Facile Fabrication of Reduction-Responsive Supramolecular Nanoassemblies for Co-delivery of Doxorubicin and Sorafenib toward Hepatoma Cells

Combination of doxorubicin with sorafenib (SF) was reported to be a promising strategy for treating hepatocellular carcinoma (HCC). In this study, we designed a reduction-responsive supramolecular nanosystem based on poly (ethylene glycol)-β-cyclodextrin (PEG-CD) and a disulfide-containing adamantine-terminated doxorubicin prodrug (AD) for efficient co-delivery of doxorubicin and sorafenib. PEG-CD/AD supramolecular amphiphiles were formed through host-guest interaction between cyclodextrin and adamantine moieties, and then self-assembled into regular spherical nanoparticles with a uniform size of 166.4 nm. Flow cytometry analysis and confocal laser scanning microscopy images showed that PEG-CD/AD nanoparticles could be successfully taken up by HepG2 cells and then released doxorubicin into the cell nuclei. Moreover, sorafenib could be facilely encapsulated into the hydrophobic cores to form PEG-CD/AD/SF nanoparticles with a slightly larger size of 186.2 nm. PEG-CD/AD/SF nanoparticles sequentially released sorafenib and doxorubicin in a reduction-response manner. In vitro cytotoxicity assay showed that PEG-CD/AD/SF nanoparticles had an approximately 4.7-fold decrease in the IC50 value compared to that of PEG-CD/AD and SF physical mixtures, indicating stronger inhibitory effect against HepG2 cells by co-loading these two drugs. In summary, this novel supramolecular nanosystem provided a simple strategy to co-deliver doxorubicin and sorafenib toward hepatoma cells, which showed promising potential for treatment of HCC

Identification of circulating miRNAs as novel prognostic biomarkers for bladder cancer

MicroRNAs (miRNAs) are a type of ncRNAs with 18-25 nucleotides in length and reported to play crucial roles in human cancers. Bladder cancer is one of the most common causes of cancer-related death. The discovery of new early biomarkers for BC may improve the patients' response to the treatment thus obtaining higher outcomes. The present study identified 7 miRNAs were up-regulated in bladder serum cancer samples compared to normal samples, including hsa-miR-185-5p, hsa-miR-663a, hsa-miR-30c-5p, hsa-miR-3648, hsa-miR-1270, hsa-miR-200c-3p, and hsa-miR-29c-5p. The dysregulation of these miRNAs were correlated to advanced stage and overall survival time in bladder cancer patients. Moreover, we identified a predictive model to predict the prognosis of bladder cancer. Kaplan-Meier survival curve analyses showed that bladder cancer patients with high-risk scores had significantly worse overall survival time than bladder patients with lower risk scores. Furthermore, we constructed a miRNA-mRNA regulating network. Bioinformatics analysis showed these miRNAs were involved in regulating sarcomere organization, positive regulation of multicellular organism growth, phosphorylation, phosphatidylinositol-mediated signaling, and peroxisome proliferator activated receptor signaling pathway. We thought this study could provide novel noninvasive early biomarkers for bladder cancer

Preferentially released miR-122 from cyclodextrin-based star copolymer nanoparticle enhances hepatoma chemotherapy by apoptosis induction and cytotoxics efflux inhibition

Chemotherapy, as one of the most commonly used treatment modalities for cancer therapy, provides limited benefits to hepatoma patients, owing to its inefficient delivery as well as the intrinsic chemo-resistance of hepatoma. Bioinformatic analysis identified the therapeutic role of a liver-specific microRNA — miR-122 for enhancing chemo-therapeutic efficacy in hepatoma. Herein, a cyclodextrin-cored star copolymer nanoparticle system (sCDP/DOX/miR-122) is constructed to co-deliver miR-122 with doxorubicin (DOX) for hepatoma therapy. In this nanosystem, miR-122 is condensed by the outer cationic poly (2-(dimethylamino) ethyl methacrylate) chains of sCDP while DOX is accommodated in the inner hydrophobic cyclodextrin cavities, endowing a sequential release manner of miR-122 and DOX. The preferentially released miR-122 not only directly induces cell apoptosis by down regulation of Bcl-w and enhanced p53 activity, but also increases DOX accumulation through inhibiting cytotoxic efflux transporter expression, which realizes synergistic performance on cell inhibition. Moreover, sCDP/DOX/miR-122 displays remarkably increased anti-tumor efficacy in vivo compared to free DOX and sCDP/DOX alone, indicating its great promising in hepatoma therapy

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

Background There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. Methods In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (â\u89¥400 mg/day for â\u89¥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1â\u80\u933 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Findings Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50â\u80\u930·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1â\u80\u9312·1) for regorafenib versus 7·8 months (6·3â\u80\u938·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), handâ\u80\u93foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. Interpretation Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. Funding Bayer

Additional file 1: of Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

TIP30 was regulated by HIF-2Îą at protein level in Hep3B. (DOCX 66.9 kb