Feiyan Ma

Tunable sustained intravitreal drug delivery system for daunorubicin using oxidized porous silicon.

Daunorubicin (DNR) is an effective inhibitor of an array of proteins involved in neovascularization, including VEGF and PDGF. These growth factors are directly related to retina scar formation in many devastating retinal diseases. Due to the short vitreous half-life and narrow therapeutic window, ocular application of DNR is limited. It has been shown that a porous silicon (pSi) based delivery system can extend DNR vitreous residence from a few days to 3months. In this study we investigated the feasibility of altering the pore size of the silicon particles to regulate the payload release. Modulation of the etching parameters allowed control of the nano-pore size from 15nm to 95nm. In vitro studies showed that degradation of pSiO2 increased with increasing pore size and the degradation of pSiO2 was approximately constant for a given particle type. The degradation of pSiO2 with 43nm pores was significantly greater than the other two particles with smaller pores, judged by observed and normalized mean Si concentration of the dissolution samples (44.2±8.9 vs 25.7±5.6 or 21.2±4.2μg/mL, p<0.0001). In vitro dynamic DNR release revealed that pSiO2-CO2H:DNR (porous silicon dioxide with covalent loading of daunorubicin) with large pores (43nm) yielded a significantly higher DNR level than particles with 15 or 26nm pores (13.5±6.9ng/mL vs. 2.3±1.6ng/mL and 1.1±0.9ng/mL, p<0.0001). After two months of in vitro dynamic release, 54% of the pSiO2-CO2H:DNR particles still remained in the dissolution chamber by weight. In vivo drug release study demonstrated that free DNR in the vitreous at post-injection day 14 was 66.52ng/mL for 95nm pore size pSiO2-CO2H:DNR, 10.76ng/mL for 43nm pSiO2-CO2H:DNR, and only 1.05ng/mL for 15nm pSiO2-CO2H:DNR. Pore expansion from 15nm to 95nm led to a 63 fold increase of DNR release (p<0.0001) and a direct correlation between the pore size and the drug levels in the living eye vitreous was confirmed. The present study demonstrates the feasibility of regulating DNR release from pSiO2 covalently loaded with DNR by engineering the nano-pore size of pSi.

One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration

PURPOSE To evaluate 6-month and 1-year outcomes of every-8-weeks (Q8W) aflibercept in patients with resistant neovascular age-related macular degeneration (AMD). DESIGN Retrospective, interventional, consecutive case series. METHODS Retrospective review of patients with resistance (multiple recurrences or persistent exudation) to every-4-weeks (Q4W) ranibizumab or bevacizumab that were switched to Q8W aflibercept. RESULTS Sixty-three eyes of 58 patients had a median of 13 (interquartile range [IQR], 7-22) previous anti-vascular endothelial growth factor (anti-VEGF) injections. At 6 months after changing to aflibercept, 60.3% of eyes were completely dry, which was maintained up to 1 year. The median maximum retinal thickness improved from 355 μm to 269 μm at 6 months (P < .0001) and 248 μm at 1 year (P < .0001). There was no significant improvement in ETDRS visual acuity at 6 months (P = .2559) and 1 year follow-up (P = .1081) compared with baseline. The mean difference in ETDRS visual acuity compared to baseline at 6 months was -0.05 logMAR (+2.5 letters) and 0.04 logMAR at 1 year (-2 letters). CONCLUSION Sixty percent of eyes with resistant AMD while on Q4W ranibizumab or bevacizumab were completely dry after changing to Q8W aflibercept at the 6-month and 1-year follow-ups, but visual acuity did not significantly improve. Only a third of eyes needed to be switched from Q8W to Q4W aflibercept owing to persistence of fluid; Q8W dosing of aflibercept without the initial 3 monthly loading doses may be a good alternative in a select group of patients who may have developed ranibizumab or bevacizumab resistance.

Porous silicon oxide–PLGA composite microspheres for sustained ocular delivery of daunorubicin

A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO2) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA-DNR microspheres without pSiO2, and pSiO2 microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water emulsion method have mean diameters of 52.33±16.37μm for PLGA-pSiO2_21/40-DNR and the mean diameter of 49.31±8.87μm for PLGA-pSiO2_6/20-DNR. The mean size, 26.00±8μm, of PLGA-DNR was significantly smaller, compared with the other two (P<0.0001). Optical microscopy revealed that PLGA-pSiO2-DNR microspheres contained multiple pSiO2 particles. In vitro release experiments determined that control PLGA-DNR microspheres completely released DNR within 38days and control pSiO2-DNR microparticles (with no PLGA coating) released DNR within 14days, while the PLGA-pSiO2-DNR microspheres released DNR for 74days. Temporal release profiles of DNR from PLGA-pSiO2 composite particles indicated that both PLGA and pSiO2 contribute to the sustained release of the payload. The PLGA-pSiO2 composite displayed a more constant rate of DNR release than the pSiO2 control formulation, and displayed a significantly slower release of DNR than either the PLGA or pSiO2 formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with antiproliferation compounds such as DNR.

Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system

There still is an unmet need for a safe and sustained intravitreal drug delivery system. In this study we are proposing and characterizing a micelle based, clear-media intravitreal drug delivery system using the lipid derivatized nucleoside analog, hexadecyloxypropyl-cidofovir (HDP-CDV, CMX 001). HDP-CDV forms micelles in water and in vitreous supernatant with the critical micelle concentration of 19 μg/mL and 9 μg/mL, respectively at 37 °C. The formed micelles had the average size of 274.7 nm and the Zeta potential of -47.1 mV. Drug release study in the excised rabbit vitreous showed a sustained release profile with a half-life of 2.7 days. The micelle formulation of HDP-CDV demonstrated a good safety profile in two animal species (rabbit and guinea pig) following intravitreal injection. The sustained efficacy was tested in a pretreatment study design and the drug potency was tested in an ongoing herpes simplex virus (HSV-1) retinitis model. The pretreatment studies using single intravitreal injection and later HSV-1 infection revealed at least 9 weeks of vitreous presence and therapeutic level of HDP-CDV, with 71% eyes protection from infection. The treatment study demonstrated that intravitreal administration halted active HSV-1 retinitis in 80% of the infected eyes while cidofovir (CDV) treatment failed to suppress active HSV-1 retinitis. In summary, lipid derivatized nucleoside analogs can be formulated as a micelle intravitreal injection and provides a sustained drug release in vitreous for chronic retinal diseases.

Macular choroidal volume variations in highly myopic eyes with myopic traction maculopathy and choroidal neovascularization.

Purpose: To compare the choroidal volume (CV) between emmetropic and highly myopic eyes, and to assess if the presence of myopic fundus abnormalities, myopic traction maculopathy, or choroidal neovascularization affects the CV. Methods: We retrospectively reviewed imaging studies of 98 eyes of 98 patients who underwent CV measurement on optical coherence tomography. We included 31 emmetropic eyes (Group 1), 36 highly myopic eyes without vitreoretinal or choroidal pathologies (Group 2), 21 highly myopic eyes with traction maculopathy (Group 3), and 10 highly myopic eyes with history of choroidal neovascularization (Group 3). Eyes with chorioretinal atrophy were excluded. Regression analysis was performed to evaluate the correlation between CV and multiple variables. Results: Choroidal volume was lower in Group 2 than in Group 1 (P < 0.001), and in Groups 3 and 4 than in Group 2 (P < 0.001 and P = 0.002, respectively). Age (P = 0.002), axial length (P < 0.001), sex (P = 0.047), staphyloma (P < 0.001), and myopic group (P = 0.05) were independent predictors for the final CV (R2 = 0.645). In highly myopic eyes, CV decreased by 0.32 mm3 for every 10 years and by 0.49 mm3 per millimeter of axial length. Conclusion: Choroidal thinning is present in highly myopic eyes compared with emmetropic eyes, and is related to age, axial length, sex, and staphyloma. However, myopic eyes with coexisting myopic traction maculopathy or history of choroidal neovascularization have more severe thinning, likely leading to insufficient metabolic supplementation for the macula.

Optical coherence tomography findings of the vitreoretinal interface in asymptomatic fellow eyes of patients with acute posterior vitreous detachment.

Purpose: To describe the vitreoretinal interface of the asymptomatic fellow eyes of patients with acute unilateral posterior vitreous detachment (PVD) based on biomicroscopic examination and spectral domain optical coherence tomography. Methods: Sixty-five eyes of 65 consecutive patients with acute unilateral PVD were examined by slit-lamp, indirect ophthalmoscopy, and spectral domain optical coherence tomography. The state of PVD in different retinal locations and premacular pocket were assessed and graded using spectral domain optical coherence tomography. Results: Nine eyes (13.85%) had no PVD, 15 (23.08%) had extrafoveal vitreous separation (Stage 1), 18 (27.69%) had partial foveal vitreous separation (Stage 2), 12 (18.46%) had complete foveal vitreous separation (Stage 3), and 11 (16.92%) had a complete PVD (Stage 4). The presence of a premacular pocket showed equal distribution in Stages 0, 1, and 2 (66.67, 80.00, and 77.78%, respectively) but was significantly less common in Stages 3 (P = 0.016) and 4 (P < 0.0001). Only certain posterior vitreous configurations were identified (P < 0.0001), suggesting an orderly progression of PVD evolution. Conclusion: Our spectral domain optical coherence tomography-based PVD staging system describes the evolution of PVDs. This can be used as a guide in predicting the occurrence and evolution of PVD in this population.

Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis

Purpose To determine the presence of structural changes in HIV retinae (i.e., photoreceptor density and retinal thickness in the macula) compared with age-matched HIV-negative controls. Methods Cohort of patients with known HIV under CART (combination Antiretroviral Therapy) treatment were examined with a flood-illuminated retinal AO camera to assess the cone photoreceptor mosaic and spectral-domain optical coherence tomography (SD-OCT) to assess retinal layers and retinal thickness. Results Twenty-four eyes of 12 patients (n = 6 HIV-positive and 6 HIV-negative) were imaged with the adaptive optics camera. In each of the regions of interest studied (nasal, temporal, superior, inferior), the HIV group had significantly less mean cone photoreceptor density compared with age-matched controls (difference range, 4,308–6,872 cones/mm2). A different subset of forty eyes of 20 patients (n = 10 HIV-positive and 10 HIV-negative) was included in the retinal thickness measurements and retinal layer segmentation with the SD-OCT. We observed significant thickening in HIV positive eyes in the total retinal thickness at the foveal center, and in each of the three horizontal B-scans (through the macular center, superior, and inferior to the fovea). We also noted that the inner retina (combined thickness from ILM through RNFL to GCL layer) was also significantly thickened in all the different locations scanned compared with HIV-negative controls. Conclusion Our present study shows that the cone photoreceptor density is significantly reduced in HIV retinae compared with age-matched controls. HIV retinae also have increased macular retinal thickness that may be caused by inner retinal edema secondary to retinovascular disease in HIV. The interaction of photoreceptors with the aging RPE, as well as possible low-grade ocular inflammation causing diffuse inner retinal edema, may be the key to the progressive vision changes in HIV-positive patients without overt retinitis.

Outer retinal tubulations response to anti-VEGF treatment

Aim To review the longitudinal changes of outer retinal tubulations (ORTs) in wet age-related macular degeneration (AMD) and their response to anti-vascular endothelial growth factor (VEGF) therapy by spectral-domain optical coherence tomography (SD-OCT), and to correlate these observations with disease activity, presence or absence of fluid, and patients’ demographics. Methods Retrospective study of wet AMD eyes treated with anti-VEGF agents and showing ORTs on SD-OCT, and the patients’ fellow eye with wet AMD but without ORTs. Results Fifty-one wet AMD eyes from 31 patients diagnosed and treated for wet AMD were included in the review and analysis of data; 33 eyes showed ORTs at baseline, while 18 fellow eyes had no ORTs. During a median follow-up treatment period of 11 months, 23 eyes had stable ORTs and 10 eyes had ORT changes. Among the 10 eyes with ORTs changes, ORTs collapsed during anti-VEGF treatment in 5 eyes but then reappeared within 12 months after stopping treatment. In two eyes, ORTs increased in size during anti-VEGF treatment, while in two other eyes ORTs collapsed without any treatment. In a single eye, ORTs collapsed within 10 months of no treatment and did not reappear upon recurrence of fluid. Eyes with ORTs tended to have lower visual acuity than eyes with no ORTs due to greater disruption of the external limiting membrane in the fovea. Conclusions ORTs documented by SD-OCT may exhibit multiple types of longitudinal changes, such as collapse, recurrence or enlargement, which could be associated with anti-VEGF treatment or spontaneous. Some ORTs may have a vascular component or may be vascular in nature, considering their response to anti-VEGF treatment, while other ORTs are likely composed only of degenerating photoreceptor cells and may collapse independently from anti-VEGF treatments.