Bio-engineered nano-vesicles for IR820 delivery: a therapy platform for cancer by surgery and photothermal therapy.

Long-term unsolved health problems from pre-/intra-/postoperative complications and thermal ablation complications pose threats to liver-cancer patients. To reduce the threats, we propose a multimodal-imaging guided surgical navigation system and photothermal therapy strategy to improve specific labeling, real-time monitoring and effective treatment of hepatocellular carcinoma. Using a bioengineering approach, G-Nvs@IR820, a kind of human-cell-membrane nano-vesicle, was generated with growth arrest-specific 6 (Gas6) expressed on the membrane and with near-infrared absorbing dye (IR820) loaded into it, which is proven to be an effective nanoparticle-drug-delivery system for Axl-overexpressing hepatocellular carcinoma. G-Nvs@IR820 shows excellent features in vitro and in vivo. As Gas6 binds to Axl specifically, G-Nvs@IR820 has good targeting ability to the tumor site and also has a good ability to guide the further accurate obliteration of carcinoma from adjacent normal tissue in surgery with its highly resolved fluorescence/photoacoustic/surgical-navigation signals. Moreover, the G-Nvs@IR820 represented a new perspective for photothermal therapy. Briefly, Nvs@IR820 was synthesized at a gram scale with high affinity, specificity, and safety. It has promising potential in clinical application for IGS and PTT in Axl-overexpressing hepatoma carcinoma.

Bio-engineered cell membrane nanovesicles as precision theranostics for perihilar cholangiocarcinoma.

Perihilar cholangiocarcinoma (PHCC) presents a formidable challenge due to its occult anatomic location, aggressive growth, insensitivity to conventional chemotherapy, and poor prognosis. Herein, we engineered a human epidermal growth factor receptor 2 (HER2) affibody to the surface of cell membrane nanovesicles (A-NVs) in a ligand-oriented manner and loaded them with indocyanine green (ICG) as precision theranostics for PHCC treatment. The A-NVs@ICG were prepared and exhibited satisfactory targeting effects in HER2-overexpressing PHCC cells. In vivo fluorescence and photoacoustic imaging demonstrated that A-NVs@ICG promoted the accumulation of ICG in PHCC tissue, leading to enhanced tumor regression and improved anti-cancer effects when combined with photoirradiation. Therefore, bio-engineered A-NVs@ICG represent a promising nanotheranostic agent for PHCC with potential for clinical translation.

The Roles of GSK-3ß in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma.

Rationale: Glycogen synthase kinase-3ß (GSK-3ß) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3ß can confer tumor growth. However, the expression and function of GSK-3ß in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3ß in HCC. Methods: We firstly clarified the expression of GSK-3ß in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3ß could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3ß in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. Results: We demonstrated that GSK-3ß is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3ß confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3ß is correlated with reduced expression of retinoic acid receptor-ß (RARß), which is caused by GSK-3ß-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARß promoter. Overexpression of functional GSK-3ß impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3ß by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RARß by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARß. Conclusions: Our findings demonstrate that GSK-3ß is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3ß may be a promising strategy for HCC treatment in clinic.

miR-221-5p acts as an oncogene and predicts worse survival in patients of renal cell cancer.

BACKGROUND: Renal cell carcinoma(RCC) is one of the most common malignancies in kidney, and usually leads to poor prognosis. Therefore, identifying novel biomarkers for predicting the progression and prognosis of RCC is essential. The purpose of this study is aimed to evaluate the function of miR-221-5p in RCC and the clinical value of miR-221-5p in RCC prognosis after surgery. MATERIALS AND METHODS: In our study, RT-qPCR, wound scratch assay, cell proliferation assay, transwell assay, and flow cytometry assay were performed to explore miR-221-5p expression level and its proliferation, migration and apoptosis in clear cell RCC(ccRCC). Besides, we collected 196 formalin-fixed and paraffin-embedded (FFPE) tissue samples of patients who received partial or radical nephrectomy from May 2006 to October 2016 at Shenzhen Traditional Chinese Medicine Hospital and People's Liberation Army 303 Hospital. The relative levels of miR-221-5p from the FFPE tissue samples was detected by RT-qPCR. The Kaplan-Meier method, Cox regression analyses, and ROC curve analysis were performed to approve the effect of the miR-221-5p expression on patient survival. RESULTS: In our study, we found that miR-221-5p is significantly upregulated in ccRCC tissues and ccRCC cell lines. Moreover, miR-221-5p promotes cell proliferation, mobility, and inhibits cell apoptosis in 786-O and ACHN cell lines. The Kaplan-Meier analysis indicated that patients with high expression of miR-221-5p had a significantly poor prognosis (P = 0.013). The Cox regression analyses showed that patients with high expression of miR-221-5p remained to have a shorter overall survival (P = 0.025). The ROC curve of miR-221-5p expression combined with tumor stage showed an area under the curve of 0.658 (P < 0.001). CONCLUSION: Our results indicated that miR-221-5p might not only be an oncogene in ccRCC cells but also might be an independent prognosis factor of ccRCC.

Self-Assembled Metal-Organic Nanoparticles for Multimodal Imaging-Guided Photothermal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a high incidence of disease and the high recurrence rate is a major limitation for HCC treatment. To resolve such a challenge, multimodal imaging-guided photothermal therapy (PTT) provides a promising candidate for HCC treatment. Herein, we use a facile method to develop a novel self-assembled theranostic nanoparticle (NP) based on manganese irons (Mn2+) and indocyanine green (ICG) under the protection of poly(vinylpyrrolidone) (PVP). The fabricated NPs possess the properties of strong NIR optical absorbance, high photothermal conversion efficiency and multimodal imaging. Through intravenous injection, these NPs could highly accumulate in HepG2 tumor via the enhanced permeability and retention effect, as revealed by fluorescence/photoacoustic/magnetic resonance imaging, leading to an obviously improved in vivo therapeutic outcome. This study demonstrates that our self-assembled NPs could be a potential platform for multimodal imaging-guided PTT of HCC in future clinical therapy.

Engineering Phototheranostic Nanoscale Metal-Organic Frameworks for Multimodal Imaging-Guided Cancer Therapy.

Many photoresponsive dyes have been utilized as imaging and photodynamic/photothermal therapy agents. Indocyanine green (ICG) is the only near-infrared region (NIR) organic dye for clinical applications approved by the United States Food and Drug Administration; however, the clinical application of ICG is limited by its poor aqueous solubility, low cancer specificity, and low sensitivity in cancer theranostics. To overcome these issues, a multifunctional nanoplatform based on hyaluronic acid (HA) and ICG-engineered metal-organic framework MIL-100(Fe) nanoparticles (MOF@HA@ICG NPs) was successfully developed for imaging-guided, anticancer photothermal therapy (PTT). The synthesized NPs showed a high loading content of ICG (40%), strong NIR absorbance, and photostability. The in vitro and in vivo imaging showed that the MOF@HA@ICG NPs exhibited greater cellular uptake in CD44-positive MCF-7 cells and enhanced tumor accumulation in xenograft tumors due to their targeting capability, compared to MOF@ICG NPs (non-HA-targeted) and free ICG. The in vitro photothermal toxicity and in vivo PTT treatments demonstrated that MOF@HA@ICG NPs could effectively inhibit the growth of MCF-7 cells/xenograft tumors. These results suggest that MOF@HA@ICG NPs could be served as a new promising theranostic nanoplatform for improved anticancer PTT through cancer-specific and image-guided drug delivery.

Inhibition of autophagy augments chemotherapy in human salivary adenoid cystic carcinoma.

Although cisplatin (DDP)-based adjuvant chemotherapy is widely used in the treatment of salivary adenoid cystic carcinoma (SACC), SACCs have developed resistance to cisplatin, resulting in chemotherapy failure. Autophagy serves as a critical adaptive response, which was increased in tumor cells in chemotherapy. However, the function of autophagy is not clear in SACC. In this study, apoptosis induced by DDP in SACC high metastatic cell line (ACC-M) was revealed using MTT assay, flow cytometry, and caspase-3 immunoblotting. The autophagy activation induced by DDP treatment was measured by transmission electron microscopy, green fluorescent protein-light chain 3 plasmid transfection LC3 immunoblotting and p62 immunoblotting. 3-methyladenine (3-MA) or small interference RNA targeting beclin 1 (beclin 1 siRNA) inhibited autophagy and significantly enhanced DDP-induced apoptosis. ACC-M xenografts in nude mice further verified the synergistic effect of DDP and 3-MA. In conclusion, autophagy activation was caused to protect cancer cells from DDP-induced apoptosis and autophagy inhibition could be a promising strategy for adjuvant chemotherapy in SACC.

[Transurethral plasmakinetic enucleation of prostate and suprapubic small cut in the treatment of high risk and senior patient with benign prostatic hyperplasia and bladder stones].

OBJECTIVE: To explore the safety and efficiency of transurethral plasmakinetic enucleation of prostate (TUPKEP) and suprapubic small cut in the treatment of high-risk and senior patients with benign prostatic hyperplasia and bladder stones. METHODS: A retrospective review was conducted for 68 high-risk and senior patients with benign prostatic hyperplasia and bladder stones. All of them were treated by TUPKEP and suprapubic small cut. RESULTS: Operation was successfully performed in all 68 cases. And there was no instance of transurethral resection syndrome, shock, myocardial infarct, cerebral infarction, cerebral hemorrhage, permanent urinary incontinence or surgical site infection. Seven patients with temporal urinary incontinence recovered at a mean time of (9.48 ± 1.52) days post-operation. The mean operative duration was (48.63 ± 4.14) min and the mean volume of blood loss (50.97 ± 5.33) ml. The changes of maximum flow rate (Qmax), international prostatic symptom score (I-PSS) and quality-of-life (QOL) were statistically significant before and after operation. Qmax increased from (4.56 ± 0.35) to (18.82 ± 1.65) ml/s (P < 0.001), I-PSS decreased form (21.96 ± 1.89) to (11.23 ± 0.86) (P = 0.018) and QOL decreased from (4.94 ± 0.35) to (1.95 ± 0.32) (P = 0.011). CONCLUSION: The approach of TUPKEP and suprapubic small cut is both safe and effective in the treatment of high-risk and senior patient with benign prostatic hyperplasia and bladder stones and should be widely applied.

Apoptosis of human cholangiocarcinoma cell lines induced by ß-escin through mitochondrial caspase-dependent pathway.

The study aimed to evaluate the effects of ß-escin on human cholangiocarcinoma cell lines (QBC939, Sk-ChA-1 and MZ-ChA-1) and to explore its mechanisms. Cell growth, cell cycle and apoptosis were investigated, respectively, by MTT assay, single PI and FITC/PI double-staining flow cytometry, and fluorescence microscopy. The protein expression was determined by western blotting. The study revealed that ß-escin inhibited cholangiocarcinoma cell growth in a dose- and time-dependent manner, and the cell cycle of QBC939 and Sk-ChA-1 cells was arrested in the G2/M phase, and MZ-ChA-1 cells in G1 phase. Apoptosis of the three cholangiocarcinoma cell lines induced by ß-escin was associated with the collapse of the mitochondrial membrane potential and the activation of caspase-3. The apoptotic effect of ß-escin was suppressed by pancaspase inhibitor z-VAD-fmk. Molecular dissection revealed that the antiapoptotic protein bcl-2 was down-regulated after cholangiocarcinoma cell lines were treated with ß-escin, while the protein levels of bax and p53 were unchanged. Apoptosis was accompanied by an increase in reactive oxygen species (ROS). These results suggest that ß-escin induces apoptosis of cholangiocarcinoma cells through an intrinsic mitochondrial caspase-dependent pathway, and the increase in the bax/bcl-2 ratio and ROS may play important roles in ß-escin-induced apoptosis of cholangiocarcinoma cells.