CD44 Receptor-Targeted and Reactive Oxygen Species-Responsive H2S Donor Micelles Based on Hyaluronic Acid for the Therapy of Renal Ischemia/Reperfusion Injury.

For the therapy attenuating renal ischemia-reperfusion (IR) injury, a novel drug delivery system was urgently needed, which could precisely deliver drugs to the pathological renal tissue. Here, we have prepared new nanomaterials with a reactive oxygen species (ROS)-responsive hydrogen sulfide (H2S) donor and hyaluronic acid that targets CD44 receptor. The novel material was synthesized and characterized via related experiments. Then, rapamycin was loaded, which inhibited kidney damage. In the in vitro study, we found that the micelles had ROS-responsiveness, biocompatibility, and cell penetration. In addition, the experimental results showed that the intracellular H2S concentration after administration was threefold higher than that of the control group. The western blot assay revealed that they have anti-inflammatory effects via H2S donor blocking the NF-κB signaling pathway. Consequently, the rising CD44 receptor-targeting and ROS-sensitive H2S donor micelles would provide a promising way for renal IR injury. This work provides a strategy for improving ischemia/reperfusion injury for pharmaceuticals.

N-acetylneuraminic acid and chondroitin sulfate modified nanomicelles with ROS-sensitive H2S donor via targeting E-selectin receptor and CD44 receptor for the efficient therapy of atherosclerosis.

Currently, very limited therapeutic approaches are available for the drug treatment of atherosclerosis(AS). H2S-donor is becoming a common trend in much life-threatening research. Several studies have documented that H2S-lyase is predominantly present in endothelial cells. N-Acetylneuraminic acid (SA), natural carbohydrate, binds specifically to the E-selectin receptor of endothelial cells. Meanwhile, recent studies related to Chondroitin sulfate have excellent target binding ability with CD44 receptor. We conjecture that the N-Acetylneuraminic acid and Chondroitin sulfate modified nanomicelles not only enhances the accumulation of the drug but also cleaves the H2S donor in the lesion, thus one stone two birds. Given these findings, we synthesized two kinds of nanoparticles, Carrier I (SCCF) and Carrier II (SCTM), for atherosclerosis to validate our guesses. Initially, S-allyl-L-cysteine and 4-methoxyphenylthiourea were used as H2S donors for SCCF and SCTM, respectively. After the introduction of ROS-sensitive groups. Then, micelles with N-Acetylneuraminic acid and Chondroitin sulfate were prepared to load rapamycin(RAP). Further, in atherosclerosis Oil Red O staining (ORO) results confirmed remarkable treatment effect with SCCF@RAP and SCTM@RAP. Thus, we conclude that the effect of dual-targeting nanomicelles with ROS-sensitive H2S donor based on N-Acetylneuraminic acid and Chondroitin sulfate will have a better role in atherosclerosis.

Novel dual ROS-sensitive and CD44 receptor targeting nanomicelles based on oligomeric hyaluronic acid for the efficient therapy of atherosclerosis.

Although the clinical usage of drugs administration was raising, the application of nanoparticles encapsulating the hydrophobic drugs with plummy efficiency was very scarce for atherosclerosis (AS) treatment. In this work, a novel dual ROS-sensitive and CD44 receptors targeting amphiphilic carrier material, oligomeric hyaluronic acid-2'-[propane-2,2-diyllbls (thio)] diacetic acl-hydroxymethylferrocene (oHA-TKL-Fc), named HASF, was synthesized and characterized by 1H-NMR spectra. Then, we combined curcumin (Cur) with HASF into nano-micelles (HASF@Cur micelles) by self-assembling method. The resulting HASF@Cur micelles had the average size of 150.8 nm and zeta potential of -35.04 mV to maintain the will-defined spheroidal structure and stability. Importantly, the HASF@Cur micelles had ultrahigh entrapment efficiency (about 51.41 %). Moreover, in vitro release study, Cur release from HASF@Cur micelles was effective in the reactive oxygen species (ROS) condition, and the release rate was interrelated with the concentration of hydrogen peroxide (H2O2). Further, fluorescence imaging showed that the HASF@Cur micelles could more selective access to Raw 264.7 cells than free Cur via oHA-receptor mediated endocytosis. The MTT assay attested the safety of amphiphilic carrier material HASF. Additionally, the results of in vivo Oil red O lipid staining studies showed that the lesion area of the aorta was reduced to 47.3±3.4 % with HASF@Cur micelles, compared with the lesion area of Cur group (63.2±2.7 %), HASF@Cur micelles had the more remarkable effect in reducing lesion area (*P < 0.05). Consequently, the novel dual ROS-sensitive and CD44 receptors targeting drug delivery system would become a promising strategy for atherosclerosis.

Development of dual-targeted nano-dandelion based on an oligomeric hyaluronic acid polymer targeting tumor-associated macrophages for combination therapy of non-small cell lung cancer.

In this study, the novel carrier materials were screened to structure targeting nano-micelles (named 'nano-dandelion') for synchronous delivery of curcumin (Cur) and baicalin (Bai), which could effectively overcome the tumor resistance. Mannose (Man) was found to bind better to CD206 receptors on the surface of tumor-associated macrophages (TAMs), thereby increasing the number of nano-dandelion engulfed by TAMs. Furthermore, oligomeric hyaluronic acid (oHA) was able to target CD44 receptors, resulting in recruitment of a higher number of nano-dandelion to locate and engulf tumor cells. The disulfide bond (S-S) in 3,3'-dithiodipropionic acid (DA) could be broken by the high concentration of glutathione (GSH) in the tumor microenvironment (TME). Based on this, we selected DA to connect hydrophobic fragments (quercetin, Que) and oHA. A reduction-sensitive amphiphilic carrier material, quercetin-dithiodipropionic acid-oligomeric hyaluronic acid-mannose-ferulic acid (Que-S-S-oHA-Man-FA; QHMF) was fabricated and synthesized by 1H NMR. Next, QHMF self-assembled into nano-dandelion, i.e. encapsulated Cur and Bai in water. Critical experimental conditions in the preparation process of nano-dandelion that could affect its final properties were explored. Nano-dandelion with a small particle size (121.0 ± 15 nm) and good normal distribution (PI = 0.129) could easily enter tumor tissue through vascular barrier. In addition, nano-dandelion with a suitable surface potential (-20.33 ± 4.02 mV) could remain stable for a long duration. Furthermore, good cellular penetration and tumor cytotoxicity of nano-dandelion were demonstrated through in vitro cellular studies. Finally, effective antitumor activity and reduced side effects were confirmed through in vivo antitumor experiments in A549 tumor-bearing nude mice.

[Intranasal administration of temozolomide for brain-targeting delivery: therapeutic effect on glioma in rats].

OBJECTIVE: To study the therapeutic effect of intranasal administration of temozolomide (TMZ) for brain-targeting delivery in a rat model bearing orthotopic C6 glioma xenografts. METHODS: Forty Wistar rat bearing brain C6 glioma xenograft were randomly divided into 4 groups and treated with physiological saline solution or with TMZ by intravenous injection, gavage or intranasal administration. The tumor size, rat survival time and pathological changes were observed in each group. RESULTS: Magnetic resonance imaging showed a significantly reduced volume of glioma in intranasal TMZ group compared with that in the control, intraveneous TMZ injection group and TMZ gavage groups (12.45∓2.49 mm(3) vs 60.16∓4.12, 33.17∓3.56, and 35.16∓4.36 mm(3), respectively, P<0.05). The median survival time of the C6 glioma-bearing rats was also significantly longer in intranasal TMZ group than in the other 3 groups (31.0 days vs 20, 19, and 21.5 days, respectively, P<0.05). In the glioma xenografts, PCNA expression was the lowest and tumor cell apoptosis rate the highest in intranasal TMZ group. CONCLUSION: Intranasal TMZ administration can suppress the growth of C6 glioma in rats and may serve as an effective strategy for glioma treatment.

[Ocular pharmacokinetics of puerarin in anesthetic rabbits by microdialysis].

OBJECTIVE: To establish the model of microdialysis, and study the ocular pharmacokinetics of puerarin in anesthetic rabbits. METHOD: Implanted the probe into anterior chamber of anesthetic rabbit by surgery. After balanced for 2 h, 1% puerarin eye drop (100 microL) was applied into the cul-de-sac with micropipette. Immediately the dialysate was collected at different time and detected by HPLC with the detection wavelength of 249 nm. The mobile phase was methanol and 0.1% citric acid solution (30:70); the flow rate was 1.0 mL x min(-1). RESULT: After the administration, puerarin can be absorbed into aqueous humor quickly. The peak concentration of puerarin appeared at about 1 h and then reduced gradually. The peak concentration(C(max)) is (2.52 +/- 0.31) mg x L(-1). The other lower peak was shown at 3.5 h during the eliminate phase. This might be attributed to the inhibition of aqueous humor production by the puerarin and resulted in a high drug concentration. The area under concentration-time curve (AUC(0-t)) is (5.04 +/- 0.21) mg x h x L(-1) and the eliminate half life (t1/2) is (0.38 +/- 0.13) h. CONCLUSION: The microdialysis technique can be used to detect the ocular pharmacokinetics of puerarin, and support the valuable pharmacokinetics parameter for the clinical applications of puerarin eye drop.

Effects of poly(amidoamine) dendrimers on ocular absorption of puerarin using microdialysis.

PURPOSE: The purpose of this study was to investigate the effects of poly(amidoamine) (PAMAM) dendrimers on ocular absorption of puerarin. METHODS: The samples of rabbits' aqueous humor were collected by in vivo microdialysis. The ocular pharmacokinetic properties of puerarin were measured to evaluate the effects of PAMAM dendrimers on ocular absorption of puerarin. RESULTS: In the pharmacokinetic studies, the AUC(0∼∞) values of puerarin solution with 0.2% (w/v) PAMAM dendrimers (G3.0, G4.0, G5.0) were greater than those in the control group by 2.3-, 3.5-, and 2.1-folds, respectively. The C(max) values of puerarin solution with 0.2% (w/v) PAMAM dendrimers were 1.5, 2.5, and 1.3 times the values of the control group and the t(1/2) values were significantly longer than that of control group. CONCLUSIONS: Using PAMAM dendrimers might be a promising strategy to enhance the absorption of puerarin. The generation of PAMAM dendrimers may play a key role in increasing the ocular absorption of puerarin.