RESUMEN
Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. STATEMENT OF SIGNIFICANCE.
Asunto(s)
Nanopartículas , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ácido Poliglicólico/farmacología , Ácido Láctico/farmacología , Línea Celular Tumoral , Células EndotelialesRESUMEN
Upon intravascular applications, i.e., cancer treatment, nanoparticles (NPs) are required to deliver through blood circulation, sustain serum protein interactions, before they penetrate the blood vessels and reach targeted sites for payload drug release. For a delivery process as such, it is elusive and difficult to comprehend the morphological change of NP surface and evaluate associated effects on its targeted delivery. Herein, we used silica NPs with different surface modifications to demonstrate the morphological impact of NPs during the application of the NP-blood protein interaction, vascular endothelial cell penetration, subsequent targeted delivery and photodynamic therapy efficacy, and pursue high drug-load NPs with surface designs. Compared to solid and mesoporous NPs, we found the spiky tubular NPs reserved the NPs' antifouling properties (or shedding of "protein corona"), promoted better endothelial penetration and less destruction in vitro and in vivo. Such effects could be attributed to their spiky surface structures, which can limit the NP-protein interaction area and promote the NP-protein steric hindrance. Further in molecular simulations, we determined that the spiky tubular morphological modification on NPs enhanced the interaction free energy and lowered the amino acids number and the subsequent frequency in contacting with VE-cadherin of vascular endothelia. As a result, the spiky tubular NPs demonstrated its advantages in mitigating damages to VE-cadherin stability and endothelial cell integrity. Exploiting such spiky tubular surface modification, we can improve the NP delivery efficiency and prohibit the leakiness of vascular endothelia, helping address challenges faced by tumor migration in nanomedicine applications for cancer therapy.
RESUMEN
Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition; this phenomenon is known as cerebral ischemia-reperfusion injury. Current studies have elucidated the neuroprotective role of the sirtuin protein family (Sirtuins) in modulating cerebral ischemia-reperfusion injury. However, the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration. In this review, the origin and research progress of Sirtuins are summarized, suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury, including inflammation, oxidative stress, blood-brain barrier damage, apoptosis, pyroptosis, and autophagy. The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways, such as nuclear factor-kappa B signaling, oxidative stress mediated by adenosine monophosphate-activated protein kinase, and the forkhead box O. This review also summarizes the potential of endogenous substances, such as RNA and hormones, drugs, dietary supplements, and emerging therapies that regulate Sirtuins expression. This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors. While Sirtuins show promise as a potential target for the treatment of cerebral ischemia-reperfusion injury, most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans, potentially influencing the efficacy of Sirtuins-targeting drug therapies. Overall, this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.