. In some embodiments, the therapeutic dose is 6 to 18 Gy. As will be described herein, the invention is not limited to 6 to 18 Gy. Without wishing to limit the present invention to any theory or mechanism, it is believed that doses within these ranges result in increased proliferation of the intima of the large choroidal vessels, while at the same time deactivating the blood vessels of the choriocapillary layer and other radiation sensitive structures of the eye such as lens) damage is minimized.

In some embodiments, the invention features the use of specialized delivery devices such as, but not limited to, those described in: U.S. Patent Application No. 10/836,140; U.S. Patent Application No. 12/350,079; U.S. Patent Application No. 12/497,644; U.S. Patent Application No. 13/111,765; U.S. Patent Application No. 13/111,780; U.S. Patent Application No. 13/742,823; 13/872,941; U.S. Patent Application No. 13/953,528; U.S. Patent Application No. 14/011,516; U.S. Patent Application No. 14/486,401; U.S. Patent Application No. 14/687,784; 15/871,756; U.S. Patent Application No. 15/023,196; U.S. Patent Application No. 15/004,538; U.S. Patent Application No. 15/628,952; U.S. Patent Application No. 16/015,892; 16/009,646; U.S. Design Application No. 29/332,021; U.S. Design Application No. 29/332,028; U.S. Design Application No. 29/332,032; U.S. Design Application No. 29/332,040; 29/368,499; U.S. Design Application No. 29/368,501; U.S. Design Application No. 29/391,557; U.S. Design Application No. 29/391,558; U.S. Design Application No. 29/391,559; 29/391,561; U.S. Design Application No. 29/564,244; U.S. Design Application No. 29/564,247; U.S. Design Application No. 29/564,249; U.S. Design Application No. 29/576,148; 29/576,159; PCT Application No. PCT/US2009/030343; PCT Application No. PCT/US2010/54958; PCT Application No. PCT/US2014/56135; PCT Application No. PCT/US2016/68391, which The specification is hereby incorporated by reference in its entirety. Use of specialized devices can allow accurate and appropriate dose delivery to well-defined target areas of the eye. In some embodiments, the present invention may minimize the risk associated with any one or more of the following adverse effects associated with radiation therapy: radiation retinopathy, radiation choroidopathy, radiation maculopathy, radiation neuropathy, cataract and choroidal neovascularization. In some embodiments, the present invention can minimize other adverse effects associated with radiation therapy, especially the risks associated with the delivery of excess radiation doses.

Any feature or combination of features described herein is included within the scope of the invention, provided that the features included in any such combination are not mutually inconsistent, as will be read from the context, this specification and one of ordinary skill in the art. The understanding is obvious. Additional advantages and aspects of the present invention are apparent in the following embodiments and claims.

Detailed Description of the Preferred Embodiment

The invention features a radionuclide brachytherapy source (RBS) for applying radiation to a target area, such as for the treatment of chronic serous chorioretinopathy (CSCR). Brachytherapy of central serous chorioretinopathy

The present invention can be used to deliver low dose radiation via episcleral brachytherapy to refractory cases of central serous chorioretinopathy (CSCR).

The pathogenesis of CSCR involves dilation and hyperpermeability of the large choroidal vessels. Low-dose radiation induces intimal proliferation and reduces hyperpermeability in large choroidal vessels. Problems with the use of brachytherapy in CSCR include damage to the choriocapillary layer or retinal vessels. This can be solved by using specialized devices that can deliver very precise and appropriate doses. The dose of delivered radiation decreases exponentially at a depth of approximately 0.5 to 1.5 mm from the device-scleral interface.

Radiation dose titration is key to minimizing damage to the choriocapillary layer and avoiding radiation retinopathy, radiation spot, radiation neuropathy and cataracts. Special devices for episcleral brachytherapy, such as the SalutarisMD, promise to provide additional safety and ease of procedure, thereby making it more practical.

Central serous chorioretinopathy (CSCR) is a disease characterized by neurosensory detachment, with or without pigment epithelium detachment due to a dysfunctional retinal pigment epithelium (RPE) and hyperpermeable choroid. The choroid of CSCR is characterized by attenuation of the choroidal capillary layer and dilation of the large choroidal vessels. Whether the dilated large vessels of the choroid cause mechanical compression of the choriocapillary layer or atrophy of the choriocapillary layer is the main event, which is still controversial.

Acute isolated episodes of CSCR resolve mostly spontaneously, but the chronic variant of the disease, also known as diffuse retinal pigment epitheliopathy, is progressive and can result in severe bilateral visual impairment. Many treatment options have been tried for this form of the disease, and photodynamic therapy (PDT) is by far the treatment of choice. However, PDT has shown limited success in 30% to 40% of cases with a risk of complications, including vision loss. The limited availability of verteporfin and laser systems in many countries, as well as off-label indications, have made PDT a disappearing treatment option. As reported in the VICI trial, the limited effects of eplerenone further limit treatment options for this debilitating disease.

The primary target of the present invention is the hyperpermeable choroidal vasculature. Cancers associated with plaque radiation therapy include platelet aggregation, development of choroidal neovascularization (CNV), radiation maculopathy, optic neuropathy, and chorioretinopathy radiation.

The radionuclide strontium-90 (90Sr) emits only high energy beta particles, which have the highest attenuation in biological tissue, making it more suitable for ocular use. Yttrium-90 (90Y) is a progeny product of 90Sr after beta decay and emits more energetic beta particles.

Stereotactic radiosurgery is another form of radiotherapy in which three highly collimated beams are passed through the underlying sclera until they overlap at the macula, delivering stereotactic, low-energy X-rays to CNV. Unlike macular brachytherapy, this outpatient-based radiation therapy does not require vitrectomy and is therefore a more practical form of radiation therapy.

The aim of the present invention is to reduce the blood flow through the large choroidal vessels without occlusion of the choriocapillary layer. The mechanism of action in this case would likely be due to the effects of radiation on endothelial cells. Radiation dose can be reduced even further to achieve the desired effect of producing intimal proliferation, thereby stopping or reducing leakage. Unlike its effect on cancer cells, which aim to generate enough deoxyribonucleic acid (DNA) double-strand breaks to induce cell death, in its CSCR application, lower radiation doses will lead to collagen around leaky blood vessels deposition, thereby changing its permeability over a period of several months.

When the RBS is placed on or near the sclera, it is possible for the radiation to affect the large choroidal vascular layer without adversely affecting the choriocapillary layer. Referring to Figures 1, 2, 3, and 4, the dose of radiation is an exponential function of a depth of approximately 0.5 mm to 1.5 mm, where the depth is measured from the front of the device (the depth of the device-sclera interface is zero). Dose = D _n exp[- 0.846 (dd _n )], where the depth of interest is d. _Dn is the dose at depth _dn , which is the normalized depth (or treatment depth). Studies have shown that the thickness of the choroid at the macula is approximately 256 µm, of which 204 µm is occupied by the larger vessels (Haler's layer) and 52 µm by the choriocapillary/Sattler's layer in normal eyes. In CSCR, the total choroidal thickness was increased (394 µm) due to the increased thickness of the large vascular layer (307 µm). The thickness of the sclera at the posterior pole is approximately 1 mm. Although sclera thickness at the posterior pole has not been measured in eyes with CSCR, the sclera thickness at 6 mm post-sclera impingement, as measured on anterior segment optical coherence tomography, was thicker than in normal eyes, and the increase in sclera thickness was associated with The pathogenesis of CSCR.

The depth of the typical human choroid in the ocular structure is generally between 0.5 mm and 1.5 mm as measured from the posterior surface of the eye. The target is the choroid, such as the approximate median depth of the choroid. The present invention describes the delivery of therapeutic doses to a specific depth range (as measured from the interface of the sclera to the delivery device). In some embodiments, the depth is in the range of 0.5 mm to 2.0 mm. In some embodiments, the depth is in the range of 0.75 mm to 2.0 mm. In some embodiments, the depth is in the range of 1.0 mm to 2.0 mm. In some embodiments, the depth is in the range of 0.5 mm to 1.5 mm. The present invention is not limited to the foregoing depth ranges in relation to therapeutic dose delivery.

The choroid is within the depth range at which the therapeutic dose is delivered, eg, in some embodiments, the target's depth (eg, choroidal median depth) is 1.25 mm from the interface of the sclera and the delivery device, so the target receives the therapeutic dose. In some embodiments, the choroidal target is 0.5 to 2 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 0.75 to 1.5 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 0.5 to 2 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 1 to 1.5 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 0.75 to 1.75 mm from the interface of the sclera to the delivery device.

Radiation doses delivered to the choriocapillary layer of less than 10 Gy induce intimal proliferation in the larger choroidal vessels, thereby reducing the hyperpermeability of these vessels while also sparing the choriocapillary layer and other more radiosensitive structures. Damage is minimized.

Salutaris Medical Devices (SalutarisMD) has introduced a new episcleral brachytherapy device for the treatment of wet AMD with precise therapeutic doses. It employs a 90Sr/90Y source RBS encapsulated in a stainless steel bracket loaded to the distal end of the curved cannula of the applicator. The device is introduced via the retro-Tenon subcapsular route and delivers radiation through the sclera to the CNV lesion within minutes (see Figure 5). A clinical trial evaluating the safety and feasibility of the device in wet AMD patients has begun and is expected to be completed by 2022.

Dose titration of radiation is critical to minimize damage to the choriocapillary layer and other radiation-sensitive structures of the eye, and to avoid radiation retinopathy, radiation maculopathy, radiation neuropathy, and cataracts. Specialized devices for episcleral brachytherapy, such as the Salutaris MD, can be used in conjunction with the present invention to provide additional safety and convenience to procedures performed using the present invention, thereby making it more practical. RBS system in chronic serous chorioretinopathy

The present invention is useful for treating chronic serous chorioretinopathy (CSCR). For example, the invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of the eye comprising inserting a cannula into the potential space below the Tenon's capsule of a patient's eye, The RBS is thus positioned over the choroidal target at the back of the eye, where a therapeutic dose of radiation is delivered to the choroidal target. The radiotherapy portion of the RBS is consumed in this method. As used herein, the term "consumed" may mean that a radioactive source is depleted through radioactive decay. The RBS may be present in the delivery device, eg, in a cannula of the delivery device.

As previously discussed, in some embodiments, the choroidal target is 0.5 to 2 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 0.75 to 1.5 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 0.5 to 2 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 1 to 1.5 mm from the interface of the sclera to the delivery device. In some embodiments, the choroidal target is 0.75 to 1.75 mm from the interface of the sclera to the delivery device.

Without wishing to limit the invention to any theory or mechanism, the therapeutic dose is generally selected to result in increased proliferation of the intima of the large choroidal vessels with concomitant damage to the vessels of the choroidal capillary layer and other radiation-sensitive structures of the eye such as the lens minimized. In general, excessive radiation exposure to structures other than the target (eg, large choroidal vessels) needs to be avoided. Radiation exposure to other radiation-sensitive structures including the lens, choriocapillary layer, retina, and retinal vessels may need to be avoided.

In some embodiments, the therapeutic dose is 6 to 18 Gy. In some embodiments, the therapeutic dose is 6 to 8 Gy. In some embodiments, the therapeutic dose is 6 to 10 Gy. In some embodiments, the therapeutic dose is 6 to 12 Gy. In some embodiments, the therapeutic dose is 6 to 16 Gy. In some embodiments, the therapeutic dose is 8 to 10 Gy. In some embodiments, the therapeutic dose is 8 to 12 Gy. In some embodiments, the therapeutic dose is 8 to 16 Gy. In some embodiments, the therapeutic dose is 8 to 18 Gy. In some embodiments, the therapeutic dose is 10 to 12 Gy. In some embodiments, the therapeutic dose is 10 to 14 Gy. In some embodiments, the therapeutic dose is 10 to 18 Gy. In some embodiments, the therapeutic dose is 12 to 16 Gy. In some embodiments, the therapeutic dose is 12 to 18 Gy. In some embodiments, the therapeutic dose is 14 to 18 Gy.

The therapeutic dose is delivered to a particular depth or range of depths, eg, as measured from the interface of the sclera with the delivery device. For example, in some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is 8 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is 8 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is 8 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 6 to 12 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 18 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 16 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 14 Gy. In some embodiments, the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is 8 to 12 Gy.

In some embodiments, the therapeutic dose is calculated based on the thickness of the choroidal target. In some embodiments, a thicker choroidal target may indicate the use of a larger therapeutic dose. In some embodiments, a thicker choroidal target may dictate the use of a smaller therapeutic dose.

In some embodiments, the thickness of the choroidal target is measured using imaging. In some embodiments, imaging may comprise optical coherence tomography (OCT), optical coherence tomography (OCT) using enhanced depth imaging (EDI), spectral domain optical coherence tomography (SD-OCT), swept source optical coherence tomography Tomography (SS-OCT) or Topcon deep range imaging OCT.

In some embodiments, the retina is exposed to less than 6 Gy. In some embodiments, the retina is exposed to less than 8 Gy. In some embodiments, the choriocapillary layer is exposed to less than 8 Gy. In some embodiments, the choriocapillary layer is exposed to less than 10 Gy. In some embodiments, the interface of the large choroidal vessels and the choriocapillary layer is exposed to less than 10 Gy. In some embodiments, the interface of the large choroidal vessels and the choriocapillary layer is exposed to less than 12 Gy. In some embodiments, the retina is exposed to less radiation than the choroidal target. In some embodiments, the choriocapillary layer is exposed to less radiation than the choroidal target. In some embodiments, the lens is exposed to less radiation than the choroidal target. In some embodiments, retinal vessels are exposed to less radiation than choroidal targets.

The dose is delivered to the choroidal target over a period of time such as the dwell time. In some embodiments, the dwell time is from 5 seconds to 10 minutes. In some embodiments, the dwell time is from 5 seconds to 15 seconds. In some embodiments, the residence time is from 5 seconds to 30 seconds. In some embodiments, the dwell time is from 5 seconds to 45 seconds. In some embodiments, the dwell time is from 5 seconds to 1 minute. In some embodiments, the dwell time is from 5 seconds to 2 minutes. In some embodiments, the dwell time is from 15 seconds to 30 seconds. In some embodiments, the dwell time is from 15 seconds to 1 minute. In some embodiments, the dwell time is from 15 seconds to 90 seconds. In some embodiments, the dwell time is from 15 seconds to 2 minutes. In some embodiments, the dwell time is from 30 seconds to 1 minute. In some embodiments, the residence time is from 1 minute to 90 seconds. In some embodiments, the residence time is from 1 minute to 2 minutes. In some embodiments, the dwell time is from 90 seconds to 2 minutes. In some embodiments, the residence time is 2 to 4 minutes. In some embodiments, the residence time is 4 to 6 minutes. In some embodiments, the residence time is 6 to 8 minutes. In some embodiments, the residence time is 8 to 10 minutes. In some embodiments, the residence time is 5 to 10 minutes. In some embodiments, the residence time is greater than 10 minutes.

In some embodiments, the RBS delivers radiation to the irradiated area. In some embodiments, the diameter of the illuminated area is at most 8 millimeters. In some embodiments, the diameter of the illuminated area is at most 12 millimeters. In some embodiments, the diameter of the illuminated area is 3 to 5 mm. In some embodiments, the diameter of the irradiated area is 1 to 3 mm. In some embodiments, the diameter of the illuminated area is 5 to 7 mm. In some embodiments, the diameter of the illuminated area is 7 to 9 mm. In some embodiments, the diameter of the illuminated area is 9 to 12 mm.

In some embodiments, the RBS is a source of particle radiation. In some embodiments, the RBS is a source of ionizing radiation. In some embodiments, the RBS is a beta radiation source. In some embodiments, the RBS is a source of alpha radiation. In some embodiments, the RBS is a source of neutron radiation. In some embodiments, the RBS is a source of X-ray radiation. In some embodiments, the RBS is another source of electromagnetic radiation. In some embodiments, RBSs are multiple types of radiation sources.

The invention also features a method of reducing hyperpermeability of large choroidal vessels in the eye of a patient with central serous chorioretinopathy in need thereof. In some embodiments, the method comprises inserting a cannula into the potential space below the Tenon's capsule of the patient's eye, the cannula having a radionuclide brachytherapy source (RBS) at the treatment site, whereby the RBS is positioned at above the choroidal target, and wherein a therapeutic dose of radiation is delivered to the choroidal target. In some embodiments, the reduction of hyperosmolarity will result in a reduction of fluid accumulation under the retina, thus treating CSCR.

The invention also features a method of increasing collagen deposition associated with large choroidal vessels in the eye of a patient with central serous chorioretinopathy in need thereof. In some embodiments, the method comprises inserting a cannula into the potential space below the Tenon's capsule of the patient's eye, the cannula having a radionuclide brachytherapy source (RBS) at the treatment site, whereby the RBS is positioned at above the choroidal target, and wherein a therapeutic dose of radiation is delivered to the choroidal target. In some embodiments, increased collagen deposition associated with large choroidal vessels results in decreased hyperosmolarity, which will result in decreased fluid accumulation under the retina, thus treating CSCR.

The invention also features a method of treating central serous chorioretinopathy in a patient in need thereof. In some embodiments, the method comprises inserting a cannula into the potential space below the Tenon's capsule of the patient's eye, the cannula having a radionuclide brachytherapy source (RBS) at the treatment site, whereby the RBS is positioned at above the choroidal target, and wherein a therapeutic dose of radiation is delivered to the choroidal target. In some embodiments, treating CSCR can be achieved by inducing decreased hyperpermeability of large choroidal vessels and/or increasing collagen deposition associated with large choroidal vessels and/or reducing subretinal fluid accumulation.

In some embodiments, the dose delivered is such that radiation retinopathy is avoided. In some embodiments, the dose delivered is such that radiation-induced choroidopathy is avoided. In some embodiments, the dose delivered is such that radiation maculopathy is avoided. In some embodiments, the dose delivered is such that radiation neuropathy is avoided. In some embodiments, the dose delivered is such that cataracts are avoided. In some embodiments, the dose delivered is such that choroidal neovascularization is avoided. In some embodiments, the dose delivered is such that other adverse events of radiation therapy are avoided.

The therapeutic dose to be administered can be calculated a priori prior to delivery of any therapeutic course (or portion thereof).

With reference to the methods herein, the therapeutic dose to be administered, eg, a course of treatment, can be fractionated (eg, divided and delivered) in multiple stages. For example, in some embodiments, treatment doses are graded in at least 2 phases. In some embodiments, treatment doses are graded in 2 phases. In some embodiments, treatment doses are graded in 3 phases. In some embodiments, treatment doses are graded in 4 phases. In some embodiments, treatment doses are graded in more than 4 periods. In some embodiments, the phases are divided into 1-week timeframes. In some embodiments, the phases are divided into 2-week timeframes. In some embodiments, the phases are divided into 3 week timeframes. In some embodiments, the phases are divided into 4 week timeframes. In some embodiments, the periods are separated by 1 to 7 days. In some embodiments, the periods are separated by 5 to 10 days. In some embodiments, the periods are separated by 5 to 14 days. In some embodiments, the periods are separated by 5 to 21 days.

In some embodiments, the patient is reassessed after a period of time following the first course of treatment to determine whether the patient requires a second course of treatment. The patient may also be reassessed after an additional course of treatment, for example, in some embodiments, the patient may be reassessed after a second course of treatment to determine whether the patient requires a third course of treatment. In some embodiments, the time between two specific treatment sessions (eg, first and second treatment sessions, second and third treatment sessions, etc.) ranges from 3 to 12 months. In some embodiments, the time between two specific treatment courses ranges from 3 to 6 months. In some embodiments, the time between two specific treatment courses ranges from 6 to 12 months. In some embodiments, the time between two specified courses of treatment ranges from 3 to 24 months. In some embodiments, the time between two specified courses of treatment ranges from 3 to 36 months. In some embodiments, the time frame between two particular treatment sessions is greater than one year. In some embodiments, the time frame between two particular treatment courses is greater than 2 years. In some embodiments, the time frame between two particular treatment courses is greater than 3 years.

As described above, the first treatment course can be stratified (eg, divided and delivered) in at least 2 phased courses. Likewise, in some embodiments, the second (or third or subsequent) course of treatment may also be graded in at least 2 stages.

In some embodiments, the RBS is contained within the cannula. In some embodiments, the cannula is part of a delivery device, wherein the delivery device comprises: a cannula comprising a curved distal portion adapted to be placed around a portion of the eyeball; a curved proximal portion, the curved distal portion and the curved proximal portions are connected to each other at an inflection point of a change in direction of curvature; and a straight proximal portion, wherein (a) the distal portion has a radius of curvature between about 9 mm and 15 mm and is between about an arc length between 25 mm and 35 mm; and (b) the proximal portion has a radius of curvature between about the inner cross-sectional radius of the cannula and about 1 meter; And the angle θ1 between the line ℓ3 tangent to the curved proximal portion and the straight proximal portion is greater than about 0° to about 180°. This application is hereby incorporated by reference in its entirety into the following patent applications: In some embodiments, the invention is characterized by the use of dedicated delivery devices such as, but not limited to, those described in Dedicated delivery devices: U.S. Patent Application No. 10/836,140; U.S. Patent Application No. 12/350,079; U.S. Patent Application No. 12/497,644; U.S. Patent Application No. 13/111,765; U.S. Patent Application No. 13 U.S. Patent Application No. 13/742,823; U.S. Patent Application No. 13/872,941; U.S. Patent Application No. 13/953,528; U.S. Patent Application No. 14/011,516; U.S. Patent Application No. 14 U.S. Patent Application No. 14/687,784; U.S. Patent Application No. 15/871,756; U.S. Patent Application No. 15/023,196; U.S. Patent Application No. 15/004,538; U.S. Patent Application No. 15 U.S. Patent Application No. 16/015,892; U.S. Patent Application No. 16/009,646; U.S. Design Application No. 29/332,021; U.S. Design Application No. 29/332,028; U.S. Design Application No. 29 U.S. Design Application No. 29/332,040; U.S. Design Application No. 29/368,499; U.S. Design Application No. 29/368,501; U.S. Design Application No. 29/391,557; U.S. Design Application No. 29 U.S. Design Application No. 29/391,559; U.S. Design Application No. 29/391,561; U.S. Design Application No. 29/564,244; U.S. Design Application No. 29/564,247; U.S. Design Application No. 29 /564,249; U.S. Design Application No. 29/576,148; U.S. Design Application No. 29/576,159; PCT Application No. PCT/US2009/030343; PCT Application No. PCT/US2010/54958; PCT/US2014/56135; PCT Application No. PCT/US2016/68391. 5, 6, 7A, 7B, 7C, and 7D show non-limiting examples of cannulas. For example, in some embodiments, the system includes a cannula (eg, as part of a delivery device). In some embodiments, cannula (100) comprises a curved distal portion (110) adapted to be placed around a portion of the eyeball; a curved proximal portion (120), the curved distal portion and the curved proximal portions They are connected to each other at inflection points (130) where the direction of curvature changes sign. In some embodiments, the cannula includes a straight proximal portion. In some embodiments, the distal portion has a radius of curvature (180) between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; The radius of curvature (190) between the radius of the inner cross-section of the tube and about 1 meter; and between the line ℓ ₃ (420) tangent to the distal portion and the curved proximal portion at the point of inflection and the straight proximal portion The angle θ ₁ (425) of is between greater than about 0 degrees and about 180 degrees. example

The following are non-limiting examples of the invention. It should be understood that this example is not intended to limit the invention in any way. Equivalents or substitutes are within the scope of the present invention.

The following are three prophetic examples of how the invention may be used in practice to treat CSCR patients.

A 42-year-old man presented with 6 months of central blurred vision, weak vision, and metamorphopsia in the left eye. The best corrected visual acuity of the left eye was 20/100. Hyperopic shift and neurosensory retinal detachment, as well as unresolved subretinal fluid, were observed on examination. The patient was diagnosed with chronic CSCR. Records show that no interventional therapy was administered to CSCR. A course of therapeutic radiation therapy was prescribed, with a total dose of 12 Gy delivered in two fractions, 3 weeks apart. Multiple fractionated treatments were used to protect the RPE and photoreceptors from long-term detachment. In each fraction, 6 Gy was delivered 1.25 mm from the sclera-delivery device interface.

A 38-year-old male patient presented with recurrent symptoms of CSCR, including visual distortion and loss of central vision in the right eye. The best corrected visual acuity of the right eye is 20/80. The records showed that acute CSCR with subretinal fluid was diagnosed 8 months ago and spontaneously resolved 10 weeks after diagnosis. Current examination revealed neurosensory retinal detachment, with subretinal fluid in areas of multiple foci of leakage, and atrophy of the retinal pigment epithelium (RPE). The patient was diagnosed with recurrent CSCR. A course of therapeutic radiation therapy was chosen, with a total dose of 15 Gy delivered in three fractions, 2 weeks apart. Higher doses are recommended for difficult (recurrent) cases with multiple leaks. In each fraction, 5 Gy was delivered 1.5 mm from the interface of the sclera to the delivery device.

A 53-year-old female patient presented with recurrent symptoms of CSCR, including metamorphopsia and loss of vision in the right eye for 3 months. Clinical examination revealed small PED and neurosensory retinal detachment with chronic subretinal fluid. The best corrected visual acuity of the right eye was 20/50. Records showed that the patient had undergone PDT for chronic CSCR episodes 15 months earlier, with good visual recovery. The patient was diagnosed with chronic CSCR. A course of therapeutic radiation therapy was chosen, delivering a single 8 Gy bolus 1.35 mm from the sclera-delivery device interface, more likely to have fewer but Resistant vessels.

As used herein, the term "about" means plus or minus 10% of the reference figure.

While preferred embodiments of the invention have been shown and described, it will be readily apparent to those of ordinary skill in the art that modifications may be made therein without exceeding the purview of the appended claims. Therefore, the scope of the present invention is only limited by the scope of the following claims. In some embodiments, the drawings presented in this patent application are drawn to scale, including angles, ratios of dimensions, and the like. In some embodiments, the drawings are representative only and the claims are not limited by the size of the drawings. In some embodiments, the description of the invention described herein using the phrase "comprising" includes can be described as "consisting essentially of" or "consisting of" and thus satisfy the requirement of a written description using the phrase "consisting essentially of" or "consisting of" to claim one or more embodiments of the invention.

The reference numbers listed in the claims below are for ease of inspection of the patent application only, are illustrative, and are not intended to limit the scope of the claims to specific features in the drawings with corresponding reference numbers in any way.

100: cannula 110, a: curved distal portion 120, b: curved proximal portion 130: inflection point 180, 190: radius of curvature 420: line ℓ ₃ 425: angle θ ₁

The features and advantages of the present invention will become apparent from consideration of the following embodiments presented in conjunction with the accompanying drawings, in which:

Figure 1 shows a depiction of the exponential fall in radiation dose with depth of the device. The graph shows that the dose of radiation decreases exponentially with the depth of the device.

Figure 2 shows the dose of radiation delivered at different depths from the scleral surface (device-sclera interface). Dose = Dn exp[- 0.846 (d- dn)], where the depth of interest is d. Dn is the dose at depth dn, which is the normalized depth (or treatment depth).

Figure 3 shows that in a normal eye, the radiation dose delivered at the sclera-choroid interface can be 12.4 Gy. The dose at the interface of the large choroidal vessels and the medium vessels/choriocapillary layer may be 10 Gy. Choroidal thickness is also shown.

Figure 4 shows that in eyes with central serous chorioretinopathy (CSCR), the radiation dose delivered at the sclera-choroid interface can be less than 12.4 Gy considering the increased sclera thickness in CSCR. Due to the increased thickness of the large choroidal vessel layer, the radiation dose at the interface of the large choroidal vessel and the medium vessel/choriocapillary layer may be 8 Gy. Choroidal thickness (increased relative to normal eye thickness) is also shown.

Figure 5 shows an episcleral brachytherapy device introduced via the sub-Tenon approach to deliver radiation to the choroidal neovascular complex via the sclera.

Figure 6 shows a non-limiting example of a cannula/delivery device.

Figure 7A shows a non-limiting example of a cannula/delivery device.

Figure 7B shows a detailed view of the radius of curvature of a portion of the cannula.

Figure 7C shows a detailed view of the radius of curvature of a portion of the cannula.

Figure 7D shows a detailed view of the relationship between the vertical portion of the cannula and the distal and proximal portions of the cannula.

Claims (60)

A radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein the RBS is present in a cannula of a delivery device, the method comprising inserting the cannula into a cannula of the eye In a potential space below the Tenon's capsule, whereby the RBS is positioned over a choroidal target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the choroidal target, wherein a radiotherapy portion of the RBS is consumed in this method. The RBS of claim 1, wherein the therapeutic dose is from 6 to 18 Gy. The RBS of claim 1, wherein the therapeutic dose is from 6 to 16 Gy. The RBS of claim 1, wherein the therapeutic dose is from 6 to 14 Gy. The RBS of claim 1, wherein the therapeutic dose is from 6 to 12 Gy. The RBS of claim 1, wherein the therapeutic dose is from 8 to 18 Gy. The RBS of claim 1, wherein the therapeutic dose is from 8 to 16 Gy. The RBS of claim 1, wherein the therapeutic dose is from 8 to 14 Gy. The RBS of claim 1, wherein the therapeutic dose is from 8 to 12 Gy. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 6 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 6 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 6 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 6 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 8 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 8 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 8 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 2 mm is from 8 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 6 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 6 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 6 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 6 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 8 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 8 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 8 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.75 mm to 1.75 mm is from 8 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 6 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 6 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 6 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 6 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 8 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 8 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 8 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 1 mm to 1.5 mm is from 8 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 6 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 6 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 6 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 6 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 8 to 18 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 8 to 16 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 8 to 14 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose delivered to a depth of 0.5 mm to 1.25 mm is from 8 to 12 Gy, wherein the depth is measured from an interface of a sclera and the delivery device. The RBS of claim 1, wherein the therapeutic dose is calculated based on the thickness of the choroidal target. The RBS of claim 42, wherein the thickness of the choroidal target is measured using imaging. The RBS of claim 1, wherein one retina is exposed to less than 8 Gy. The RBS of claim 1, wherein one choriocapillary layer is exposed to less than 10 Gy. The RBS of claim 1, wherein an interface between a large choroidal vessel and a choriocapillary layer is exposed to less than 12 Gy. The RBS of claim 1, wherein a retina is exposed to less radiation than the choroid target. The RBS of claim 1, wherein a choriocapillary layer is exposed to less radiation than the choroid target. The RBS of claim 1, wherein the dosage is graded in multiple stages. The RBS of claim 49, wherein the dosage is graded in at least 2 stages. The RBS of claim 1, wherein the dose is delivered to the choroidal target within a dwell time. The RBS of claim 51, wherein the dwell time is from 5 seconds to 2 minutes. The RBS of claim 51, wherein the dwell time is from 5 seconds to 1 minute. The RBS of claim 51, wherein the dwell time is from 2 to 4 minutes. The RBS of claim 51, wherein the residence time is from 5 to 10 minutes. The RBS of claim 1, wherein the RBS delivers radiation to an irradiated area, wherein a diameter of the irradiated area is at most 8 millimeters. The RBS of claim 1, wherein the RBS is an ionizing radiation source. The RBS of claim 1, wherein the RBS is a beta radiation source. The RBS of claim 1, wherein the RBS is an X-ray radiation source. The RBS of claim 1, wherein the cannula is part of a delivery device, wherein the delivery device comprises: a cannula (100) comprising a curved distal portion adapted to be placed around a portion of the eyeball ( 110); a curved proximal portion (120), the curved distal portion and the curved proximal portions are connected to each other at an inflection point (130) of the sign of the change in direction of curvature; and a straight proximal portion, wherein (a) The distal portion has a radius of curvature (180) between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and (b) the proximal portion has a radius between A radius of curvature (190) of between about an inner cross-sectional radius of the cannula and about 1 meter; and wherein a line ℓ ₃ (420) tangent to the distal portion and the curved proximal portion at the point of inflection An angle θ ₁ (425) from the proximal portion of the line is between greater than about 0 degrees and about 180 degrees.

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