Cationic albumin-conjugated pegylated nanoparticles allow gene delivery into brain tumors via intravenous administration.
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.
Lu
Wei
W
Department of Pharmaceutics, School of Pharmacy, Fudan University (Fenglin Campus), P.O. Box 130, 138 Yi Xue Yuan Road, Shanghai 200032, P.R. China.
Sun
Qing
Q
Wan
Jin
J
She
Zhenjue
Z
Jiang
Xin-Guo
XG
D001692:Biological Transport; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000188:drug therapy* / Q000628:therapy; D006801:Humans; D007262:Infusions, Intravenous; D049329:Nanostructures / Q000008:administration & dosage*; D012709:Serum Albumin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000493:pharmacokinetics
D012709:Serum Albumin; D053221:TNF-Related Apoptosis-Inducing Ligand