Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations

Abstract

Glioblastoma (GBM) is the most aggressive tumor type whose resistance to conventional treatment is mediated, in part, by the angiogenic process. New treatments involving the application of nanoformulations composed of encapsulated drugs coupled to peptide motifs that direct drugs to specific targets triggered in angiogenesis have been developed to reach and modulate different phases of this process. We performed a systematic review with the search criterion (Glioblastoma OR Glioma) AND (Therapy OR Therapeutic) AND (Nanoparticle) AND (Antiangiogenic OR Angiogenesis OR Anti-angiogenic) in Pubmed, Scopus, and Cochrane databases, in which 312 articles were identified; of these, only 27 articles were included after selection and analysis of eligibility according to the inclusion and exclusion criteria. The data of the articles were analyzed in five contexts: the characteristics of the tumor cells; the animal models used to induce GBM for antiangiogenic treatment; the composition of nanoformulations and their physical and chemical characteristics; the therapeutic anti-angiogenic process; and methods for assessing the effects on antiangiogenic markers caused by therapies. The articles included in the review were heterogeneous and varied in practically all aspects related to nanoformulations and models. However, there was slight variance in the antiangiogenic effect analysis. CD31 was extensively used as a marker, which does not provide a view of the effects on the most diverse aspects involved in angiogenesis. Therefore, the present review highlighted the need for standardization between the different approaches of antiangiogenic therapy for the GBM model that allows a more effective meta-analysis and that helps in future translational studies.

Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma

“…The mechanisms of high neovascularization in GBM have received great attention, including the presence of bizarre vessels and resistance to antiangiogenic therapy, which can be related to different types of angiogenesis [1][2][3][4][5][9][10][11][12][13][14][15][16][17]. It has been suggested that intussusception (intussusceptive microvascular growth) could be a mechanism of compensatory vascular growth occurring in human glioma [18,19], with advantages and inconveniences over classic sprouting angiogenesis [18].…”

Evaluation of Microvascular Density in Glioblastomas in Relation to p53 and Ki67 Immunoexpression

“…It is now recognized that tumors present alternative mechanisms of vascularization, such as vascular mimicry and the transdifferentiation pathway of tumor cells into endothelial cells. Vascular mimicry represents a model of functional microcirculation generated by tumor cells, lacking endothelial lining, demonstrated by immunohistochemical studies with various endothelial markers, such as CD34 or CD105 [ 19 , 20 , 21 ]. Anti-angiogenic treatments (bevacizumab) and surgical resection followed by temozolomide and radiotherapy have not achieved the expected effect and have not contributed to improving patient survival in the case of glioblastomas [ 21 , 22 ].…”