Immunomodulatory Nanomedicine.

Immunity has a major impact on inflammatory diseases and cancer, and biologics targeting immune cells and their factors reach a quarter trillion of market volume by this year. Adaptive leukocytes have recently been engaged in cancer immunotherapy, whereas modulation of the innate immune cells, specifically macrophages, is expected as next breakthrough. With patents of major biologics expiring, nanomedicine has the potential to substitute therapeutic proteins by using miniaturized macromolecules. This review includes an overview on the involvement of major immune cell types into disease and a summary on selected current therapies based on biologics and small molecules. Novel developments in nanomedicine-based immunotherapies, including associated chances and risks, are presented.

Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro.

N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter 2 compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. Although compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis.

Alzheimer's therapeutics: neurotrophin small molecule mimetics.

A substantial portion of neuronal populations undergoing degeneration in Alzheimer's and other neurodegenerative disorders express neurotrophin receptors. Neurotrophin small molecule mimetics constitute candidate compounds that might be useful in preventing or delaying loss of neuronal function, neural networks or neuronal death in neurodegenerative states. We are testing the hypothesis that pharmacophores based on a combination of the crystal structures of neurotrophins and structure-activity relationships of active neurotrophin peptidomimetics can be used to screen small molecule libraries to identify non-peptide small molecules with neurotrophin agonist or antagonist activity. In preliminary screens using pharmacophores based on two nerve growth factor (NGF) loop domains, a number of small molecules have been identified that display neurotrophic activity using in vitro bioassays. Current studies are focused on determining whether these small molecules function via neurotrophin receptors and whether they activate neurotrophin signaling cascades. Assessment of structure-activity relationships between active and inactive small molecules will allow modification of pharmacophores and provide a basis for the iterative process if identifying compounds with increased potency and efficacy. A collection of such compounds will provide a basis for synthesis of compounds with targeted pharmacological properties.

AnergiX.RA Corixa.

Corixa (formerly Anergen), in collaboration with Organon, is developing AnergiX.RA, a complex of solubilized HLA DRB1-0401(a) together with a specific peptide from the human cartilage glycoprotein HCgp39, for the potential treatment of rheumatoid arthritis (RA) [307156]. Phase I/II trials were completed in April 2000 and the final results from the randomized, blinded, placebo-controlled dose-escalation study are expected later this year [363409]. The product utilizes Anergen's AnergiX technology, and combines an MHC-derived protein with an Organon autoantigen peptide, derived from myelin basic protein and involved in the development of RA [212659,363409]. Engagement of T-cell receptors with AnergiX.RA induces apoptosis in autoreactive T-cells [227421]. Researchers at Organon identified the central component in AnergiX.RA; results from preclinical studies identifying this target protein were published in June 1997 in Arthritis & Rheumatism. Researchers demonstrated that HC (human cartilage) gp39 is recognized by T-cells from RA patients and has the potential to block arthritis in the mouse model [248543,354821].

From serendipity to design: the evolution of drug development in oncology.

Although screening of natural products remains the major method of discovering new anticancer drugs, newer techniques of rational drug design, computer-aided drug design, and combinatorial synthesis promise to broaden the scope of compounds available for screening. Recent changes in Food and Drug Administration rules allow for accelerated approval of drugs for treating cancer and other life-threatening illnesses, although the three-phase process of clinical trials remains largely unchanged.