Pyrrolidone Modification Prevents PAMAM Dendrimers from Activation of Pro-Inflammatory Signaling Pathways in Human Monocytes.

Abstract

The biological features of dendrimers are affected by the character of highly reactive terminal moieties. In some polyamine dendrimer types the surface charge makes them bioincompatible and prevent their direct medical application. Moreover, foreign particles can induce the immune response which is undesirable due to the adverse side effects in vivo. The reduction of cytotoxicity of positively charged macromolecules is possible through chemical modifications of terminal groups. In our study, we have developed new derivatives of PAMAM dendrimers modified with 4-carbomethoxypyrrolidone and evaluated their immunomodulatory properties. The experiments were conducted on two human cancer myeloid cell lines: THP-1 and U937. To evaluate the cytotoxicity of dendrimers, the reasazurin assay was applied. The expression level of NF-κB targets (NFKBIA, BTG2) and cytokine genes (IL1B, TNF) was determined by quantitative real-time RT-PCR. The measurement of binding of NF-κB to a consensus DNA probe was determined by electrophoretic mobility shift assay. The ELISA cytokine assay was performed to measure protein concentration of IL-1β and TNFα. We have found that PAMAM-pyrrolidone dendrimers did not impact THP-1 and U937 viability even at high concentrations (up to 200 μM). The surface modification prevented PAMAM dendrimers from stimulating NF-κB-related signal transduction, which have been determined on the level of nuclear translocation, gene expression and protein secretion. Pyrrolidone modification efficiently prevents PAMAM dendrimers from stimulating pro-inflammatory response in human cancer myeloid cell lines, thus it can be used to improve the biocompatibility of positively charged dendrimers and to broaden the scope of their biological applications.

• Authors: Anna Janaszewska, Michał Gorzkiewicz, Mario Ficker, Johannes Fabritius Petersen, Valentina Paolucci, Jørn Bolstad Christensen, Barbara Klajnert-Maculewicz
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 15 Issue 1 Pg. 12-20 (01 02 2018) ISSN: 1543-8392 [Electronic] United States
• PMID: 29191014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dendrimers
• Immediate-Early Proteins
• Interleukin-1beta
• NF-kappa B
• NFKBIA protein, human
• PAMAM Starburst
• Pyrrolidinones
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Proteins
• NF-KappaB Inhibitor alpha
• BTG2 protein, human

Topics

• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dendrimers (chemistry)
• Humans
• Immediate-Early Proteins (genetics)
• Inflammation (immunology, metabolism)
• Interleukin-1beta (genetics)
• Monocytes (metabolism)
• NF-KappaB Inhibitor alpha (genetics)
• NF-kappa B (metabolism)
• Pyrrolidinones (chemistry, pharmacology)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (genetics)
• Tumor Suppressor Proteins (genetics)