Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Abstract

PURPOSE. We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery.METHODS. The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. RESULTS.The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections.CONCLUSIONS. To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.Keywords: thermally responsive hydrogel, ocular drug delivery, sustained release, biocompatibility, injectable gel C horoidal neovascularization (CNV) is the hallmark of many blinding disorders, most notably wet age-related macular degeneration (AMD) and diabetic retinopathy. It is characterized by pathologic blood vessel growth, which originates in the choroid and progresses through the Bruch's membrane into the subretinal space.1 These vessels are fragile and permeable, causing hemorrhage, retinal detachment, scarring, and ultimately, loss of central vision. Elevated levels of VEGF is a central cause of CNV.2-4 Thus, intravitreal injection of anti-VEGF medications, such as bevacizumab (Avastin) or ranibizumab (Lucentis), has emerged as a leading treatment strategy. [5][6][7] The efficacy of these drugs, however, is limited severely by rapid clearance from the eye; their half-lives are on the order of 7 days. 8,9 This necessitates frequent injections, imposing a significant burden on patients and increasing healthcare costs as well as procedure-related complications, such as endophthalmitis, retinal detachment, cataract, and uveitis.10-13 Therefore, a delivery system that extends the presence of intravitreal drugs in the eye is highly desirable for reducing injection frequency and adverse effects, w...

Injectable Chemically Crosslinked Hydrogel for the Controlled Release of Bevacizumab in Vitreous: A 6-Month In Vivo Study

“…The trend is consistent with other reports on intravitreal in situ gel injection. 22 The value of IOP elevation was not as high as other reports, because we injected 40 lL instead of 50 lL gel (as used by other authors) intentionally to minimize IOP elevation and allow faster recovery. Conditions associated with IOP elevation including cataract and retinal ganglion cell loss were not observed by BIO or histology.…”

“…However, although promising in vitro protein release has been demonstrated by this approach, 19,21 the in vivo performance was not satisfactory and has only been demonstrated in one study. 22 Moreover, hydrophobic interaction between protein and the polymer may potentially affect the chemical or physical stability of the protein. 24 The nontransparent appearance of these gels may also hinder its application in the eye.…”

“…After purification with tangential flow filtration (TFF, mPES MidiKros TFF Filter, NMWL ¼ 3 kDa, D02-E003-05-N, Spectrum Laboratory, Inc., CA), the polymers were adjusted to pH 5.2, sterilized by filtering through a 0. 22 Cell Culture and Cytocompatibility of Hydrogel ARPE-19 cells were maintained according to published protocols. 12 The cytocompatibility of hydrogel incubation and the in situ gelation process were examined by the Live/Dead assay (Life Technologies).…”

A new model for in vitro testing of vitreous substitute candidates

“…The synthetic polymer hydrogel PEG is used in different biomedical application, has been tested for intravitreal administration of drugs [24,39] and is FDA approved for use intravitreally. The in vivo trials showed favorable biocompatibility but inadequate stability in vivo using PEG where the substance was largely tolerated with minor changes in retinal cytoarchitecture and GFAPupregulation, and minor electrophysiological changes [38].…”

Slow-release Drug Delivery through Elvax 40W to the Rat Retina: Implications for the Treatment of Chronic Conditions

“…It would only require a simple implantation process into the vitreous cavity close to the limbus of the eye, and would not require suturing after implantation. Recently, there has been an emergence in several novel delivery systems, such as encapsulated cell technology (ECT) 24,25 , hydrogels 26 , and microfilms 27 . However, the method used in the current study for preparing and delivering the drug-resin complex is both easy to follow and inexpensive, thereby being more advantageous for use in a basic research environment.…”