as-1411 and Glioblastoma

Chemotherapy is still the main adjuvant strategy after surgery in glioblastoma therapy. As the main obstacles of chemotherapeutic drugs for glioblastoma treatment, the blood brain barrier (BBB) and non-specific delivery to non-tumor tissues greatly limit the accumulation of drugs into tumor tissues and simultaneously cause serious toxicity to nearby normal tissues which altogether compromised the chemotherapeutic effect. In the present study, we established an aptamer AS1411-functionalized poly (l-γ-glutamyl-glutamine)-paclitaxel (PGG-PTX) nanoconjugates drug delivery system (AS1411-PGG-PTX), providing an advantageous solution of combining the precisely active targeting and the optimized solubilization of paclitaxel. The receptor nucleolin, highly expressed in glioblastoma U87 MG cells as well as neo-vascular endothelial cells, mediated the binding and endocytosis of AS1411-PGG-PTX nanoconjugates, leading to significantly enhanced uptake of AS1411-PGG-PTX nanoconjugates by tumor cells and three-dimension tumor spheroids, and intensive pro-apoptosis effect of AS1411-PGG-PTX nanoconjugates. In vivo fluorescence imaging and tissue distribution further demonstrated the higher tumor distribution of AS1411-PGG-PTX as compared with PGG-PTX. As a result, the AS1411-PGG-PTX nanoconjugates presented the best anti-glioblastoma effect with prolonged median survival time and most tumor cell apoptosis in vivo as compared with other groups. In conclusion, the AS1411-PGG-PTX nanoconjugates exhibited a promising targeting delivery strategy for glioblastoma therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aptamers, Nucleotide; Brain; Brain Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Glioblastoma; Human Umbilical Vein Endothelial Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Nanoconjugates; Oligodeoxyribonucleotides; Paclitaxel; Proteins

The three oncogenes, ErbB receptors, Ras proteins and nucleolin may contribute to malignant transformation. Previously, we demonstrated that nucleolin could bind both Ras protein and ErbB receptors. We also showed that the crosstalk between the three proteins facilitates anchorage independent growth and tumor growth in nude mice, and that inhibition of this interaction in prostate and colon cancer cells reduces tumorigenicity. In the present study, we show that treatment with Ras and nucleolin inhibitors reduces the oncogenic effect induced by ErbB1 receptor in U87-MG cells. This combined treatment enhances cell death, reduces cell proliferation and cell migration. Moreover, we demonstrate a pivotal role of nucleolin in ErbB1 activation by its ligand. Nucleolin inhibitor prevents EGF-induced receptor activation and its downstream signaling followed by reduced proliferation. Furthermore, inhibition of Ras by Salirasib (FTS), mainly reduces cell viability and motility. The combined treatment, which targets both Ras and nucleolin, additively reduces tumorigenicity both in vitro and in vivo. These results suggest that targeting both nucleolin and Ras may represent an additional opportunity for inhibiting cancers, including glioblastoma, that are driven by these oncogenes.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aptamers, Nucleotide; Brain Neoplasms; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; ErbB Receptors; Farnesol; Glioblastoma; Humans; Mice, Nude; Nucleolin; Oligodeoxyribonucleotides; Phosphoproteins; Phosphorylation; ras Proteins; Receptor Cross-Talk; RNA-Binding Proteins; Salicylates; Signal Transduction; Time Factors; Tumor Burden