carbocyanines and Lymphoma--Large-B-Cell--Diffuse

Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.

Topics: Adenine; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Carbocyanines; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Neoplasms, Experimental; Piperidines; Protein Engineering; Protein Kinase Inhibitors; Static Electricity

We have recently characterized a strain of rabbits that shows a low atherosclerotic response (LAR) to dietary hypercholesterolemia in contrast to the usual high atherosclerotic response (HAR) of rabbits [1]. Presently, we have focused on three well established and important stages of atherogenesis, i.e., monocyte adhesion to endothelium, cell mediated peroxidative modification of lipoproteins and induction of a receptor that recognizes modified low density lipoprotein (LDL). The results obtained show that (1) beta-very low density lipoprotein (beta-VLDL) from LAR and HAR rabbits enhanced monocyte adhesion to endothelial cells to the same extent; (2) Cell mediated peroxidation of LDL and beta-VLDL, tested by loss of alpha-tocopherol and formation of thiobarbituric acid reacting substances (TBARS), was compared using macrophages, fibroblasts and smooth muscle cells (SMC) of LAR and HAR rabbits and no significant differences were found; (3) Induction of scavenger receptor by phorbol ester (phorbol 12-myristate 13-acetate (PMA)) and platelet-derived growth factor-BB (PDGF-BB) was determined in SMC or fibroblasts from LAR and HAR rabbits using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-acetylated LDL (DiL-acLDL). We found a significantly higher uptake of DiI-acLDL in SMC and fibroblasts derived from HAR rabbits as compared with cells from LAR rabbits. Similar results were also obtained with [125I]-acLDL in fibroblasts from LAR and HAR rabbits with respect to cellular lipoprotein degradation after PMA pretreatment. Even though the attenuated atherosclerotic response to hypercholesterolemia of LAR rabbits may have multiple underlying causes, the most prominent so far is an apparent difference in inducibility of scavenger receptor in SMC and fibroblasts.

Topics: Animals; Arteriosclerosis; Carbocyanines; Cell Adhesion; Cells, Cultured; Diet, Atherogenic; Endothelium, Vascular; Fibroblasts; Gene Expression Regulation; Humans; Hypercholesterolemia; Lipid Peroxidation; Lipoproteins; Lymphoma, Large B-Cell, Diffuse; Macrophages; Membrane Proteins; Monocytes; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Rabbits; Receptors, Immunologic; Receptors, LDL; Receptors, Lipoprotein; Receptors, Scavenger; Scavenger Receptors, Class B; Tetradecanoylphorbol Acetate; Thiobarbituric Acid Reactive Substances; Tumor Cells, Cultured; Vitamin E