Tumor Anti-angiogenic Gene Therapy with Microencapsulated Recombinant CHO Cells

Microencapsulation of recombinant cells is a novel promising approach to tumor therapy in which therapeutic protein is sustainable and long-term delivered by microencapsulated cells. The semi-permeable membrane of microcapsule can protect cell from host’s immune rejection, increase the chemical stability of therapeutic protein and circumvent the problems of toxicity, limited half-lives and variation in circulating levels. Endostatin, a potent and specific angiogenesis inhibitor, could suppress the growth of primary and metastatic lesions in multiple murine tumor models. In this paper, APA microcapsules with high strength kept intact over 35 days and recombinant CHO cells kept the rapid proliferation viability and the continuous endostatin-expression function. The study of tumor treatment showed that the implantation of microencapsulated recombinant CHO cells decreased the neovascularization of tumor tissue by 59.4% and inhibited the B16 melanoma growth by 77.4%. Twenty days after tumor cell injection, 80% of animals treated with microencapsulated CHO-endo cells were alive compared to only 50% of animals in either control or mock control groups. Therefore, continuous delivery of endostatin from microencapsulated recombinant cells represents a feasible approach to tumor therapy.

[1]  P. Aebischer,et al.  Regeneration of Transected Sciatic Nerves Through Semi‐Permeable Nerve Guidance Channels: Effects of Extracellular Matrix Protein Additives , 1986, ASAIO transactions.

[2]  William Arbuthnot Sir Lane,et al.  Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth , 1997, Cell.

[3]  Jones,et al.  Angiogenesis in urological malignancy: prognostic indicator and therapeutic target , 1999, BJU international.

[4]  Lars Holmgren,et al.  Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma , 1994, Cell.

[5]  M. Kusano,et al.  Intrasplenic Transplantation of Encapsulated Hepatocytes Decreases Mortality and Improves Liver Functions in Fulminant Hepatic Failure from 90% Partial Hepatectomy in Rats , 2005, Transplantation.

[6]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[7]  A. Al-Hendy,et al.  Correction of the growth defect in dwarf mice with nonautologous microencapsulated myoblasts--an alternate approach to somatic gene therapy. , 1995, Human gene therapy.

[8]  H. Redmond,et al.  Significance of angiogenesis in cancer therapy , 1998, The British journal of surgery.

[9]  P. Brunetti,et al.  Standard technical procedures for microencapsulation of human islets for graft into nonimmunosuppressed patients with type 1 diabetes mellitus. , 2006, Transplantation proceedings.

[10]  V. Sukhatme,et al.  Endostatin Induces Endothelial Cell Apoptosis* , 1999, The Journal of Biological Chemistry.

[11]  A. Sun,et al.  Generation of alginate-poly-l-lysine-alginate (APA) biomicrocapsules: the relationship between the membrane strength and the reaction conditions. , 1994, Artificial cells, blood substitutes, and immobilization biotechnology.

[12]  P. Chang,et al.  Delivery of recombinant gene products with microencapsulated cells in vivo. , 1993, Human gene therapy.

[13]  Jeong-Ok Lim,et al.  Immunoisolated chromaffin cells implanted into the subarachnoid space of rats reduce cold allodynia in a model of neuropathic pain: a novel application of microencapsulation technology. , 2004, Artificial organs.

[14]  J. Folkman,et al.  Endostatin therapy reveals a U-shaped curve for antitumor activity , 2006, Cancer Gene Therapy.

[15]  R. Vile,et al.  VSV-G pseudotyped, MuLV-based, semi-replication-competent retrovirus for cancer treatment , 2006, Gene Therapy.

[16]  R. Bjerkvig,et al.  Cell Encapsulation Technology as a Therapeutic Strategy for Cns Malignancies 1 Immunoisolation Technology Address Correspondence and Reprint Requests To , 2001 .

[17]  J. Mier,et al.  Canstatin Inhibits Akt Activation and Induces Fas-dependent Apoptosis in Endothelial Cells* , 2003, Journal of Biological Chemistry.

[18]  A. Patz,et al.  Prolonged tumor dormancy by prevention of neovascularization in the vitreous. , 1976, Cancer research.

[19]  T. Ohira,et al.  Genetic immunotherapy by intrapleural, intraperitoneal and subcutaneous injection of IL‐2 gene‐modified Lewis lung carcinoma cells , 1997, International journal of cancer.

[20]  Thomas Boehm,et al.  Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance , 1997, Nature.

[21]  D. A. Cieslinski,et al.  Tissue engineering of a bioartificial kidney , 1994, Biotechnology and bioengineering.

[22]  C. Schnell,et al.  Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin. , 2000, Human gene therapy.

[23]  G. Painter,et al.  Molecular and Biological Properties of Ionophores , 1980 .

[24]  Liang Cheng,et al.  Combination therapy of androgen-independent prostate cancer using a prostate restricted replicative adenovirus and a replication-defective adenovirus encoding human endostatin-angiostatin fusion gene , 2006, Molecular Cancer Therapeutics.

[25]  V. Sukhatme,et al.  Endostatin: yeast production, mutants, and antitumor effect in renal cell carcinoma. , 1999, Cancer research.

[26]  J. Folkman,et al.  Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. , 1991, The New England journal of medicine.

[27]  K. Kurachi,et al.  Treatment of hemophilia B in mice with nonautologous somatic gene therapeutics. , 2002, The Journal of laboratory and clinical medicine.

[28]  Jennifer S. Lin,et al.  Inhibition of human nasopharyngeal carcinoma growth and metastasis in mice by adenovirus-associated virus–mediated expression of human endostatin , 2006, Molecular Cancer Therapeutics.

[29]  K. Hamano,et al.  The influence of tumour resection on angiostatin levels and tumour growth--an experimental study in tumour-bearing mice. , 2001, European journal of cancer.

[30]  P. Aebischer,et al.  Functional Recovery in Hemiparkinsonian Primates Transplanted with Polymer-Encapsulated PC12 Cells , 1994, Experimental Neurology.

[31]  R. Kalluri,et al.  Two RGD-independent αvβ3 Integrin Binding Sites on Tumstatin Regulate Distinct Anti-tumor Properties* , 2000, The Journal of Biological Chemistry.

[32]  R. Kalluri,et al.  Identification of the Anti-angiogenic Site within Vascular Basement Membrane-derived Tumstatin* , 2001, The Journal of Biological Chemistry.

[33]  R. Kalluri,et al.  Canstatin, a Novel Matrix-derived Inhibitor of Angiogenesis and Tumor Growth* , 2000, The Journal of Biological Chemistry.

[34]  Yan Gao,et al.  Soluble multimer of recombinant endostatin expressed in E. coli has anti-angiogenesis activity. , 2006, Biochemical and biophysical research communications.

[35]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[36]  Kyuhyun Lee,et al.  Adeno‐associated virus‐mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice , 2006, Hepatology.

[37]  C. Addison,et al.  The inhibitory effects of endostatin on endothelial cells are modulated by extracellular matrix. , 2006, Experimental cell research.

[38]  A. Al-Hendy,et al.  Delivery of human factor IX in mice by encapsulated recombinant myoblasts: a novel approach towards allogeneic gene therapy of hemophilia B. , 1996, Blood.

[39]  Giovanni Luca,et al.  Grafts of microencapsulated pancreatic islet cells for the therapy of diabetes mellitus in non‐immunosuppressed animals , 2004, Biotechnology and applied biochemistry.

[40]  D. Stefanik,et al.  Acidic and basic fibroblast growth factors are present in glioblastoma multiforme. , 1991, Cancer research.

[41]  M. Gondo,et al.  Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene , 1999, Nature Biotechnology.

[42]  P. Aebischer,et al.  A bioartificial parathyroid. , 1986, ASAIO transactions.

[43]  Anthony Atala,et al.  Continuous release of endostatin from microencapsulated engineered cells for tumor therapy , 2001, Nature Biotechnology.

[44]  Ying Zhang,et al.  Development of an in Vitro Multicellular Tumor Spheroid Model Using Microencapsulation and Its Application in Anticancer Drug Screening and Testing , 2008, Biotechnology progress.

[45]  T. Chang,et al.  Secretion of Erythropoietin from Microencapsulated Rat Kidney Cells: Preliminary Results , 1993, The International journal of artificial organs.

[46]  R. Weichselbaum,et al.  Anti-angiogenic cues from vascular basement membrane collagen. , 2000, Cancer research.

[47]  P. Chang,et al.  Delivery of recombinant gene product to canine brain with the use of microencapsulation. , 2003, The Journal of laboratory and clinical medicine.

[48]  R. Timpl,et al.  Local endostatin treatment of gliomas administered by microencapsulated producer cells , 2001, Nature Biotechnology.

[49]  N. Ferrara.  Molecular and biological properties of vascular endothelial growth factor , 1999, Journal of Molecular Medicine.