Folate-targeted nanoparticles show efficacy in the treatment of inflammatory arthritis.

摘要: Folate receptors (FR) comprise a family of glycosylphophatidylinositol (GPI)-anchored, high affinity for folic acid (FA), and are the products at least four different genes; FRα, β, γ, δ (1, 2). Although much research has focused on folate receptor-α (FRα) as target therapy imaging in oncology, several recent studies have used FRβ therapeutic macrophages inflammatory diseases (3–5). In rheumatoid arthritis (RA), example, been shown to be specifically expressed activated inflamed joints, thus providing delivery both therapeutics agents (6–9). Studies demonstrated specific internalization/accumulation radionuclide-conjugated FA joints mice, rats, dogs, horses even humans (3). The feasibility using mediate molecules is based unique biological characteristics FR. First, expression myelomonocytic/macrophage lineages hematopoietic cells, while there negligible this molecule other blood cells such lymphocytes, granulocytes or erythrocytes (9, 10). Second, elevated levels functional glycosylated only involved responses, but not quiescent resident (5, 11). addition, FRα known preferentially apical (luminal) side (e.g., urine kidney tubules air sac lungs) normal tissues; therefore it possible that will minimal binding circulating folate-targeted drugs tissues (12). Finally, although free MTX can access through ubiquitously reduced carrier (RFC), uptake channel does occur when conjugated macromolecule like nanoparticle. These findings together suggest predominant could bind internalize targeted nanoparticle from circulation FRβ. Methotrexate (MTX) an “antifolate” drug competes with dihydrofolate reductase enzyme blocks one-carbon transfer reaction biosynthesis nucleotides. This inhibits DNA formation results cell proliferation induction apoptosis. For over two decades employed disease-modifying anti-rheumatic (DMARD) treatment RA, either single agent combination biologics TNF inhibitors (13, 14). mechanisms by which suppresses complex may extend beyond inhibition synthesis cells. It include increased release adenosine, altered production cytokines, reactive oxygen species, T apoptosis, suppression B responses (4, 15, 16). Several suggested one mechanism activity RA anti-proliferative effects following into these via 5, 9, 10, 13, 17–19). Unfortunately, about one-third patients respond poorly another third develop toxic effects. Patients polymorphisms proteins RFC 5,10-methylenetetrahydrofolate transport metabolism (20–22). Since result its action preventing targeting independent prevent problems. Poly(amidoamine) (PAMAM) dendrimers extensively macromolecular platform attractive properties purpose (Figure 1). uniformity, biocompatibility, defined structure capability chemically coupling multiple molecular entities primary surface amino groups (23–26). Many functions coupled dendrimer’s retained variety including hormones (27, 28), peptides (29), antibodies (30), chemotherapeutic (28, 31), apoptosis-sensing fluorochrome (32). Importantly, prior our laboratory bearing FRα-expressing xenograft tumors mice increase index carried more than 10-fold (31). report, anti-inflammatory indomethacin (IM) encapsulated generation 4 dendrimer-FA conjugate presumably (33). present study, we investigated FA-bearing G5 vitro deliver collagen-induced model rats. Figure 1 Schematic representation structures generations PAMAM dendrimers, starting ethylene diamine (EDA) core, functionalized dendrimer G5-FA-MTX. details steps ...