1-2-dioleoyloxy-3-(trimethylammonium)propane and Pneumonia

Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune Deficiency Syndrome patients. Antiviral drugs ganciclovir (GCV) and phosphonoformate (PFA) are first-line agents for pneumonia caused by herpesvirus infection. However, the therapy suffers from various limitations such as low efficiency, drug resistance, toxicity, and lack of specificity.. The antiviral drugs GCV and PFA were loaded into the pH-responsive nanoparticles fabricated by poly(lactic-co-glycolic acid) (PLGA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and further coated with cell membranes derived from bone marrow mesenchymal stem cells to form artificial stem cells, namely MPDGP. We evaluated the viral suppression effects of MPDGP in vitro and in vivo.. MPDGP showed significant inflammation tropism and efficient suppression of viral replication and virus infection-associated inflammation in the CMV-induced pneumonia model. The synergistic effects of the combination of viral DNA elongation inhibitor GCV and viral DNA polymerase inhibitor PFA on suppressing the inflammation efficiently.. The present study develops a novel therapeutic intervention using artificial stem cells to deliver antiviral drugs at inflammatory sites, which shows great potential for the targeted treatment of pneumonia. To our best knowledge, we are the first to fabricate this kind of artificial stem cell to deliver antiviral drugs for pneumonia treatment.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Fatty Acids, Monounsaturated; Foscarnet; Ganciclovir; Humans; Inflammation; Nanoparticle Drug Delivery System; Pneumonia; Polylactic Acid-Polyglycolic Acid Copolymer; Quaternary Ammonium Compounds; Stem Cells

Phase 1 clinical trials of liposome-mediated gene therapy for cystic fibrosis have been completed and in all cases the expression level achieved has been low and transient. Clearly, improvements in the efficiency of gene transfer are required. It is now being recognised that delivery of high doses of DNA/liposomes to the mouse airway epithelium can achieve reproducible evidence of transgene, but is often associated with an unacceptable level of inflammation/ toxicity. It has recently been shown that instillation of bacterial DNA causes inflammation in the lower respiratory tract of rodents. The increased number and unmethylated status of CpG motifs, particularly when present in a particular base context, was identified as an important factor in this response. It was suggested that the immune system recognises this molecular pattern as 'foreign' thus activating appropriate immune responses. We have found that methylation of DNA decreases the level of several inflammatory cytokines in lavage fluid and surprisingly has a differential effect on expression of the plasmids pCMV CFTR-int6ab and pCMV CAT which only differ in the actual transcription cassette. The severe lung pathology observed did not show a corresponding decrease with methylation suggesting that these cytokines are not the only contributors to the toxicity/inflammation observed. Gene Therapy (2000) 7, 384-392.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; DNA, Bacterial; Fatty Acids, Monounsaturated; Gene Expression; Gene Transfer Techniques; Methylation; Mice; Pneumonia; Quaternary Ammonium Compounds; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Transgenes