pH-sensitive peptide hydrogel encapsulating the anti-angiogenesis drug conbercept and chemotherapeutic drug dox as a combination therapy for retinoblastoma

Abstract

Retinoblastoma (RB) is a malignant tumor originating from the retina. Radiotherapy, chemotherapy, photodynamic therapy, cryotherapy, and surgery are commonly used in the clinical treatment of RB, but the overall efficacy is poor and often accompanied with tumor metastasis. Vascular endothelial growth factor (VEGF) has been confirmed to be highly expressed in the aqueous humor of RB patients and is closely related to the occurrence and metastasis of tumors. Therefore, we combined the anti-VEGF fusion protein conbercept, which is frequently used in the treatment of macular lesions, and the traditional chemotherapeutic drug doxorubicin (DOX). In order to reduce the frequency of drug administration and adverse drug effects and improve treatment compliance, we designed and successfully synthesized a pH-sensitive heptapeptide (DDIIIOH-NH₂) encapsulating conbercept and doxorubicin to form a stable hydrogel at a concentration of 20 mg mL⁻¹ under pH 7.4. The hydrogel was characterized using transmission electron microscopy and rheological tests. Its drug-release properties under acidic and neutral conditions were also analyzed, with the results illustrating that the hydrogel had ideal solid stability, injectability, sustained-release behavior, and pH sensitivity. Meanwhile, the drug-delivery system effectively diminished Y79 tumor cells as well as inhibited the VEGF-induced proliferation of retinal endothelial cells (HRECs) and the following angiogenesis. In vivo experiments showed that the drug-delivery system could effectively inhibit the proliferation and angiogenesis of tumor tissues. We believe that the pH-sensitive hydrogel is an ideal drug-delivery system for the treatment of retinoblastoma.