Delivery of rapamycin to dendritic cells using degradable microparticles.
Degradable microparticles have the potential to protect and release drugs over extended periods and, if sized appropriately, can be passively targeted to phagocytic cells in vivo. Dendritic cells (DC) are a class of phagocytic cells known to play important roles in transplant rejection. Previously, we have demonstrated that DC treated with an immunosuppressive drug, rapamycin, have the ability to suppress transplant rejection. Herein, we describe a strategy to deliver an intracellular depot of rapamycin to DC. To achieve this, rapamycin was encapsulated into ~3.4 microm sized poly(lactic-co-glycolic)acid (PLGA) microparticles (rapaMPs), and release behavior was examined under intra-phagosomal (pH=5) and extracellular (pH=7.4) conditions. It was observed that 4 days following phagocytosis of rapaMP, DC have significantly reduced ability to activate T cells, in comparison to DC treated with soluble rapamycin. Hence, we conclude that DC-specific intracellular delivery of rapamycin results in better efficacy of the drug, with respect to its ability to modulate DC function, when compared to treating DC with extracellular rapamycin.
Jhunjhunwala
S
S
Department of Bioengineering, University of Pittsburgh, PA 15260, USA.
Raimondi
G
G
Thomson
A W
AW
Little
S R
SR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051940:B7-2 Antigen / Q000378:metabolism; D001682:Biological Availability; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013499:Surface Properties
D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D020123:Sirolimus