Cationic albumin-conjugated pegylated nanoparticles allow gene delivery into brain tumors via intravenous administration

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 24; pp. 11878 - 11887
• Main Authors: WEI LU, QING SUN, JIN WAN, ZHENJUE SHE, JIANG, Xin-Guo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-12-2006
• Subjects: Antineoplastic agents; Biological and medical sciences; Biological Transport; Blood-Brain Barrier; Brain Neoplasms - drug therapy; Brain Neoplasms - therapy; Genetic Therapy - methods; Genetic Vectors; Glioma - drug therapy; Glioma - therapy; Humans; Infusions, Intravenous; Medical sciences; Nanostructures - administration & dosage; Neurology; Pharmacology. Drug treatments; Serum Albumin - administration & dosage; Serum Albumin - pharmacokinetics; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - pharmacokinetics; Tumors; Tumors of the nervous system. Phacomatoses; Intracranial; Nervous system diseases; Intravenous administration; Nanoparticle; Albumin; Intracranial tumor; Cerebral disorder; Genetic transfer; Treatment; Central nervous system disease; Microparticle; Pegylated form; Gene therapy
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-2354

Patients with malignant gliomas have a poor prognosis because these tumors do not respond well to conventional treatments. Studies of glioma xenografts suggest that they may be amenable to gene therapy with cytotoxic genes, such as the proapoptotic Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). Gene therapy of gliomas ideally employs i.v. given vectors, thus excluding viral vectors as they cannot cross the brain microvascular endothelium or blood-brain barrier. Recently, we reported the synthesis of cationic albumin-conjugated pegylated nanoparticles (CBSA-NP) and showed their accumulation in mouse brain cells upon i.v. administration. In this study, plasmid pORF-hTRAIL (pDNA) was incorporated into CBSA-NP, and the resulting CBSA-NP-hTRAIL was evaluated as a nonviral vector for gene therapy of gliomas. Thirty minutes after transfection of C6 glioma cells, CBSA-NP-hTRAIL was internalized and mostly located in the cytoplasm, whereas NP-hTRAIL was entrapped in the endolysosomal compartment. At 6 and 48 hours after transfection, respectively, released pDNA was present in the nuclei and induced apoptosis. At 30 minutes after i.v. administration of CBSA-NP-hTRAIL to BALB/c mice bearing i.c. C6 gliomas, CBSA-NP-hTRAIL colocalized with glycoproteins in brain and tumor microvasculature and, via absorptive-mediated transcytosis, accumulated in tumor cells. At 24 and 48 hours after i.v. administration of CBSA-NP-hTRAIL, respectively, hTRAIL mRNA and protein were detected in normal brain and tumors. Furthermore, repeated i.v. injections of CBSA-NP-hTRAIL induced apoptosis in vivo and significantly delayed tumor growth. In summary, this study indicates that CBSA-NP-hTRAIL is a promising candidate for noninvasive gene therapy of malignant glioma.