Feasibility of Therapeutic Ultrasound Application in Topical Scleral Delivery of Avastin

Abstract

Purpose Macromolecules have been shown to be effective in vision-saving treatments for various ocular diseases, such as age-related macular degeneration and diabetic retinopathy. The current delivery of macromolecules requires frequent intraocular injections and carries a risk of serious adverse effects. Methods We tested the application of therapeutic ultrasound as a minimally invasive approach for the delivery of Avastin into the diseased regions of the eye. Avastin (bevacizumab) is an anti-vascular endothelial growth factor (VEGF) antibody with a molecular weight of 149 kDa. We tested the effectiveness and safety of Avastin delivery through rabbit sclera in vitro using a standard diffusion cell model. Ultrasound at frequencies of 400 kHz or 3 MHz with an intensity of 1 W/cm 2 was applied for the first 5 minutes of 1-hour drug exposure. Sham treatments mimicked the ultrasound treatments, but ultrasound was not turned on. Absorbance measurements of the receiver compartment solution were performed at 280 nm using a spectrophotometer. Results Absorbance measurements indicated no statistical difference between the sham ( n = 13) and 400 kHz ultrasound group ( n = 15) in the delivery of Avastin through the sclera. However, the absorbance values were statistically different ( P < 0.01) between the 3 MHz ultrasound group (0.004, n = 8) and the matched sham group (0.002, n = 7). There was 2.3 times increase in drug delivery in the 3 MHz ultrasound when compared to the corresponding sham group. Histological studies indicated no significant damage in the ultrasound-treated sclera due to ultrasound application. Conclusions Our preliminary results provided support that therapeutic ultrasound may be effective in the delivery of Avastin through the sclera. Translational Relevance Our study offers clinical potential for a minimally invasive retinopathy treatment.

Therapeutic Ultrasound for Topical Corneal Delivery of Macromolecules

“…In ophthalmic research, rabbit eyes are the most used model for human ocular physiology. 16 , 33 – 35 The rabbit eye diameter is 6.5 mm smaller than the human eye. Rabbit cornea is 0.25 mm thinner than the human cornea, whereas the rabbit corneal epithelium is 30 to 40 µm in thickness 36 and thinner than the human epithelium of 50 to 60 µm.…”

“… 13 , 14 The clinical need is to minimize the time of barrier recovery while maximizing the bioavailability of the administered drug. 15 , 16 For example, peptide drugs, such as cyclosporine, growth factors, interferons, and interleukins demonstrated treatment of uveitis, corneal wound healing, corneal herpes simplex infections, and modification of ocular immune response. However, most peptide drugs are impermeable when applied topically to the eye due to their high molecular weight.…”

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis

“…Angiogenesis is an attractive therapeutic target for patients with cancer, and it can be inhibited by bevacizumab (3). Bevacizumab (Avastin, Genentech, South San Francisco, CA) is a recombinant humanized immunoglobulin monoclonal antibody that binds with and inhibits the activity of human vascular endothelial growth factor-A (VEGF-A) (4). Bevacizumab enhances the effect of chemotherapy in colorectal cancer and was approved by the FDA as the first angiogenesis inhibitor to treat metastatic colorectal cancer (mCRC) (5).…”