Development of novel substrates for tumor immunotherapy

• Published in: Journal of controlled release Vol. 91; no. 1; pp. 209 - 224
• Main Authors: Shalaby, Waleed S.W., Yeh, Heidi, Woo, Edward, Hendren, Samantha, Corbett, Joel T., Gray, Heidi, June, Carl H., Shalaby, Shalaby W.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier B.V 28.08.2003; Elsevier
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Biomaterials; CD28 antigen; CD28 Antigens - immunology; CD3 antigen; CD3 Complex - immunology; Cytokines - chemistry; Dendritic cell; Dendritic Cells - immunology; Flow Cytometry; General pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Humans; Immunotherapy; Lymphocyte Activation; Medical sciences; Mice; Mice, Inbred BALB C; Microparticles; Microscopy, Electron; Microspheres; Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - prevention & control; Neoplasms - therapy; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyglycolic Acid - chemistry; T cell; T-Lymphocytes - immunology; Tumor immunotherapy; Dendritic cell; Tumor immunotherapy; T cell; Microparticles; Biomaterials; Pharmaceutical technology; Cytokine; Immobilization; Drug carrier; Monoclonal antibody; Malignant tumor; In vitro; Biological activity; Prevention; Substrate; In vivo; Granulocyte colony stimulating factor; Immunotherapy; T-Lymphocyte; Dosage form; Microparticle; Active ingredient; Subcutaneous administration; Release
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(03)00238-4

Acid-terminated polyglycolide microparticles (PG-MP) were prepared as a versatile substrate that could be surface-modified for either immobilization of anti-cd3 and anti-cd28 mAb to activate T cells or sustained release of granulocyte-macrophage colony stimulating factor (GM-CSF) for dendritic cell (DC) recruitment and maturation. PG-MP were prepared with a volume-weighted mean diameter of 56 or 57 μm. Accessible carboxylic acid group concentration was determined by potentiometric titration to be 0.3 mmole/g and corresponded to a zeta potential of −21.87 mV. PG-MP immobilized with either anti-human CD3/CD28 or anti-mouse cd3/cd28 induced significant proliferation of T cells. Intracellular flow cytometry in activated mouse T cells was significant for IFN-γ, but not IL-4. Microparticles surface-modified for GM-CSF release were prepared from either PG-MP or PG pre-treated with poly- l-lysine (PG-Lys) to manipulate surface charge. GM-CSF released from PG-Lys-MP was observed for up to 26 days. The biologic activity of released GM-CSF was confirmed by using a h-GM-CSF-dependent cell line. The efficacy of the α-cd3/cd28-MP and GMCSF-MP was studied in a syngeneic mouse tumor prevention and regression model. Co-injection of Meth A fibrosarcoma cells with α-cd3/cd28-MP and GMCSF-MP completely prevented tumor implantation (0/24). The regression model showed complete tumor regression in four of seven animals and stable disease in three of seven. In the latter study, a dramatic level of DC infiltration was observed compared to controls.