bq-123 and Glioblastoma

Blood perfusion was always lower in tumor tissues as compared with that in surrounding normal tissues which lead to inadequate nanomedicine delivery to tumors. Inspired by the upregulation of both endothelin-1 (ET1) and its ETA receptor in tumor tissues and the crucial contribution of ET1-ETA receptor signaling to maintain myogenic tone of tumor vessels, we supposed that inhibition of ET1-ETA receptor signaling might selectively improve tumor perfusion and help deliver nanomedicine to tumors. Using human U87 MG glioblastomas with abundant vessels as the tumor model, immunofluorescence staining demonstrated that ETA receptor was overexpressed by in glioblastomas tissues compared with normal brain tissues. A single administration of ETA receptor antagonist BQ123 at the dose of 0.5 mg/kg could effectively improve tumor perfusion which was evidenced by in vivo photoacoustic imaging. Additionally, a single treatment of BQ123 could significantly improve the accumulation of nanoparticles (NPs) around 115 nm in tumors with a more homogeneous distribution pattern by in vivo imaging, ex vivo imaging as well as in vivo distribution experiments. Furthermore, BQ123 successfully increased the therapeutic benefits of paclitaxel-loaded NPs and significantly elongated the survival time of orthotropic glioblastomas-bearing animal models. In summary, the present study provided a new strategy to selectively improve tumor perfusion and therefore benefit nanomedicine delivery for tumor therapy. As ET1-ETA receptor signaling was upregulated in a variety of tumors, this strategy might open a new avenue for tumor treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Delivery Systems; Endothelin Receptor Antagonists; Glioblastoma; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Paclitaxel; Peptides, Cyclic

We identified and characterized 125I-endothelin-1 (125I-ET-1) binding sites in tumor capillaries isolated from human glioblastomas, using the quantitative receptor autoradiographic technique with pellet sections. Quantification was done using the computerized radioluminographic imaging plate system. High-affinity ET receptors were localized in capillaries from glioblastomas and the surrounding brain tissues (KD = 4.7 +/- 1.0 x 10(-10) and 1.6 +/- 0.3 x 10(-10) M, respectively; Bmax = 161 +/- 38 and 140 +/- 37 fmol/mg, respectively; mean +/- SEM, n = 5). BQ-123, a selective antagonist for the ETA receptor, potently competed for 125I-ET-1 binding to sections of the microvessels with IC50 values of 5.1 +/- 0.3 and 5.1 +/- 1.5 nM, and 10(-6) M BQ-123 displaced 84 and 58% of ET binding to capillaries from tumors and brains, respectively. In addition, competition curves obtained in the presence of increasing concentrations of ET-3 showed two components (IC50 = 5.7 +/- 2.5 x 10(-10) and 1.4 +/- 0.2 x 10(-6) M for tumor microvessels, 1.8 +/- 0.6 x 10(-10) and 1.1 +/- 0.3 x 10(-6) M for brain microvessels, respectively). Our results indicate that (a) the method we used is simple and highly sensitive for detecting and characterizing various receptors in tumor capillaries, especially in the case of a sparse specimen, and (b) capillaries in glioblastomas express specific high-affinity ET binding sites, candidates for biologically active ET receptors, which predominantly belong to the ETA subtype.

Topics: Adult; Aged; Amino Acid Sequence; Autoradiography; Binding, Competitive; Capillaries; Endothelins; Female; Glioblastoma; Humans; Iodine Radioisotopes; Male; Middle Aged; Molecular Sequence Data; Peptides, Cyclic; Receptors, Endothelin