Polymeric Particle BAM15 Targeting Macrophages Attenuates the Severity of LPS-Induced Sepsis: A Proof of Concept for Specific Immune Cell-Targeted Therapy.
Kanyarat UdompornpitakThansita BhunyakarnjanaratWilasinee SaisornChonnavee ManipunteeKittawat PlengplangSamarch SittichaitaweekulPanisa JenphatanapongSuwasin UdomkarnjananunWarerat KaewduangduenKasirapat Ariya-AnandechAmanee SamaengNumpon InsinPatcharee RitprajakAsada LeelahavanichkulPublished in: Pharmaceutics (2023)
Macrophage polarization requires different energy sources and metabolic processes. Therefore, cell energy interference to alter macrophage functions has been proposed as a treatment for severe inflammatory diseases, including sepsis. In this study, targeting cell energy using BAM15 (a mitochondrial uncoupling agent) in human THP-1 and mouse RAW264.7 macrophages prominently interfered with M1 but not M2 polarization. Free BAM15 (BAM15) and BAM15-loaded PLGA particles (BAM15 particles) reduced the inflammatory response of M1 macrophages and enhanced the expression of M2 signature genes with the restoration of mitochondrial activity (extracellular flux analysis) in RAW264.7 cells. Furthermore, BAM15 particles but not BAM15 showed specific effects on the inflammatory response of macrophages but not neutrophils, and the particles were actively captured by splenic and liver macrophages in vivo. Administration of BAM15 and BAM15 particles attenuated the severity of sepsis in LPS-induced sepsis mice. Interestingly, BAM15 particles but not BAM15 alleviated LPS-induced liver injury by reducing hepatic inflammation. Our findings substantiate the superior efficacy of macrophage-targeted therapy using a BAM15 particle-delivery system and provide further support for clinical development as a potential therapy for severe inflammatory diseases.
Keyphrases
- lps induced
- inflammatory response
- oxidative stress
- lipopolysaccharide induced
- intensive care unit
- acute kidney injury
- drug delivery
- toll like receptor
- cancer therapy
- adipose tissue
- single cell
- type diabetes
- septic shock
- skeletal muscle
- cell therapy
- poor prognosis
- insulin resistance
- climate change
- transcription factor
- signaling pathway
- binding protein
- long non coding rna
- metabolic syndrome
- pi k akt
- high fat diet induced