Progression of solid tumors depends on vascularization and angiogenesis in a malignant tissue. Among a whole range of proangiogenic factors, a vascular endothelial growth factor A (VEGF-A) plays a key role. Blockade of VEGF may lead to regression of vascular network and inhibition of a tumor growth. In the present time, bevacizumab has been introduced into wide clinical practice in therapy of breast cancer, colorectal cancer and recurrent high-grade gliomas (HGGs). Coadministration of antiangiogenic therapy with irinotecan may increase probability of the response to the treatment and prolong progression-free survival rate (PFS). Moreover, bevacizumab is well tolerated and significantly improves patient's quality of life. However, in the case of brain tumors, the efficiency of such an approach is controversial. The antiangiogenic therapy can slightly delay tumor growth and does not lead to complete recovery. In addition, it contributes to enhanced tumor cell invasion into the normal brain. The mechanisms of resistance include activation of alternative proangiogenic signaling pathways, of an invasive population of tumor cells, metabolic change toward glycolysis and recruitment of myeloid bone marrow-derived cells to tumors. Obviously, that anti-VEGF therapy as monotherapy was not effective against HGGs. To enhance the antitumor treatment efficacy, it is necessary to develop a multi-target strategy to inhibit critical processes in malignancy progression such as angiogenesis, invasion, autophagy, metastatic spread, recruitment of bone marrow-derived endothelial cells and tumor stem-like cells. In addition, anti-VEGF antibodies have shown a promising result as a tumor-targeting vector for delivery therapeutic and diagnostic drugs in brain tumors.

A reproducible in vivo model of C6 glioma was developed in Wistar rats. Analysis of histological preparations showed similar morphology of rat C6 glioma and human glioblastoma. The formation of a glial border at the periphery of the glioma, consisting of GFAP-positive reactive astrocytes, was shown by the immunohistochemical method. The border appeared on day 8 after implantation, astrogliosis was observed until animal death (day 28). Reactive astrocytes with branched processes surrounded not only the primary glioma focus, but also all sites of tumor invasion in the nervous tissue. Expression of EBA (blood-brain barrier marker) was disturbed and synthesis of AMVB1 (endothelial antigen) increased in neoplastic endotheliocytes, which suggested pronounced functional restructuring of the blood-tumor barrier in comparison with the blood-brain barrier. The phenomenon of predominant expression of GFAP and AMVB in the tumor tissue can be used for the development of systems for targeted drug transport into the tumor by means of appropriate antibodies.

No abstract

(2015) Treatment of glioma by cisplatin-loaded nanogels conjugated with monoclonal antibodies against Cx43 and BSAT1, Drug Delivery, 22:3, 276-285, DOI: 10.3109/10717544.2013 AbstractTargeted drug delivery for brain tumor treatment is one of the important objectives in nanomedicine. Human glioblastoma is the most frequent and aggressive type of brain tumors. The preferential expression of membrane protein connexin 43 (Cx43) and brain-specific anion transporter (BSAT1) in the tumor and peritumoral area is a key component for targeted drug delivery. The purpose of this study was to design cisplatin-loaded nanogels conjugated with monoclonal antibodies to Cx43 and BSAT1 for treatment of intracranial gliomas 101/8. MRI volumetric analysis of tumor-bearing rats indicated significantly reduced tumor volume with cisplatin-loaded targeted-nanogel treatment compared to other formulations. The median survival of rats treated with targeted nanogels conjugated with specific mAbs against extracellular loops of Cx43 and BSAT1 were 27 and 26.6 days higher than that in control group, respectively. For the first time we demonstrated the efficiency of mAb-targeted cisplatin-loaded nanogels in the experimental model of glioma 101/8. This approach could facilitate the development of new drug delivery systems for the treatment of gliomas.