RGD-Modified Nanocarrier-Mediated Targeted Delivery of HIF-1α-AA Plasmid DNA to Cerebrovascular Endothelial Cells for Ischemic Stroke Treatment

Abstract

Studies have shown that the use of proangiogenic genes can improve the prognosis of ischemic stroke by promoting angiogenesis at the injury site. For example, within this study, hypoxia-inducible factor 1-α (HIF-1α) has exhibited an angiogenic effect. Our previous study reported a more stable HIF-1α mutant form (HIF-1α-AA), which was transfected into mesenchymal stem cells to provide neuroprotective effects against ischemic stroke. The safety of nonviral gene vectors has attracted researchers’ attention. This study encapsulated the HIF-1α-AA plasmid DNA into a newly synthesized effective nonviral gene vector, a hyperbranched cationic amylopectin derivative (DMAPA-Amyp) nanocarrier. In addition, a targeting strategy was applied to select the RGD peptides and bind to the designed nanocarrier as a molecule targeting endothelial cells. The targeting strategy is used to directly deliver the nanocarriers to the vascular endothelial cells of the brain peri-infarct site. This study emphasizes the targeting ability of nanocarrier and its therapeutic effect on cerebral ischemia. The results showed that RGD-DMAPA-Amyp had good biocompatibility and a high cell uptake rate, indicating that it is a safe nonviral gene vector that can be endocytosed by human cells. In rat models of ischemic stroke, compared with the nontargeted nanocarrier group, more RGD-DMAPA-Amyp nanoparticles aggregated in vascular endothelial cells of the peri-infarct region and significantly improved the recovery of neurological function. It is indicated that the RGD-modified nanomedicine promotes the recovery of nerve function more efficiently. Further study on the mechanism of RGD-DMAPA-Amyp/HIF-1α-AA in the treatment of cerebral ischemia displayed potential to significantly promote the formation of new blood vessels in vivo. Our findings suggest that the RGD-modified nonviral gene vector containing HIF-1α-AA appears to be a safe and promising therapeutic strategy for ischemic stroke gene therapy.

Erythrocyte Membrane-Enveloped Salvianolic Acid B Nanoparticles Attenuate Cerebral Ischemia-Reperfusion Injury

“…These results indicated that the modification of RGD significantly enhanced the ischemic brain target of RR@SABNPs, which was attributable to integrin αvβ3. It has been reported that the RGD peptide sequence has a high affinity to integrin αvβ3, 29 , 32 which is involved in angiogenesis after ischemia and expressed in the vessels of both the ischemic core and penumbra but not in the non-ischemic regions. 33 Additionally, a higher fluorescence distribution in the non-ischemic area of RR@SABNPs group which had a slight expression of integrin αvβ3, further demonstrated the advantage of longer circulation time endowed by RBCM coating.…”

An Insight to Brain Targeting Utilizing Polymeric Nanoparticles: Effective Treatment Modalities for Neurological Disorders and Brain Tumor

“…In vivo results indicated significant promotion in new blood vessel formation by RGD-DMAPA-Amyp/HIF-1α-AA. The results indicated that RGD-modified NPs are the safe and promising therapeutic strategy for delivering non-viral gene vectors to the brain for ischemic stroke therapy (Deng et al, 2019).…”

Recent advances in peptide-based nanomaterials for targeting hypoxia

“…The results demonstrated that this nanocomplex had good biocompatibility and could significantly improve the recovery of nerve function and the formation of new blood vessels in vivo. 107 Because many polysaccharides have a high potential for binding to oligonucleotides, nanocarriers formed by peptide functionalized polysaccharides have been used as an effective targeted gene vector into hypoxic cells. These strategies can enhance the efficiency of gene transfection and the therapeutic effect of cancer or ischemic diseases.…”

“…The results demonstrated that this nanocomplex had good biocompatibility and could significantly improve the recovery of nerve function and the formation of new blood vessels in vivo . 107 …”