Resveratrol protects against postmenopausal atherosclerosis progression through reducing PCSK9 expression via the regulation of the ERα-mediated signaling pathway.

Elevated circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels are an important contributor to postmenopausal atherosclerosis (AS). We have previously reported that resveratrol (RSV), as a phytoestrogen, reduces hepatocyte steatosis and PCSK9 expression in L02 cells. This study aimed to investigate how RSV reduces PCSK9 expression to inhibit postmenopausal AS progression. Here, we found that treatment of Ovx/ApoE -/- mice with RSV significantly reduced dyslipidemia, plasma PCSK9 concentration and aortic plaque area. In addition, RSV significantly inhibited liver fat accumulation and improved the hepatocyte ultrastructure. Further studies showed that RSV upregulated estrogen receptor α (ERα) expression, while reduced the liver X receptor α (LXRα) expression and sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity. In vitro, RSV inhibited insulin-induced elevated intracellular/extracellular PCSK9 levels, enhanced receptor-mediated uptake of low-density lipoproteins in HepG2 cells. Furthermore, RSV attenuated the activity of the SRE-dependent PCSK9 promoter. However, these effects can be partially reversed by the antiestrogen ICI 182,780. Attenuation of these changes with ERα inhibition suggest that RSV may prevent the progression of postmenopausal AS by reducing PCSK9 expression in hepatocytes through ERα-mediated signaling.

In situ hydrogelation of forky peptides in prostate tissue for drug delivery.

Herein, we have designed and synthesized a novel forky peptide D3F3 that transforms into a hydrogel through crosslinking induced by ZIs stimuli. We have employed D3F3 as a suitable drug carrier that is conjugated with DOX. Since the concentration of zinc ions necessary for triggering gelation falls into the physiological range present in prostate tissue, while other cationic ions fail to trigger at physiological concentrations, the peptide-based drug delivery system (DDS) is injectable and would achieve prostate tissue-specific self-assembly in situ. The D3F3 hydrogels exhibited an optimal gelation time, satisfactory mechanical strength (can be enhanced after incorporation of DOX) as well as excellent thixotropic properties. The DDS reserved some DOX in the prostate 24 h after the injection, making local sustained release possible. In addition, the peptide materials demonstrated no cytotoxicity against normal fibroblast cells and no damage was observed to the prostate tissue of rats. The drug release followed a non-Fickian diffusion model, with no burst release observed. Importantly, the DOX-hydrogel system exhibited good anti-cancer efficacy when incubated with prostate cancer cells DU-145. Therefore, this study lays the groundwork for the future design of tissue-specific DDSs that are triggered by cationic ions (e.g. zinc ions), and the platform could be further developed to incorporate other potent drugs utilized in the field of prostate cancer therapy, thereby increasing their potency and reducing their side effects.

In situ hydrogelation of bicalutamide-peptide conjugates at prostate tissue for smart drug release based on pH and enzymatic activity.

Tissue-specific self-assemblies of supramolecular hydrogels have attracted great interest in material design and biomedical applications, for in situ-formed hydrogels serve as an excellent local depot with tunable release of drug therapeutics. Here we report the design and syntheses of a novel class of histidine-containing hexapeptide derivatives (Nap-1 and ID-1) for in situ hydrogelation at the zinc ion-rich prostate tissue. Thanks to the efficient co-ordination between zinc and histidine, both Nap-1 and ID-1 displayed excellent self-assembly capability with a high sensitivity to zinc ions at ∼0.1 equivalency. To foster a prostate-specific drug delivery system (DDS), ID-1 was chosen for further conjugation with bicalutamide (BLT), a clinically used drug for prostate cancer. The as-synthesized ID-1-BLT retained the self-assembly capability with zinc ions, and conferred supramoelcular hydrogels at the prostate site. Interestingly, ID-1-BLT hydrogels demonstrated tunable drug release profiles in a typical tumor microenvironment, with acidic pH and esterase activity regulating the drug release in a dose dependent manner. Consequently, the hydrogel-based DDS demonstrated enhanced potency and selective cytotoxicity against prostate cancer cell DU145 over normal fibroblast cell NIH3T3, plausibly due to differential cellular uptake of drugs as well as the elevated esterase activities in cancer cells. Finally, the biocompatible hydrogel system demonstrated sustained delivery of drugs at the prostate gland of rats, with a superior in situ drug distribution profile compared to that of aqueous solution of BLT alone.

The conjugates of forky peptides and nonsteroidal anti-inflammatory drugs (NSAID) self-assemble into supramolecular hydrogels for prostate cancer-specific drug delivery.

Herein, we report supramolecular hydrogelators made of forky peptides and nonsteroidal anti-inflammatory drugs (NSAID). Two zinc ions (ZIs)-responsive short peptide dendrons (E3FID and E3FNP) modified by NSAID (indometacinand naproxen) were designed and synthesized successfully. These novel small molecule hydrogelators can self-assemble in water to form stable supramolecular nanofibers/hydrogels. The formation of these supramolecular hydrogels can be triggered by zinc ions, which are highly concentrated in prostate tissue. The anticancer drug docetaxel (DTX) was employed as chemotherapeutic and loaded into the hydrogels to construct a novel drug delivery system for prostate cancer therapy. This approach is anticipated realizing the sustained release of antitumour drugs into the prostate and cancer associated pain relief, simultaneously. The E3FID hydrogel and E3FNP hydrogel have excellent biocompatibility and viscoelastic properties as a promising drug delivery materials. The result of drugs release in vitro indicated that DTX was released slowly following a non-Fickian diffusion mechanism. In addition, the results of the in vitro cytotoxicity assay demonstrated that these DTX-loaded hydrogels exhibited dose-dependent cytotoxicity to both DU-145 cells and PC-3 cells, in particular, the drug-loaded hydrogel of E3FID had better anticancer efficacy. As a drug delivery strategy, the system realizes better anticancer efficacy, excellent sustained-release and relief of cancer pain, simultaneously, the most important being that the DDS facilitates local delivery of drug to the prostate.

Zinc-ion-mediated self-assembly of forky peptides for prostate cancer-specific drug delivery.

A novel forky peptide was designed and synthesized. The peptide self-assembled into supramolecular hydrogels triggered by zinc ions (ZIs). The hydrogels were designed for a drug delivery system (DDS), loaded with docetaxel and applied for the therapy of prostate cancer. In this research, we have discussed the response mechanism and evaluated the anticancer effect of the DDS.

Overcoming multidrug resistance by a combination of chemotherapy and photothermal therapy mediated by carbon nanohorns.

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy due to the overexpression of P-glycoprotein (P-gp). Herein, etoposide (ETO) was loaded onto oxidized carbon nanohorns (oxCNHs), which were modified by polyethylene glycol (PEG) and further functionalized with the targeting ligand P-gp monoclonal antibody (PA) in an attempt to overcome MDR. The obtained drug delivery system (ETO@oxCNHs/PEG-PA) showed high drug loading efficiency, enhanced drug release under laser irradiation, improved cellular uptake and increased therapeutic effect both in vitro and in vivo. In addition, NIR laser irradiation had a synergistic effect on overcoming MDR. The MDR-overcoming mechanism could be the efficient cellular uptake, enhanced drug release and reduced drug efflux by P-gp. These results demonstrated that ETO@oxCNHs/PEG-PA could be a promising drug delivery system for cancer MDR reversion.