PMID- 15203918
OWN - NLM
STAT- MEDLINE
DCOM- 20040907
LR  - 20220309
IS  - 1061-186X (Print)
IS  - 1026-7158 (Linking)
VI  - 11
IP  - 8-10
DP  - 2003
TI  - Biodegradable nanoparticle mediated antigen delivery to human cord blood derived 
      dendritic cells for induction of primary T cell responses.
PG  - 495-507
AB  - Dendritic cells (DCs) in the peripheral tissues act as sentinels of the immune 
      system. They detect and capture pathogens entering the body and present their 
      antigens to T cells to trigger responses directed towards elimination of the 
      pathogen. The induction of peripheral tolerance against self and certain foreign 
      antigens is also believed to be mediated through DCs. The outcome of any immune 
      response is largely controlled by the microenvironment of antigen capture, 
      processing and presentation by DCs. The "context" of antigen delivery to DCs will 
      directly influence the microenvironment of antigen presentation and hence the 
      regulation of immune responses. We report here preliminary investigations 
      describing the formulation of a pharmaceutically acceptable, biodegradable, and 
      strategic nanoparticulate delivery system, and its application for efficient 
      antigen loading of DCs to achieve antigen specific T cell activation. 
      "Pathogen-mimicking" nanoparticles capable of interacting with DCs were 
      fabricated by incorporating monophosphoryl lipid A (MPLA; toll-like receptor 
      (TLR) 4 ligand) or CpG ODN (seq #2006; TLR9 ligand) in biodegradable copolymer, 
      poly(D,L,-lactic-co-glycolic acid) (PLGA). The uptake of PLGA nanoparticles by 
      human umbilical cord blood derived DCs (DCs propagated from CD34 progenitors) was 
      conclusively demonstrated by scanning electron microscopy (SEM), fluorescence 
      activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM). Cell 
      phenotype at day 12 of cultures was determined as immature DC using specific cell 
      surface markers, i.e. CD11c (approximately 90%), MHC-II (approximately 70%), CD86 
      (approximately 20%), CD83 (approximately 5%), CD80 (approximately 40%), CD40 
      (approximately 40%), and CCR7 (approximately 5%). Tetanus toxoid (TT), a model 
      antigen, was encapsulated in nanoparticles along with an immunomodulator, i.e. 
      either MPLA or CpG ODN. DCs pulsed with various antigen formulations were 
      co-cultured with autologous naive T cells at various cell ratios (DC: T cells 
      were 1:5-20). The DCs pulsed with TT and MPLA together in nanoparticles induced 
      significantly higher T cell proliferation (P<0.05) as compared to when DCs pulsed 
      with TT and MPLA in solution were employed. A similar trend was observed when CpG 
      ODN was used instead of MPLA in the TT nanoparticles. This strategy of antigen 
      delivery to DCs was then tested with a cancer vaccine candidate, a MUC1 
      lipopeptide. The T cell proliferation observed in the presence of nanoparticulate 
      MUC1 and MPLA pulsed-DCs was much higher than DCs pulsed with soluble antigen 
      (P<0.0005). These results indicate that PLGA nanoparticles mimicking certain 
      features of pathogens are efficient delivery systems for targeting vaccine 
      antigens to DCs and activation of potent T cell responses.
FAU - Diwan, Manish
AU  - Diwan M
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      Canada.
FAU - Elamanchili, Praveen
AU  - Elamanchili P
FAU - Lane, Helena
AU  - Lane H
FAU - Gainer, Anita
AU  - Gainer A
FAU - Samuel, John
AU  - Samuel J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Drug Target
JT  - Journal of drug targeting
JID - 9312476
RN  - 0 (CPG-oligonucleotide)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Drug Carriers)
RN  - 0 (Lipid A)
RN  - 0 (MUC1 tandem repeat peptide)
RN  - 0 (Mucin-1)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (Peptide Fragments)
RN  - 0 (Polymers)
RN  - 0 (Tetanus Toxoid)
RN  - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer)
RN  - 26009-03-0 (Polyglycolic Acid)
RN  - 33X04XA5AT (Lactic Acid)
RN  - MWC0ET1L2P (monophosphoryl lipid A)
SB  - IM
MH  - Cancer Vaccines/administration & dosage/immunology
MH  - Dendritic Cells/*immunology/metabolism
MH  - Drug Carriers
MH  - Fetal Blood
MH  - Humans
MH  - In Vitro Techniques
MH  - Lactic Acid/chemistry
MH  - Lipid A/*analogs & derivatives/chemistry
MH  - Mucin-1/*administration & dosage/chemistry/immunology
MH  - Nanotechnology
MH  - Oligodeoxyribonucleotides/chemistry
MH  - Peptide Fragments/*administration & dosage/chemistry/immunology
MH  - Polyglycolic Acid/chemistry
MH  - Polylactic Acid-Polyglycolic Acid Copolymer
MH  - Polymers/chemistry
MH  - T-Lymphocytes/*immunology
MH  - Tetanus Toxoid/*administration & dosage/chemistry/immunology
EDAT- 2004/06/19 05:00
MHDA- 2004/09/08 05:00
CRDT- 2004/06/19 05:00
PHST- 2004/06/19 05:00 [pubmed]
PHST- 2004/09/08 05:00 [medline]
PHST- 2004/06/19 05:00 [entrez]
AID - T2TXETDRN0T0DQL7 [pii]
AID - 10.1080/10611860410001670026 [doi]
PST - ppublish
SO  - J Drug Target. 2003;11(8-10):495-507. doi: 10.1080/10611860410001670026.