The use of nanolipoprotein particles to enhance the immunostimulatory properties of innate immune agonists against lethal influenza challenge.
Recent studies have demonstrated that therapies targeting the innate immune system have the potential to provide transient, non-specific protection from a variety of infectious organisms; however, the potential of enhancing the efficacy of such treatments using nano-scale delivery platforms requires more in depth evaluation. As such, we employed a nanolipoprotein (NLP) platform to enhance the efficacy of innate immune agonists. Here, we demonstrate that the synthetic Toll-like receptor (TLR) agonists monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotides (CpG) can be readily incorporated into NLPs. Conjugation of MPLA and CpG to NLPs (MPLA:NLP and CpG:NLP, respectively) significantly enhanced their immunostimulatory profiles both in vitro and in vivo compared to administration of agonists alone, as evidenced by significant increases in cytokine production, cell surface expression of activation markers, and upregulation of immunoregulatory genes. Importantly, enhancement of cytokine production by agonist conjugation to NLPs was also observed in primary human dendritic cells. Furthermore, BALB/c mice pretreated with CpG:NLP constructs survived a lethal influenza challenge whereas pretreatment with CpG alone had no effect on survival.
Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94551, USA.
Dina R
DR
Weilhammer
Craig D
CD
Blanchette
Nicholas O
NO
Fischer
Shabnam
S
Alam
Gabriela G
GG
Loots
Michele
M
Corzett
Cynthia
C
Thomas
Cheri
C
Lychak
Alexis D
AD
Dunkle
Joyce J
JJ
Ruitenberg
Smita A
SA
Ghanekar
Andrea J
AJ
Sant
Amy
A
Rasley
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry
C408982:CPG-oligonucleotide; D016207:Cytokines; D007155:Immunologic Factors; D008050:Lipid A; D009838:Oligodeoxyribonucleotides; C048436:monophosphoryl lipid A
Antimicrobial; Drug delivery; Immunomodulation; Immunostimulation; Nanoparticle