Aptamer-Peptide Conjugates as Targeted Chemosensitizers for Breast Cancer Treatment.

High levels of heat shock protein 70 (HSP70) in tumors are commonly associated with poor prognosis, enhanced doxorubicin (DOX)-induced cardiotoxicity, and even drug resistance in DOX-related cancer chemotherapy. Several peptides possess remarkable protein inhibition and chemosensitization effects, which are attributed to their specific targeting ability against HSP70. However, the inherent poor cell penetration capacity considerably restricts the biomedical applications of these peptides. We herein describe the design and development of anti-MUC1 aptamer-peptide conjugates (ApPCs) as targeted chemosensitizers to overcome the above-mentioned issues. Moreover, DOX could be loaded on the ApPC to deliver the DOX-enclosed agent ApPC-DOX, which simultaneously acts as a targeted chemosensitizer and anticancer agent for combating drug resistance in breast cancer therapy. This innovative, engineered biocompatible conjugate not only enhances the sensitivity of DOX-resistant cells but also alleviates cardiotoxicity of DOX in vivo, highlighting the success of this targeted chemosensitizer strategy.

Aptamer Enables Consistent Maytansine Delivery through Maintaining Receptor Homeostasis for HER2 Targeted Cancer Therapy.

Although the extensive clinical use of the ADC trastuzumab-DM1(T-DM1) for human epidermal growth factor receptor 2 (HER2) targeted cancer therapy, many patients who initially respond to T-DM1 treatment eventually met the insufficient efficacy issue, which is partly attributed to the decreased amount of surface HER2 caused by HER2 degradation in target cells. In our study, we have engineered a HER2 targeted DNA aptamer-DM1 conjugate (HApDC) that can maintain the homeostasis of surface HER2 on the target cancer cell. These conclusions are supported by determining the efficient internalization of HApDC into HER2 overexpressed BT474 and SKBR3 cancer cell lines and by identifying the membranal HER2 level on HApDC-treated BT474 cells. Consistent with the impressive in vitro properties of our newly developed anticancer agent, DM1 could precisely be delivered to the tumor tissue in BT474 xenografted mouse models, because of the specific recognition of aptamer. Noteworthy, HApDC exhibited excellent in vivo tumor inhibition function with much lower healthy organ toxicity, compared with the free drug, which might be explained by the persistently targeted DM1 delivery, which is attributed to the remaining HER2 levels on cells.

Anticancer-Active N-Heteroaryl Amines Syntheses: Nucleophilic Amination of N-Heteroaryl Alkyl Ethers with Amines.

A mild amination protocol of N-heteroaryl alkyl ethers with various amines is described. This transformation is achieved by utilizing simple and readily available base as promoter via C-O bond cleavage, offering a new amination strategy to access several anticancer-active compounds. This work is highlighted by the excellent functional group compatibility, scalability, wide substrate scope, and easy derivatization of a variety of drugs.

Effects of resveratrol on ARPE-19 cell proliferation and migration via regulating the expression of proliferating cell nuclear antigen, P21, P27 and p38MAPK/MMP-9.

AIM: To explore whether resveratrol (Res) can inhibit human retinal pigment epithelial cell (ARPE-19 cell) proliferation and migration, and to research the molecular mechanisms. METHODS: ARPE-19 cells were pretreated with various concentrations at 0, 50, 100, 150, 200 and 300 µmol/L of Res, and with 0 µmol/L Res as the control for 24, 48 and 72h. The cell proliferation, apoptosis and migration were measured with cell counting kit-8 (CCK-8), flow cytometry, and wound-healing and Transwell assays, respectively. The expression of proliferating cell nuclear antigen (PCNA), P21 and P27, as well as matrix metalloproteinase-9 (MMP-9) and p38 mitogen-activated protein kinases (p38MAPK) was identified by Western blot. RESULTS: Cell proliferation was effectively inhibited by Res (P<0.05). When pretreated with Res, cells arrested in S-phase increased remarkably (P<0.05), but the apoptosis ratios showed no significant difference between the treatment and control groups (P>0.05). Cell migration was suppressed by Res both in wound-healing assay and Transwell migration assay (P<0.05). Decreases of PCNA, MMP-9 and p38MAPK, as well as increases of P21 and P27 were detected by Western blot (P<0.05). CONCLUSION: Res can inhibit APRE-19 cell proliferation and migration in a concentration-dependent manner with up-regulation of the expression of P21 and P27, and down-regulation of PCNA, MMP-9 and p38MAPK.

Bevacizumab versus ranibizumab for neovascular age-related macular degeneration: a Meta-analysis.

AIM: To systematically compare the efficacy and safety of off-label bevacizumab versus licensed ranibizumab intravitreal injections as well as monthly regimen versus pro re nata [PRN (as needed)] regimen in the treatment of neovascular age-related macular degeneration (nAMD). METHODS: Relevant publications were identified through automatically retrieve of database and manually retrieving. The methodological quality of studies included was assessed using the Jadad score and the risk-of-bias assessment. The efficacy estimates were measured by the weight mean difference (WMD) for the improvement of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) reduction. The safety estimates were measured by odds ratios (OR) for adverse events rates. Statistical analysis was conducted by Revman 5.2.7. RESULTS: Seven studies were included in the Meta-analysis. There were no statistically significant differences between bevacizumab and ranibizumab in BCVA at 1 and 2y (P=0.37, P=0.18, respectively), However, both drugs has better BCVA given monthly than given as needed at 1 and 2y (P<0.05). The results demonstrated the mean decrease in CRT was less in bevacizumab group than ranibizumab group at 1y (P<0.05), while the difference was not significant at 2y (P=0.24). Treatment monthly gained much more decrease in CRT at 1 and 2y (P<0.005). There were no differences between drugs in the rates of death, arterial thrombotic events and venous thrombotic events (P=0.41, P=0.55, P=0.10, respectively), while the rates of medical dictionary for regulatory activities (MedDAR) system organ class events and ≥1 systemic serious adverse events were higher in bevacizumab group than ranibizumab group (P<0.05). But the incidences of death, arterial thrombotic events, venous thrombotic events, MedDAR system organ class events as well as ≥1 systemic serious adverse events were not statistically different between both treatment regimens of monthly and as needed (P=0.14, P=0.76, P=0.73, P=0.12, P=0.11, respectively). CONCLUSION: Bevacizumab was equivalent to ranibizumab for BCVA, however bevacizumab tended to gain less decrease in CRT and had higher rates of serious adverse events. Compared with treatment as needed, treatment monthly showed superior efficacy in BCVA improvement and CRT reduction, while the rates of adverse events were similar in the two dosing regimens.