Poly(ethylenimine)-Cyclodextrin-Based Cationic Polymer Mediated HIF-1α Gene Delivery for Hindlimb Ischemia Treatment.
Jingyu LiZhuoting LuLiwang XuJing WangShaojie QianQinglian HuYunfen GePublished in: ACS applied bio materials (2024)
Hindlimb ischemia is a common disease worldwide featured by the sudden decrease in limb perfusion, which usually causes a potential threat to limb viability and even amputation or death. Revascularization has been defined as the gold-standard therapy for hindlimb ischemia. Considering that vascular injury recovery requires cellular adaptation to the hypoxia, hypoxia-inducible factor 1 α (HIF-1α) is a potential gene for tissue restoration and angiogenesis. In this manuscript, effective gene delivery vector PEI-β-CD (PC) was reported for the first application in the hindlimb ischemia treatment to deliver HIF-1α plasmid in vitro and in vivo. Our in vitro finding demonstrated that PC/HIF-1α-pDNA could be successfully entered into the cells and mediated efficient gene transfection with good biocompatibility. More importantly, under hypoxic conditions, PC/HIF-1α-pDNA could up-regulate the HUEVC cell viability. In addition, the mRNA levels of VEGF , Ang-1 , and PDGF were upregulated, and transcriptome results also demonstrated that the cell-related function of response to hypoxia was enhanced. The therapeutic effect of PC/HIF-1α-pDNA was further estimated in a murine acute hindlimb ischemia model, which demonstrated that intramuscular injection of PC/HIF-1α-pDNA resulted in significantly increased blood perfusion and alleviation in tissue damage, such as tissue fibrosis and inflammation. The results provide a rationale that HIF-1α-mediated gene therapy might be a practical strategy for the treatment of limb ischemia.
Keyphrases
- endothelial cells
- gene therapy
- oxidative stress
- genome wide
- copy number
- magnetic resonance
- gene expression
- stem cells
- coronary artery disease
- dna methylation
- hepatitis b virus
- mass spectrometry
- smooth muscle
- computed tomography
- liver failure
- mesenchymal stem cells
- atrial fibrillation
- replacement therapy
- ionic liquid
- cell proliferation
- binding protein
- ultrasound guided