Continuous release of endostatin from microencapsulated engineered cells for tumor therapy.
Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67. 2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 x 10(5) encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.
Joki
T
T
Brain Tumor Laboratory, Department of Neurosurgery, Department of Surgery, Brigham Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Machluf
M
M
Atala
A
A
Zhu
J
J
Seyfried
N T
NT
Dunn
I F
IF
Abe
T
T
Carroll
R S
RS
Black
P M
PM
D000464:Alginates; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D001672:Biocompatible Materials; D001932:Brain Neoplasms / Q000628:therapy*; D002196:Capillaries; D002214:Capsules; D002417:Cattle; D017690:Cell Transplantation; D002478:Cells, Cultured; D003094:Collagen / Q000008:administration & dosage* / Q000235:genetics* / Q000627:therapeutic use; D006224:Cricetinae; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000235:genetics* / Q000627:therapeutic use; D011107:Polylysine / Q000031:analogs & derivatives; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D013552:Swine; D014162:Transfection; D014183:Transplantation, Heterologous
D000464:Alginates; D020533:Angiogenesis Inhibitors; D001672:Biocompatible Materials; D002214:Capsules; D043169:Endostatins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C051546:alginate-polylysine-alginate; D011107:Polylysine; D003094:Collagen