Poly-beta amino ester-containing microparticles enhance the activity of nonviral genetic vaccines.
Current nonviral genetic vaccine systems are less effective than viral vaccines, particularly in cancer systems where epitopes can be weakly immunogenic and antigen-presenting cell processing and presentation to T cells is down-regulated. A promising nonviral delivery method for genetic vaccines involves microencapsulation of antigen-encoding DNA, because such particles protect plasmid payloads and target them to phagocytic antigen-presenting cells. However, conventional microparticle formulations composed of poly lactic-co-glycolic acid take too long to release encapsulated payload and fail to induce high levels of target gene expression. Here, we describe a microparticle-based DNA delivery system composed of a degradable, pH-sensitive poly-beta amino ester and poly lactic-co-glycolic acid. These formulations generate an increase of 3-5 orders of magnitude in transfection efficiency and are potent activators of dendritic cells in vitro. When used as vaccines in vivo, these microparticle formulations, unlike conventional formulations, induce antigen-specific rejection of transplanted syngenic tumor cells.
Little
Steven R
SR
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Lynn
David M
DM
Ge
Qing
Q
Anderson
Daniel G
DG
Puram
Sidharth V
SV
Chen
Jianzhu
J
Eisen
Herman N
HN
Langer
Robert
R
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D016503:Drug Delivery Systems / Q000379:methods*; D004952:Esters / Q000737:chemistry*; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D006016:Glycolates / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology; D010879:Piperazines / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D014162:Transfection / Q000379:methods*; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics* / Q000276:immunology
D019496:Cancer Vaccines; D004952:Esters; D006016:Glycolates; D010879:Piperazines; D011091:Polyesters; D011108:Polymers; D019444:Vaccines, DNA; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid