Cyclic-RGDyC functionalized liposomes for dual-targeting of tumor vasculature and cancer cells in glioblastoma: An in vitro boron neutron capture therapy study

Abstract

The efficacy of boron neutron capture therapy depends on the selective delivery of 10B to the target. Integrins αvβ3 are transmembrane receptors over-expressed in both glioblastoma cells and its neovasculature. In this study, a novel approach to dual-target glioblastoma vasculature and tumor cells was investigated. Liposomes (124 nm) were conjugated with a αvβ3 ligand, cyclic arginine-glycine-aspartic acid-tyrosine-cysteine peptide (c(RGDyC)-LP) (1% molar ratio) through thiol-maleimide coupling. Expression of αvβ3 in glioblastoma cells (U87) and human umbilical vein endothelial cells (HUVEC), representing tumor angiogenesis, was determined using Western Blotting with other cells as references. The results showed that both U87 and HUVEC had stronger expression of αvβ3 than other cell types, and the degree of cellular uptake of c(RGDyC)-LP correlated with the αvβ3-expression levels of the cells. In contrast, control liposomes without c(RGDyC) showed little cellular uptake, regardless of cell type. In an in vitro boron neutron capture therapy study, the c(RGDyC)-LP containing sodium borocaptate generated more rapid and significant lethal effects to both U87 and HUVEC than the control liposomes and drug solution. Interestingly, neutron irradiated U87 and HUVEC showed different types of subsequent cell death. In conclusion, this study has demonstrated the potential of a new dual-targeting strategy using c(RGDyC)-LP to improve boron neutron capture therapy for glioblastoma.

Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo

“…Cilengitide is an antagonist of integrins and preliminary but promising results have suggested that the microenvironment plays a role in glioblastoma progression and that ITGB3 inhibitors can act in a neoadjuvant setting to prevent metastasis rather than reduce tumours once formed [ 65 ]. Recently, other studies have used drugs to target integrin αvβ3 in glioblastoma and more recently in lung cancer [ 77 , 78 ].…”

Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood–Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor‐Associated Macrophages

“…The positive effect of iRGD conjugation on DOX uptake and cytotoxicity in the human TNBC cells is possibly due to integrin‐mediated endocytosis of iRGD‐DMTPLN via αv integrins overexpressed on both cell lines 19b,c. In RAW 264.7 macrophages, indistinguishable drug uptake and cytotoxicity between DMTPLN and iRGD‐DMTPLN are ascribed to the lack of αv integrin overexpression …”

“…The treatment with iRGD‐DMTPLN resulted in a more reduction in F4/80 positive area compared to DMTPLN treatment, though the difference was not statistically significant (Figure b). Although macrophages do not overexpress αvβ3 integrin, their baseline expression of αvβ3 was reported to enable RGD peptide targeting to reduce TAM recruitment in a murine glioblastoma xenografts model . Thus, in addition to delivering more drugs to the metastatic microenvironment, iRGD‐DMTPLN may also inhibit TAM recruitment, resulting in greater TAM reduction as shown in Figure .…”

Optical in vivo imaging detection of preclinical models of gut tumors through the expression of integrin αVβ3

“…The role of integrins in cancer progression has been extensively described, being involved in tumor cell migration, invasion and control of angiogenesis, lymphangiogenesis and inflammation [ 10 , 11 ]. Among integrins, αvβ3 is probably the most strongly involved in the regulation of angiogenesis [ 11 , 13 , 40 ]. It has been reported that, differently from the quiescent endothelium, integrin αvβ3 is highly expressed by tumor-associated vessels, possibly mediating the interaction between endothelial cells and provisional matrix protein, such as vitronectin, fibrinogen and proteolized collagen [ 11 , 15 , 41 , 42 ].…”