ABSTRACT
Ultra-small 1-2 nm gold nanoparticles (NP) were conjugated with a poorly-soluble peptide auto-antigen, associated with type 1 diabetes, to modify the peptide pharmacokinetics, following its intradermal delivery. Peptide distribution was characterized, in vivo, after delivery using either conventional intradermal injection or a hollow microneedle device. The poorly-soluble peptide was effectively presented in distant lymph nodes (LN), spleen and draining LN when conjugated to the nanoparticles, whereas peptide alone was only presented in the draining LN. By contrast, nanoparticle conjugation to a highly-soluble peptide did not enhance in vivo distribution. Transfer of both free peptide and peptide-NPs from the skin to LN was reduced in mice lacking lymphoid homing receptor CCR7, suggesting that both are actively transported by migrating dendritic cells to LN. Collectively, these data demonstrate that intradermally administered ultra-small gold nanoparticles can widen the distribution of poorly-soluble auto-antigenic peptides to multiple lymphoid organs, thus enhancing their use as potential therapeutics.
Subject(s)
Antigens/metabolism , Gold/chemistry , Metal Nanoparticles/chemistry , Peptides/pharmacology , Amino Acid Sequence , Animals , Cell Proliferation , Dendritic Cells/drug effects , Injections, Intradermal , Mice, Inbred C57BL , Mice, Transgenic , Needles , Peptides/chemistry , Peptides/pharmacokinetics , Phenotype , Skin/drug effects , Solubility , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
IntegraGen SA is at the stage of commercializing a series of innovative IntegraTests™ to position itself as a leader within the rapidly growing market of predictive medicine. By applying its proprietary gene-mapping technology GenomeHIP™ (Genome Hybrid Identity Profiling) in premier patient collections, IntegraGen has rapidly discovered novel genes and genetic markers associated with a variety of complex, multifactorial diseases to use in its IntegraTests - a new class of personalized medicine diagnostics. IntegraTests provide prediction, prevention, detailed diagnosis and tailored treatment of complex diseases. Depending on the disease and the applied set of genetic markers, these tests can calculate the personal risk for acquiring the disease, define the various subforms of complex diseases, predict susceptibility to severe comorbidities, and help to define a personalized health management program. Focusing on metabolic syndrome and neuropsychiatric disorders, IntegraGen will launch its first tests in Europe in 2005.
ABSTRACT
Nuclear receptors are ligand-modulated transcription factors. On the basis of the completed human genome sequence, this family was thought to contain 48 functional members. However, by mining human and mouse genomic sequences, we identified FXRbeta as a novel family member. It is a functional receptor in mice, rats, rabbits, and dogs but constitutes a pseudogene in humans and primates. Murine FXRbeta is widely coexpressed with FXR in embryonic and adult tissues. It heterodimerizes with RXRalpha and stimulates transcription through specific DNA response elements upon addition of 9-cis-retinoic acid. Finally, we identified lanosterol as a candidate endogenous ligand that induces coactivator recruitment and transcriptional activation by mFXRbeta. Lanosterol is an intermediate of cholesterol biosynthesis, which suggests a direct role in the control of cholesterol biosynthesis in nonprimates. The identification of FXRbeta as a novel functional receptor in nonprimate animals sheds new light on the species differences in cholesterol metabolism and has strong implications for the interpretation of genetic and pharmacological studies of FXR-directed physiologies and drug discovery programs.
