A Triple-Targeted Rutin-Based Self-Assembled Delivery Vector for Treating Ischemic Stroke by Vascular Normalization and Anti-Inflammation via ACE2/Ang1-7 Signaling.

Changes in the cerebral microenvironment caused by acute ischemic stroke-reperfusion are the main obstacle to the recovery of neurological function and an important cause of stroke recurrence after thrombolytic therapy. The intracerebral microenvironment after ischemia-reperfusion reduces the neuroplasticity of the penumbra and ultimately leads to permanent neurological damage. To overcome this challenge, we developed a triple-targeted self-assembled nanodelivery system, which combines the neuroprotective drug rutin with hyaluronic acid through esterification to form a conjugate, and then connected SS-31, a small peptide that can penetrate the blood brain barrier and target mitochondria. Brain targeting, CD44-mediated endocytosis, hyaluronidase 1-mediated degradation, and the acidic environment synergistically promoted the enrichment of nanoparticles and drug release in the injured area. Results demonstrate that rutin has a high affinity for ACE2 receptors on the cell membrane and can directly activate ACE2/Ang1-7 signaling, maintain neuroinflammation, and promote penumbra angiogenesis and normal neovascularization. Importantly, this delivery system enhanced the overall plasticity of the injured area and significantly reduced neurological damage after stroke. The relevant mechanism was expounded from the aspects of behavior, histology, and molecular cytology. All results suggest that our delivery system may be an effective and safe strategy for the treatment of acute ischemic stroke-reperfusion injury.

A multi-bioresponsive self-assembled nano drug delivery system based on hyaluronic acid and geraniol against liver cancer.

Herein, a multi-bioresponsive self-assembled nano-drug delivery system (HSSG) was constructed by conjugating the anticancer drug Geraniol (GER) to hyaluronic acid (HA) via a disulfide bond. The HSSG NPs displayed a uniform spherical shape with an average diameter of ∼110 nm, maintained high stability, and realized controlled drug release in the tumor microenvironment (pH/glutathione/hyaluronidase). Results of fluorescence microscopy and flow cytometry verified that HSSG NPs were selectively uptaken by human hepatocellular carcinoma cell lines HepG2 and Huh7 via CD44 receptor-mediated internalization. Studies on H22 tumor-bearing mice demonstrate that HSSG NPs could effectively accumulate at the tumor site for a long period. In vitro and in vivo studies show that HSSG NPs significantly promoted the death of cancer cells while reducing the toxicity as compared to GER. Therefore, the HSSG NPs have great potential in the treatment of tumors.

A Water-Soluble Quercetin Conjugate with Triple Targeting Exerts Neuron-Protective Effect on Cerebral Ischemia by Mitophagy Activation.

The existing treatments for ischemic stroke cannot meet the clinical needs so far. Quercetin (QT) is an effective apoptosis inhibitor and antioxidant flavonoid, but its water solubility is poor and has no targeting. In this study, QT is modified with hyaluronic acid (HA) to form a water-soluble conjugate HA-QT, which can specifically bind to CD44 receptors and response to hyaluronidase. Next, a novel delivery system SS31-HA-QT is prepared by further modification with SS31, a polypeptide capable of penetrating the blood-brain barrier (BBB) and indiscriminately targeting mitochondria. Meanwhile, IR780, a near-infrared dye, is conjugated onto HA-QT and SS31-HA-QT to form diagnosis tools to trace HA-QT and SS31-HA-QT. In vitro and in vivo results shows that SS31 can four-fold increase the drug penetration into BBB without any toxicity. The highly expressed CD44 and hyaluronidase in ischemic area ensured the targeted delivery of QT to the ischemic region. Importantly, the mitochondrial targeting of damaged neurons is also achieved by SS31. Further studies confirmed that SS31-HA-QT exerted neuron-protection by activating mitophagy, and its mechanism involved Akt/mTOR related TFEB and HIF-1α activation. Hence, SS31-HA-QT shall be a promising neuroprotective drug due to its high water-solubility, superior triple-targeted neuroprotective ability, low toxicity, and high efficiency.

Curcumin Derivative Cur20 Attenuated Cerebral Ischemic Injury by Antioxidant Effect and HIF-1α/VEGF/TFEB-Activated Angiogenesis.

In this paper, a curcumin derivative Cur20 was synthesized for better hydrolytic stability, which showed a higher angiogenic effect on zebrafish model than curcumin. In order to reveal the potential effects on neuroprotection, a mouse model of vascular dementia (VaD) induced by permanent right common carotid artery occlusion (rUCCAO) was established. After two weeks of curcumin administration, the cognitive function of mice was detected by Morris water maze and Y maze. The alteration on oxidative injuries and morphological damage were also analyzed by reactive oxygen species, superoxide dismutase, GSH, malondialdehyde tests, and Nissl stain on cortex/hippocampus. The angiogenesis and related signal factors were evaluated as well. The results showed that Cur20 significantly attenuated the cognitive dysfunction and histopathological changes of the VaD mice with enhanced antioxidant system and angiogenesis. In addition, primary rat brain microvessel endothelial cells (rBMECs) with oxygen glucose deprivation (OGD) were applied to further verify the possible mechanisms of Cur20-induced angiogenesis. The results demonstrated that the proliferation effect and the activation of pro-angiogenesis factors such as HIF-1α, VEGF, and TFEB might contribute to the protection of ischemic injury. Based on the above, our conclusion is that Cur20 can be considered as a promising therapeutic strategy for VaD.