Yu Yu, Lau Laurence Chi Ming, Lo Amy Cheuk-Yin, Chau Ying
Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon Hong Kong, China.
Department of Ophthalmology, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
Transl Vis Sci Technol. 2015 Mar 10;4(2):5. doi: 10.1167/tvst.4.2.5. eCollection 2015 Mar.
To evaluate the biocompatibility and 6-month in vivo release of bevacizumab from a hyaluronic acid/dextran-based in situ hydrogel after intravitreal injection in rabbit eye.
The in situ hydrogel was formed by the catalyst-free chemical crosslinking between vinylsulfone functionalized hyaluronic acid (HA-VS) and thiolated dextran (Dex-SH) at physiological condition. The pH 7.4 buffered mixture containing HA-VS, Dex-SH, and bevacizumab were injected into the vitreous of rabbit eyes by a 30-G needle. The biocompatibility was evaluated by intraocular pressure measurement, binocular indirect ophthalmoscope (BIO), full-field electroretinogram (ERG), and histology. The concentrations of both total and active bevacizumab in rabbit vitreous were determined by enzyme-linked immunosorbent assay. The concentration of bevacizumab in rabbit vitreous after bolus injection was simulated by one-compartment first order elimination model.
A transparent gel was seen in the vitreous after injection. BIO images, ERG, and histology showed that the gel does not induce hemorrhage, retinal detachment, inflammation, or other gross pathological changes in rabbit eyes after injection. While the bolus intravitreal injected bevacizumab follows the first order elimination kinetics in rabbit eye, the in situ gel formation was able to prolong the retention of bevacizumab in rabbit eye at therapeutic relevant concentration for at least 6 months. The concentration of bevacizumab 6 months after injection was about 10 times higher than bolus injection.
The new in situ hydrogel formulation of bevacizumab was biocompatible and able to prolong the retention of drug in rabbit eyes in vivo at therapeutic relevant concentration for at least 6 months.
Although proven to be effective, monthly intravitreal injection of bevacizumab or other protein drugs may cause various complications. Extending the residence time of protein therapeutics in the eye can reduce the injection frequency, its associated complications, and treatment cost, which will be beneficial to both the patients and doctors. In this study, we showed that the in situ hydrogel-based controlled release system is a feasible option to tackle this problem.
评估玻璃体内注射到兔眼后，基于透明质酸/葡聚糖的原位水凝胶中贝伐单抗的生物相容性及6个月的体内释放情况。
原位水凝胶通过乙烯砜功能化透明质酸（HA-VS）与硫醇化葡聚糖（Dex-SH）在生理条件下的无催化剂化学交联形成。将含有HA-VS、Dex-SH和贝伐单抗的pH 7.4缓冲混合物用30G针头注射到兔眼玻璃体内。通过眼压测量、双目间接检眼镜（BIO）、全视野视网膜电图（ERG）和组织学评估生物相容性。用酶联免疫吸附测定法测定兔玻璃体内总贝伐单抗和活性贝伐单抗的浓度。用单室一级消除模型模拟推注注射后兔玻璃体内贝伐单抗的浓度。
注射后在玻璃体内可见透明凝胶。BIO图像、ERG和组织学显示，注射后该凝胶在兔眼中未引起出血、视网膜脱离、炎症或其他明显的病理变化。虽然推注玻璃体内注射的贝伐单抗在兔眼中遵循一级消除动力学，但原位凝胶形成能够将贝伐单抗在兔眼中的治疗相关浓度下的保留时间延长至少6个月。注射6个月后贝伐单抗的浓度比推注注射高约10倍。
贝伐单抗新的原位水凝胶制剂具有生物相容性，能够在治疗相关浓度下将药物在兔眼中的体内保留时间延长至少6个月。
尽管已证明玻璃体内每月注射贝伐单抗或其他蛋白质药物有效，但可能会引起各种并发症。延长蛋白质治疗药物在眼内的停留时间可以减少注射频率、相关并发症和治疗成本，这对患者和医生都有益。在本研究中，我们表明基于原位水凝胶的控释系统是解决这一问题的可行选择。
