Publications by authors named "Hongjuan Zhao"

71 Publications

Bio-Responsive nanoparticle for tumor targeting and enhanced photo-immunotherapy.

Colloids Surf B Biointerfaces 2021 Mar 8;202:111681. Epub 2021 Mar 8.

Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. Electronic address:

Despite the potential of immunotherapy in various solid tumors, the efficiency of immunotherapy is limited by little tumor-infiltrating lymphocytes (TILs) and abundant immunosuppressive M2-type tumor-associated macrophages (M2-TAMs) in the tumor microenvironment (TME). Herein, we design a versatile photo-immunotherapy nanoparticle (termed as HA-AuNR/M-M2pep NP) to conquer above challenges. The HA-AuNR/M-M2pep NP is composed of hyaluronic acid modified gold nanorod (HA-AuNR) surface-modified with matrix metalloproteinase-2 (MMP2)-responsive M2pep fusion peptides (M-M2pep). Upon tumor site, the fabricated HA-AuNR/M-M2pep NP releases M2pep through the cleavage of MMP2-sensitive peptide to selectively deplete M2-TAMs and improve immunoactivity of TME. Meanwhile, HA-AuNR could target to tumor cells and realize precise tumor photothermal therapy (PTT) under near infrared light irradiation, which further triggers immunogenic cell death (ICD) of tumor cells and elicits antitumor immunity. In vivo antitumor studies reveal that HA-AuNR/M-M2pep NPs-mediated PTT and M2-TAMs depletion recruit TILs, activate effector T lymphocytes, secrete antitumor cytokines (e.g. IFN-γ, TNF-α), and effectively inhibit the growth of tumor. Collectively, HA-AuNR/M-M2pep NP-mediated photo-immunotherapy based on dual targeted delivery and bio-responsive drug release holds tremendous promise to enhance antitumor efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.colsurfb.2021.111681DOI Listing
March 2021

Circulating microRNAs as candidate biomarkers for the ovarian response during in vitro fertilization.

Medicine (Baltimore) 2021 Feb;100(6):e24612

Department of Gynecology and Obstetrics, Inner Mongolia Medical University affiliated Hospital, 1 Tongdao North Street, Hohhot, China.

Abstract: MicroRNAs (miRNAs) in the let-7 family have established regulatory roles in pregnancy; in this study, we evaluated whether miRNAs detectable in the circulation are associated with the ovarian response to stimulation.In total, 25 patients with infertility were divided into 3 groups: poor response (n = 9), moderate response (n = 8), and hyper-response (n = 8). Serum and endometrial tissue samples on the second day of the menstrual phase, serum samples during the mid-luteal phase, and follicular fluid samples were collected from women undergoing in vitro fertilization. The levels of let-7g-5p, let-7f-5p, and let-7i-5p in were evaluated.The levels of circulating let-7g-5p,7f-5p, and 7i-5p in the basal sera were significantly higher in the moderate ovarian response group than in the poor response group (P < .05). The expression levels of these genes tended to be down-regulated in the mid-luteal phase in the high response group (P < .05). There were no significant differences in expression levels in the endometria and follicular fluid among groups (P > .05).Circulating let-7g-5p, 7f-5p, and 7i-5p were differentially expressed between the moderate response group and the high and poor response groups. The combination of these serum miRNAs during the menstrual phase might serve as a non-invasive predictive marker for the ovarian response to in vitro fertilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000024612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886401PMC
February 2021

protects against renal injury by decreasing the level of reactive oxygen species in female mice.

Am J Physiol Renal Physiol 2020 11 5;319(5):F876-F884. Epub 2020 Oct 5.

Department of Urology, School of Medicine, Stanford University, Stanford, California.

Renal injury leads to chronic kidney disease, with which women are not only more likely to be diagnosed than men but have poorer outcomes as well. We have previously shown that expression of small proline-rich region 2f (), a member of the small proline-rich region () gene family, is increased several hundredfold after renal injury using a unilateral ureteral obstruction (UUO) mouse model. To better understand the role of in renal injury, we generated a knockout (-KO) mouse model using CRISPR-Cas9 technology. -KO female mice showed greater renal damage after UUO compared with wild-type (-WT) animals, as evidenced by higher hydroxyproline levels and denser collagen staining, indicating a protective role of during renal injury. Gene expression profiling by RNA sequencing identified 162 genes whose expression levels were significantly different between and after UUO in -KO mice. Of the 162 genes, 121 genes were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in -WT animals, suggesting a protective role of in UUO through defense against oxidative damage. Consistently, bilateral ischemia-reperfusion injury resulted in higher serum blood urea nitrogen levels and higher tissue reactive oxygen species in -KO compared with -WT female mice. Moreover, cultured renal epithelial cells from -KO female mice showed lower viability after oxidative damage induced by menadione compared with -WT cells that could be rescued by supplementation with reduced glutathione, suggesting that induction after renal damage acts as a defense against reactive oxygen species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00318.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789986PMC
November 2020

The mA RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor.

Proc Natl Acad Sci U S A 2020 09 19;117(35):21441-21449. Epub 2020 Aug 19.

Department of Radiation Oncology, Stanford University, Stanford, CA 94305;

Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the mA RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide mA-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2000516117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474618PMC
September 2020

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging.

Int J Cancer 2020 07 21;147(1):256-265. Epub 2020 Jan 21.

Department of Urology, Stanford University, Stanford, California.

Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Intraoperative frozen section (IFS) analysis is used to confirm the diagnosis during partial nephrectomy. However, surgical margin evaluation using IFS analysis is time consuming and unreliable, leading to relatively low utilization. In our study, we demonstrated the use of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) as a molecular diagnostic and prognostic tool for ccRCC. DESI-MSI was conducted on fresh-frozen 23 normal tumor paired nephrectomy specimens of ccRCC. An independent validation cohort of 17 normal tumor pairs was analyzed. DESI-MSI provides two-dimensional molecular images of tissues with mass spectra representing small metabolites, fatty acids and lipids. These tissues were subjected to histopathologic evaluation. A set of metabolites that distinguish ccRCC from normal kidney were identified by performing least absolute shrinkage and selection operator (Lasso) and log-ratio Lasso analysis. Lasso analysis with leave-one-patient-out cross-validation selected 57 peaks from over 27,000 metabolic features across 37,608 pixels obtained using DESI-MSI of ccRCC and normal tissues. Baseline Lasso of metabolites predicted the class of each tissue to be normal or cancerous tissue with an accuracy of 94 and 76%, respectively. Combining the baseline Lasso with the ratio of glucose to arachidonic acid could potentially reduce scan time and improve accuracy to identify normal (82%) and ccRCC (88%) tissue. DESI-MSI allows rapid detection of metabolites associated with normal and ccRCC with high accuracy. As this technology advances, it could be used for rapid intraoperative assessment of surgical margin status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32843DOI Listing
July 2020

miR-22 Regulates Invasion, Gene Expression and Predicts Overall Survival in Patients with Clear Cell Renal Cell Carcinoma.

Kidney Cancer 2019 Aug 7;3(2):119-132. Epub 2019 Aug 7.

Department of Urology, School of Medicine, Stanford University, Stanford, California, USA.

Background: Clear cell renal cell carcinoma (ccRCC) is molecularly diverse and distinct molecular subtypes show different clinical outcomes. MicroRNAs (miRNAs) are essential components of gene regulatory networks and play a crucial role in progression of many cancer types including ccRCC.

Objective: Identify prognostic miRNAs and determine the role of miR-22 in ccRCC.

Methods: Hierarchical clustering was done in R using gene expression profiles of over 450 ccRCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was performed to identify prognostic miRNAs in the TCGA dataset. RNA-Seq was performed to identify miR-22 target genes in primary ccRCC cells and Matrigel invasion assay was performed to assess the effects of miR-22 overexpression on cell invasion.

Results: Hierarchical clustering analysis using 2,621 prognostic genes previously identified by our group demonstrated that ccRCC patients with longer overall survival expressed lower levels of genes promoting proliferation or immune responses, while better maintaining gene expression associated with cortical differentiation and cell adhesion. Targets of 26 miRNAs were significantly enriched in the 2,621 prognostic genes and these miRNAs were prognostic by themselves. MiR-22 was associated with poor overall survival in the TCGA dataset. Overexpression of miR-22 promoted invasion of primary ccRCC cells and modulated transcriptional programs implicated in cancer progression including DNA repair, cell proliferation and invasion.

Conclusions: Our results suggest that ccRCCs with differential clinical outcomes have distinct transcriptomes for which miRNAs could serve as master regulators. MiR-22, as a master regulator, promotes ccRCC progression at least in part by enhancing cell invasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/KCA-190051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839454PMC
August 2019

Biomimetic Decoy Inhibits Tumor Growth and Lung Metastasis by Reversing the Drawbacks of Sonodynamic Therapy.

Adv Healthc Mater 2020 01 25;9(1):e1901335. Epub 2019 Nov 25.

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P. R. China.

Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)-associated danger-associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo-Ce6/TPZ@M ) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia-activated tirapazamine (TPZ) in the red blood cells-PLTs hybrid membrane (M )-camouflaged pH-sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high-effective synergistic therapy. Meanwhile, DAMPs-mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet-mediated metastasis. In addition, ICD-mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.201901335DOI Listing
January 2020

Amplified Cancer Immunotherapy of a Surface-Engineered Antigenic Microparticle Vaccine by Synergistically Modulating Tumor Microenvironment.

ACS Nano 2019 11 8;13(11):12553-12566. Epub 2019 Nov 8.

School of Pharmaceutical Sciences , Zhengzhou University , Zhengzhou 450001 , People's Republic of China.

Efficient cancer vaccines not only require the co-delivery of potent antigens and highly immunostimulatory adjuvants to initiate robust tumor-specific host immune response but also solve the spatiotemporal consistency of host immunity and tumor microenvironment (TME) immunomodulation. Here, we designed a biomaterials-based strategy for converting tumor-derived antigenic microparticles (T-MPs) into a cancer vaccine to meet this conundrum and demonstrated its therapeutic potential in multiple murine tumor models. The internal cavity of T-MPs was employed to store nano-FeO (FeO/T-MPs), and then dense adjuvant CpG-loaded liposome arrays (CpG/Lipo) were tethered on the surface of FeO/T-MP through mild surface engineering to get a vaccine (FeO/T-MPs-CpG/Lipo), demonstrating that co-delivery of FeO/T-MPs and CpG/Lipo to antigen presenting cells (APCs) could elicit strong tumor antigen-specific host immune response. Meanwhile, vaccines distributed in the TME could reverse infiltrated tumor-associated macrophages into a tumor-suppressive M1 phenotype by nano-FeO, amazingly induce abundant infiltration of cytotoxic T lymphocytes, and transform a "cold" tumor into a "hot" tumor. Furthermore, amplified antitumor immunity was realized by the combination of an FeO/T-MPs-CpG/Lipo vaccine and immune checkpoint PD-L1 blockade, specifically inhibiting ∼83% of the progression of B16F10-bearing mice and extending the median survival time to 3 months. Overall, this study synergistically modulates the tumor immunosuppressive network and host antitumor immunity in a spatiotemporal manner, which suggests a general cell-engineering strategy tailored to a personalized vaccine from autologous cancer cell materials of each individual patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.9b03288DOI Listing
November 2019

Borneol-modified chitosan: Antimicrobial adhesion properties and application in skin flora protection.

Carbohydr Polym 2020 Jan 26;228:115378. Epub 2019 Sep 26.

Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, PR China; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address:

Antimicrobial modifications of chitosan usually endow the products with strong bactericidal activities. However, if the products come into direct contact with human skin, the skin flora, which is beneficial to human health, may be damaged. To address this issue, we developed a stereochemical antimicrobial strategy by grafting borneol 4-formylbenzoate to chitosan using a stable Schiff base bond; this process yielded borneol-modified chitosan (BMC) as a novel antimicrobial material. This material was challenged with gram-negative Escherichia coli, gram-positive Bacillus subtilis, and Aspergillus niger. All tests showed excellent antimicrobial adhesive properties. Guinea pig skin experiments further demonstrated that BMC did not damage the skin flora. Owing to the antimicrobial mechanism of borneol stereochemistry, BMC successfully defended against pathogens and protected the skin flora. Thus, this material may have excellent potential applications in multifunctional textiles, healthcare, and flexible skin electronics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carbpol.2019.115378DOI Listing
January 2020

S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma.

Cancer Res 2019 11 4;79(22):5758-5768. Epub 2019 Oct 4.

Department of Radiation Oncology, Stanford University, Palo Alto, California.

Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC. SIGNIFICANCE: These findings show that angiogenesis in renal cell carcinoma (RCC) is regulated through AXL/S100A10 signaling and support the combination of AXL inhibitors with antiangiogenic agents for the treatment of RCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-1366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015045PMC
November 2019

A Probiotic Spore-Based Oral Autonomous Nanoparticles Generator for Cancer Therapy.

Adv Mater 2019 Oct 6;31(43):e1903793. Epub 2019 Sep 6.

School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450001, China.

Spores, the dormant life forms of probiotics, can germinate to metabolically active vegetative cells with the disintegration of their hydrophobic protein coat in the intestinal microenvironment, which provides the possibility for the formation of nanoparticles (NPs) in vivo. Inspired by the natural physiological process of spores, herein, an oral autonomous NPs generator is developed to overcome the spatially variable gastrointestinal tract environment and multibiological barriers. Spores modified with deoxycholic acid (DA) and loaded with chemotherapeutic drugs (doxorubicin and sorafenib, DOX/SOR) serve as an autonomous production line of NPs, which can efficaciously protect the drugs passing through the rugged environment of the stomach and furthermore can be transported to the intestinal environment and colonized rapidly. Subsequently, the DOX/SOR/Spore-DA NPs are produced by the autonomous NPs generator in the intestinal regions based on the disintegrated hydrophobic protein and the hydrophilic DA, and they can efficiently penetrate the epithelial cells via the bile acid pathway, increasing basolateral drug release. In vitro and in vivo studies confirm that this biological nanogenerator can autonomously produce substantial NPs in the intestine, providing a promising strategy for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adma.201903793DOI Listing
October 2019

An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy.

Nanoscale 2019 Aug;11(34):15958-15970

School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.

Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by β-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9nr03802gDOI Listing
August 2019

Early detection of unilateral ureteral obstruction by desorption electrospray ionization mass spectrometry.

Sci Rep 2019 07 29;9(1):11007. Epub 2019 Jul 29.

Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Desorption electrospray ionization mass spectrometry (DESI-MS) is an emerging analytical tool for rapid in situ assessment of metabolomic profiles on tissue sections without tissue pretreatment or labeling. We applied DESI-MS to identify candidate metabolic biomarkers associated with kidney injury at the early stage. DESI-MS was performed on sections of kidneys from 80 mice over a time course following unilateral ureteral obstruction (UUO) and compared to sham controls. A predictive model of renal damage was constructed using the LASSO (least absolute shrinkage and selection operator) method. Levels of lipid and small metabolites were significantly altered and glycerophospholipids comprised a significant fraction of altered species. These changes correlate with altered expression of lipid metabolic genes, with most genes showing decreased expression. However, rapid upregulation of PG(22:6/22:6) level appeared to be a hitherto unknown feature of the metabolic shift observed in UUO. Using LASSO and SAM (significance analysis of microarrays), we identified a set of well-measured metabolites that accurately predicted UUO-induced renal damage that was detectable by 12 h after UUO, prior to apparent histological changes. Thus, DESI-MS could serve as a useful adjunct to histology in identifying renal damage and demonstrates early and broad changes in membrane associated lipids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-47396-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662848PMC
July 2019

Construction of ratiometric hydrogen sulfide probe with two reaction sites and its applications in solution and in live cells.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Jan 17;224:117391. Epub 2019 Jul 17.

Key Lab of Textile Cleaning, Dalian Polytechnic University, #1 Qinggongyuan, Dalian 116034, PR China.

Hydrogen sulfide (HS), as the third multifunctional signaling biomolecule, it acts as a neuromodulator in the human brain and is recognized as an important gas transmitter in human physiology. The abnormal concentrations of HS in human cells can result in several common diseases. Therefore, accurate, fast, and reliable methodologies are required for measuring the in vitro and in vivo concentrations of HS to further investigate its function. In this study, a novel DR-SON fluorescent probe containing the fluorophore Disperse Red 277 and a sulfonyl azide group was developed and exploited based on the structural characteristic of Disperse Red 277 that contains the active site easily can be attacked by HS. Therefore, this probe featured two reaction sites that involved the reduction and Michael addition of HS and exhibited rapid ratiometric fluorescence changes and high selectivity towards HS with a 619-fold enhancement factor. Further, the density functional theory (DFT)/time-dependent density functional theory (TDDFT) studies are conducted to understand the photophysical properties of DR-SON and the final product DRHS-SONH, which makes the proposed mechanism more reasonable. Furthermore, the probe was successfully applied for the ratiometric fluorescence imaging of exogenous HS in living cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.saa.2019.117391DOI Listing
January 2020

Stereochemical Strategy Advances Microbially Antiadhesive Cotton Textile in Safeguarding Skin Flora.

Adv Healthc Mater 2019 08 11;8(15):e1900232. Epub 2019 Jun 11.

Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.

Microbial contamination on cotton textiles (CT) negatively affects people's health as well as the textile itself during use and storage. Using antimicrobial CT in a body-safe manner is currently still a challenge because it is difficult to balance killing microbes and protecting skin flora. Herein, a borneol-decorated CT (BDCT) through coupling of borneol 4-formylbenzoate molecules onto the amino-modified CT is reported. This BDCT shows strong and broad-spectrum microbially antiadhesive activities against gram-positive bacteria (Staphylococcus aureus and S. epidermidis), gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and fungi (Aspergillus niger, Mucor racemosus, and Candida albicans). Because of its unique stereochemical microbial antiadhesion mechanism, BDCT is harmless to skin flora. In addition, BDCT exhibits prominent durability of microbially antiadhesive capability by bearing 50 times of accelerated laundering. Therefore, this stereochemical BDCT strategy shows great potential for applications in the new generation of textiles, food packaging, and medical protection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.201900232DOI Listing
August 2019

A Core-Shell Nanoplatform for Synergistic Enhanced Sonodynamic Therapy of Hypoxic Tumor via Cascaded Strategy.

Adv Healthc Mater 2018 11 10;7(22):e1800819. Epub 2018 Oct 10.

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P. R. China.

Sonodynamic therapy (SDT) always causes tumor hypoxia aggravation which can induce malignant cell proliferation and drug resistance. To overcome these disadvantages, a cascaded drug delivery system (Lipo/HMME/ACF@MnO -AS1411) is constructed for synergistic enhanced sonodynamic therapy. First, hematoporphyrin monomethyl ether (HMME) and acriflavine (ACF) are encapsulated in the lipid layers and the inner aqueous cores of the liposomes, respectively. Then the ultrathin manganese dioxide (MnO ) nanosheets are coated on the surface of the liposomes by using KMnO and polyethylene glycol through "one step reduction and modification" method. Furthermore, the nanoparticles are decorated with tumor-targeting AS1411 aptamer through the phosphate groups on the DNA strand which can bind to Mn sites to obtain Lipo/HMME/ACF@MnO -AS1411 delivery system. Herein, HMME can act as a sonosensitizer, and ACF is used to prevent the formation of HIF-1α/HIF-1β dimerization to overcome the negative effects after SDT. The Lipo/HMME/ACF@MnO -AS1411 delivery system has multiple functions, including codelivery of HMME and ACF, pH/glutathione/ultrasound triple responses, synergistic cascaded enhancement of SDT, precise tumor-targeting, and magnetic resonance imaging. The in vitro and in vivo results suggest that the Lipo/HMME/ACF@MnO -AS1411 delivery system is a promising core-shell nanoplatform for synergistic enhancement of sonodynamic therapy, which can provide a new approach in the related research fields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.201800819DOI Listing
November 2018

C-C Chemokine Ligand 2 (CCL2) Recruits Macrophage-Membrane-Camouflaged Hollow Bismuth Selenide Nanoparticles To Facilitate Photothermal Sensitivity and Inhibit Lung Metastasis of Breast Cancer.

ACS Appl Mater Interfaces 2018 Sep 7;10(37):31124-31135. Epub 2018 Sep 7.

Collaborative Innovation Center of New Drug Research and Safety Evaluation , Henan Province , Zhengzhou 450001 , People's Republic of China.

Poor tumor accumulation, rapid clearance from blood circulation, and high risk of invasive and metastasis are the major barriers that encumber the conventional nanodrug-based tumor therapy. In this work, macrophage membrane (M)-camouflaged quercetin (QE)-loaded hollow bismuth selenide nanoparticles (abbreviated as M@BS-QE NPs) are fabricated for combination therapy of breast cancer. The resulting M@BS-QE NPs are comprehensively characterized, possessing prolonged circulation life, as well as accelerated and enhanced tumoritropic accumulation, compared with those of bare BS NPs because of the immune evading capacity, C-C chemokine ligand 2 (CCL2)-mediated recruitment properties, and active targeting ability. The subsequent QE release under near-infrared (NIR) laser irradiation can selectively sensitize cancer cells to photothermal therapy (PTT) by depleting heat shock protein 70 (HSP70, one malignancy-specific-overexpressed thermoresistance-related chaperone) to realize such a cascaded synergistic effect. At the same time, M@BS-QE NPs down-regulated p-Akt and matrix metalloproteinase-9 (MMP-9, which degrades the extracellular matrix to promote invasion and metastasis of tumors) signal axis to suppress breast cancer lung metastasis. Thus, our results provide a biomimetic strategy, using the characteristics of breast cancer and biological properties of macrophages, that hold great promise to enhance the therapeutic efficacy and improve the accuracy of treatment with minimal side effects on both primary and lung metastasis of breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.8b11645DOI Listing
September 2018

Tumor-targeting core-shell structured nanoparticles for drug procedural controlled release and cancer sonodynamic combined therapy.

J Control Release 2018 09 17;286:74-84. Epub 2018 Jul 17.

School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, PR China; Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, 100 Kexue Avenue, Zhengzhou 450001, PR China. Electronic address:

Combination therapy with multiple drugs or/and multiple assistant treatments has become a hot spot in cancer therapy. In this study, a new type of core-shell structured dual-drug delivery system based on poly (lactic-co-glycolic acid) (PLGA, inner cores) and hyaluronic acid (HA, outer shells) was constructed. Firstly, HA was conjugated to PLGA for preparation of HA-PLGA block copolymer. Secondly, 5-amino levulinic acid (ALA) was connected to PLGA through a pH-sensitive hydrazone bond for synthesization of PLGA-HBA-ALA. Finally, the core-shell structured nanoparticles (HA-PLGA@ART/ALA NPs) were constructed by self-assembled method for artemisinin (ART) loading in PLGA cores. In this co-delivery system, ALA and ART can be released in a manner of procedural controlled release. ALA was released from the NPs at first though the pH sensitive hydrazone bond cleavage in order to generate protoporphyrin IX (PpIX) for heme formation. And the increase of heme can effectively improve the curative effect of the subsequent released ART. Furthermore, this system has also shown obvious sonodynaimc activity which can be used for cancer sonodynamic combination therapy. The in vitro and in vivo anticancer results demonstrate that HA-PLGA@ART/ALA delivery system could provide a prospective comprehensive treatment strategy for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2018.07.028DOI Listing
September 2018

An intelligent dual stimuli-responsive photosensitizer delivery system with O-supplying for efficient photodynamic therapy.

Colloids Surf B Biointerfaces 2018 Jul 10;167:299-309. Epub 2018 Apr 10.

Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, Zhengzhou 450001, PR China. Electronic address:

The effects of photodynamic therapy (PDT) are limited by the hypoxic tumor microenvironment (TME). In this paper, a new type of biocompatible multifunctional photosensitizer delivery system was fabricated to relieve tumor hypoxia and improve the efficacy of PDT. The photosensitizer hematoporphyrin monomethyl ether (HMME) and catalase (CAT) were encapsulated in the pores of mesoporous graphitic-phase carbon nitride nanosheets (mpg-CN). Next, hyaluronic (HA) was coated on the surface of the mpg-CN via an amide linkage to construct the tumor-targeting HAase/CAT dual activatable and mpg-CN/HMME response photosensitizer delivery system (HA@mpg-CN-HMME/CAT). Upon intravenous injection, HA@mpg-CN-HMME/CAT shows high tumor accumulation owing to the tumor-targeting HA coating. Meanwhile, CAT within mpg-CN could trigger decomposition of endogenic TME HO to increase oxygen supply in-situ to relieve tumor hypoxia. This effect together with mpg-CN/HMME dual response is able to dramatically improve PDT efficiency. The hypoxia status of tumors was evaluated in vivo to demonstrate the success of the O-supplying. And the in vitro and in vivo results showed the excellent therapeutic effect of the HA@mpg-CN-HMME/CAT photosensitizer delivery system. O-supplying PDT may enable the enhancement of traditional PDT and future PDT design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.colsurfb.2018.04.011DOI Listing
July 2018

Antifungal graphene oxide-borneol composite.

Colloids Surf B Biointerfaces 2017 Dec 14;160:220-227. Epub 2017 Sep 14.

The State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China. Electronic address:

Although antibacterial activities of graphene oxide (GO) and its derivatives have been investigated comprehensively, their antifungal properties are still less reported. Yet, fungal contamination seriously threatens the public health. Herein, we present a design of graphene oxide-borneol (GOB) composite, and report its great antifungal effect. This GOB composite is prepared by esterification of borneol with thiomalic-acid-modified GO sheets, where the linker molecule is used to increase surface carboxyl groups. As a result, the antifungal activity displays a dramatically conversion from no activity of GO and its derivatives to distinct antifungal adhesion and growth inhibition of the GOB. Under microscopy, few spores can be found on the GOB surface, while large numbers of sporangia and spores adhere and grow on the control groups. It is also worth noting that on the GOB sample the fallen spore does not germinate even after 5days, demonstrating a long-term antifungal effect of the GOB composite. Further studies confirm that carbon stereochemistry rather than wettability plays a crucial role on the antifungal adhesion properties. This study not only highlights a promising GOB composite as a candidate of graphene-based antifungal agent, but also provides us with in-depth understanding of the interactions between fungi and graphene-based materials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.colsurfb.2017.09.023DOI Listing
December 2017

Tumor acidity-activatable manganese phosphate nanoplatform for amplification of photodynamic cancer therapy and magnetic resonance imaging.

Acta Biomater 2017 10 24;62:293-305. Epub 2017 Aug 24.

School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, PR China; Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, 100 Kexue Avenue, Zhengzhou 450001, PR China. Electronic address:

Amorphous biodegradable metal phosphate nanomaterials are considered to possess great potential in cancer theranostic application due to their promise in providing ultra-sensitive pH-responsive therapeutic benefits and diagnostic functions simultaneously. Here we report the synthesis of photosensitising and acriflavine-carrying amorphous porous manganese phosphate (PMP) nanoparticles with ultra-sensitive pH-responsive degradability and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF1α/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Carboxymethyl dextran (CMD) is chemically anchored on the surface of porous manganese phosphate theranostic system through the pH-responsive boronate esters. Upon the stimulus of the tumor acid microenvironment, manganese phosphate disintegrates and releases Mn ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. Meanwhile, the released photosensitizer chlorin e6 (Ce6) produces ROS under irradiation while acriflavine (ACF) inhibits the HIF-1α/VEGF pathway during the burst release of VEGF in tumour induced by photodynamic therapy (PDT), resulting in increased therapeutic efficacy. Considering the strong pH responsivity, MRI signal amplification and drug release profile, the PMP nanoparticles offer new prospects for tumor acidity-activatable theranostic application by amplifying the PDT through inhibiting the HIF-1α /VEGF pathway timely while enhancing the MRI effect.

Statement Of Significance: In this study, we report the synthesis of the tumor acidity-activatable amorphous porous manganese phosphate nanoparticles and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF-1α/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Besides, upon the stimulus of the tumor acid microenvironment, the manganese phosphate nanoparticles finally disintegrate and release Mn ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. This nanoplatform is featured with distinctive advantages such as ultra pH-responsive drug release, MRI function and rational drug combination exploiting the blockage of the treatment escape signalling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2017.08.028DOI Listing
October 2017

Gold nanorod-based poly(lactic-co-glycolic acid) with manganese dioxide core-shell structured multifunctional nanoplatform for cancer theranostic applications.

Int J Nanomedicine 2017 13;12:3059-3075. Epub 2017 Apr 13.

School of Pharmaceutical Sciences, Zhengzhou University.

Recently, photothermal therapy has become a promising strategy in tumor treatment. However, the therapeutic effect was seriously hampered by the low tissue penetration of laser. Therefore, in this study, radiofrequency (RF) with better tissue penetration was used for tumor hyperthermia. First, one type of gold nanorods (AuNRs) suitable for RF hyperthermia was selected. Then, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with AuNRs and docetaxel (DTX) (PLGA/AuNR/DTX) NPs were constructed. Finally, manganese dioxide (MnO) ultrathin nanofilms were coated on the surfaces of PLGA/AuNR/DTX NPs by the reduction of KMnO to construct the PLGA/AuNR/DTX@MnO drug delivery system. This drug delivery system can not only be used for the combined therapy of chemotherapy and RF hyperthermia but can also produce Mn to enable magnetic resonance imaging. Furthermore, the RF hyperthermia and the degradation of MnO can significantly promote the controlled drug release in a tumor region. The in vitro and in vivo results suggested that the PLGA/AuNR/DTX@MnO multifunctional drug delivery system is a promising nanoplatform for effective cancer theranostic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S128844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399988PMC
September 2017

The immunomodulatory anticancer agent, RRx-001, induces an interferon response through epigenetic induction of viral mimicry.

Clin Epigenetics 2017 19;9. Epub 2017 Jan 19.

Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA.

Background: RRx-001, a dinitroazetidine derivative, is a novel anticancer agent currently in phase II clinical trials. It mediates immunomodulatory effects either directly through polarization of tumor associated macrophages or indirectly through vascular normalization and increased T-lymphocyte infiltration. With multiple additional mechanisms of action including upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis and epigenetic modulation, RRx-001 is being studied as a radio- and chemo-sensitizer to resensitize tumors to prior therapy and to prime tumors to respond to radiation, chemotherapy and immunotherapy in combination therapy studies. Here, we identified another mechanism, viral mimicry, which refers to the "unsilencing" of epigenetically repressed viral genes present in the tumor that provokes an immune response and may contribute to the anticancer activity of RRx-001.

Results: RRx-001 inhibited the growth of colon cancer cells (HCT 116) and decreased levels of the DNA methyltransferases DNMT1 and DNMT3a in a time and dose-dependent manner. Treatment of HCT 116 cells with 0.5 μM RRx-001 for 24 h significantly increased transcripts of interferon (IFN)-responsive genes and this induction was sustained for up to 4 weeks after transient exposure to RRx-001. ELISA assays showed that RRx-001 increased secretion of type I and III IFNs by HCT 116 cells, and these IFNs were confirmed to be bioactive. Transcription of endogenous retrovirus ERV-Fc2 and LTRs from the ERV-L family (MLT2B4 and MLT1C49) was induced by RRx-001. The induction of ERV-Fc2-env was through demethylation of ERV-Fc2 LTR as determined by methylation-specific polymerase chain reaction and combined bisulfite restriction analysis. Immunofluorescence staining with J2 antibody confirmed induction of double-stranded RNA.

Conclusions: Transient exposure of HCT 116 cells to low-dose RRx-001 induced transcription of silenced retroviral genes present in the cancer cell DNA with subsequent synthesis of IFN in response to this "pseudo-pathogenic" stimulus, mimicking an antiviral defense. RRx-001-mediated IFN induction may have the potential to improve the efficacy of immunotherapies as well as radiotherapy, standard chemotherapies and molecularly targeted agents when used in combination. The striking safety profile of RRx-001 in comparison to other more toxic epigenetic and immunomodulatory agents such as azacitidine makes it a leading candidate for such clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-017-0312-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270305PMC
July 2017

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials.

Expert Opin Investig Drugs 2017 01;26(1):109-119

g Murtha Cancer Center , Walter Reed National Military Medical Center ; Bethesda , MD , USA.

Introduction: According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543784.2017.1268600DOI Listing
January 2017

Polyester Fabric's Fluorescent Dyeing in Supercritical Carbon Dioxide and its Fluorescence Imaging.

J Fluoresc 2017 Mar 28;27(2):483-489. Epub 2016 Nov 28.

Zhejiang Jihua group Co., Ltd., Hangzhou, Zhejiang, 311228, People's Republic of China.

As one of the most important coumarin-like dyes, disperse fluorescent Yellow 82 exhibits exceptionally large two-photon effects. Here, it was firstly introduced into the supercritical CO dyeing polyester fabrics in this work. Results of the present work showed that the dyeing parameters such as the dyeing time, pressure and temperature had remarkable influences on the color strength of fabrics. The optimized dyeing condition in supercritical CO dyeing has been proposed that the dyeing time was 60 min; the pressure was 25 MPa and the temperature was 120 °C. As a result, acceptable products were obtained with the wash and rub fastness rating at 5 or 4-5. The polyester fabrics dyed with fluorescent dyes can be satisfied for the requirement of manufacturing warning clothing. Importantly, the confocal microscopy imaging technology was successfully introduced into textile fields to observe the distribution and fluorescence intensity of disperse fluorescent Yellow 82 on polyester fabrics. As far as we know, this is the first report about supercritical CO dyeing polyester fabrics based on disperse fluorescent dyes. It will be very helpful for the further design of new fluorescent functional dyes suitable for supercritical CO dyeing technique.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10895-016-1975-0DOI Listing
March 2017

Cabozantinib inhibits tumor growth and metastasis of a patient-derived xenograft model of papillary renal cell carcinoma with MET mutation.

Cancer Biol Ther 2017 Nov 11;18(11):863-871. Epub 2016 Aug 11.

a Department of Urology , Stanford University School of Medicine , Stanford , CA , USA.

MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2γC mice to establish first generation TSG-RCC-030. Histologic and genetic fidelity and metastatic potential of this model were characterized by immunohistochemistry, direct DNA sequencing and quantitative polymerase chain reaction (qPCR). The effect of cabozantinib on tumor growth and metastasis was evaluated. Whether measurements of circulating tumor DNA (ctDNA) by allele-specific qPCR could be used as a biomarker of tumor growth and response to therapy was determined. Subrenal and subcutaneous tumor grafts showed high take rates and metastasized to the lung. Both primary tumors and metastases expressed typical markers of pRCC and carried the same activating MET mutation as the parental tumor. Cabozantinib treatment caused striking tumor regression and inhibited lung metastasis in TSG-RCC-030. Plasma ctDNA levels correlated with tumor volume in control mice and changed in response to cabozantinib treatment. TSG-RCC-030 provides a realistic preclinical model to better understand the development and progression of pRCC with MET mutation and accelerate the development of new therapies for pRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384047.2016.1219816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710673PMC
November 2017

Spheroid culture of LuCaP 136 patient-derived xenograft enables versatile preclinical models of prostate cancer.

Clin Exp Metastasis 2016 Apr 12;33(4):325-37. Epub 2016 Feb 12.

Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

LuCaP serially transplantable patient-derived xenografts (PDXs) are valuable preclinical models of locally advanced or metastatic prostate cancer. Using spheroid culture methodology, we recently established cell lines from several LuCaP PDXs. Here, we characterized in depth the features of xenografts derived from LuCaP 136 spheroid cultures and found faithful retention of the phenotype of the original PDX. In vitro culture enabled luciferase transfection into LuCaP 136 spheroids, facilitating in vivo imaging. We showed that LuCaP 136 spheroids formed intratibial, orthotopic, and subcutaneous tumors when re-introduced into mice. Intratibial tumors responded to castration and were highly osteosclerotic. LuCaP 136 is a realistic in vitro-in vivo preclinical model of a subtype of bone metastatic prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10585-016-9781-2DOI Listing
April 2016

A Protective Role for Androgen Receptor in Clear Cell Renal Cell Carcinoma Based on Mining TCGA Data.

PLoS One 2016 27;11(1):e0146505. Epub 2016 Jan 27.

Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.

Androgen receptor (AR) is expressed in normal murine and human kidneys of both genders, but its physiologic role is uncertain. Several studies showed loss of AR in renal cell carcinoma (RCC) in conjunction with increasing clinical stage and pathological grade, but others found that higher AR expression correlated with worse outcomes. Limited functional studies with renal cell lines suggested tumor-promoting activity of AR. In this study, we queried transcriptomic, proteomic, epigenetic and survival data from The Cancer Genome Atlas (TCGA) to evaluate AR expression and its association with overall survival in three subtypes of RCC (clear cell [ccRCC], papillary [pRCC], and chromophobe [chRCC]). We found that although there was no significant difference in AR mRNA expression in ccRCC of males vs. females, AR protein expression in ccRCC was significantly higher in male compared to female patients. More importantly, higher expression of AR at both transcript and protein levels was associated with improved overall survival in both genders with ccRCC, but did not predict survival of either gender with pRCC or chRCC. Genes whose transcript levels were associated with AR mRNA levels significantly overlapped between ccRCC and pRCC, but not with chRCC, suggesting a similar transcriptional program mediated by AR in ccRCC and pRCC. Ingenuity pathway analysis also identified overlapping pathways and upstream regulators enriched in AR-associated genes in ccRCC and pRCC. Hypermethylation of CpG sites located in the promoter and first exon of AR was associated with loss of AR expression and poor overall survival. Our findings support a tumor suppressor role for AR in both genders that might be exploited to decrease the incidence or progression of ccRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146505PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729482PMC
July 2016

Epigenetic effects of RRx-001: a possible unifying mechanism of anticancer activity.

Oncotarget 2015 Dec;6(41):43172-81

Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.

RRx-001 is a novel aerospace-derived compound currently under investigation in several ongoing Phase II studies. In a Phase I trial, it demonstrated anti-cancer activity and evidence of resensitization to formerly effective therapies in heavily pre-treated patients with relapsed/refractory solid tumors. RRx-001 generates reactive oxygen and nitrogen species (ROS and RNS) and nitric oxide (NO), elicits changes in intracellular redox status, modulates tumor blood flow, hypoxia and vascular function and triggers apoptosis in cancer cells. We investigated the effect of RRx-001 on the epigenome of SCC VII cancer cells. RRx-001 at 0.5 and 2 μM significantly decreased global DNA methylation, i.e., 5-methylcytosine levels, in SCC VII cells. Consistently, 0.5-5 μM RRx-001 significantly decreased Dnmt1 and Dnmt3a protein expression in a dose- and time-dependent manner. In addition, global methylation profiling identified differentially methylated genes in SCC VII cells treated with 0.5, 2, and 5 μM RRx-001 compared to control cells. Twenty-three target sites were hypomethylated and 22 hypermethylated by >10% in the presence of at least two different concentrations of RRx-001. Moreover, RRx-001 at 2 μM significantly increased global acetylated histone H3 and H4 levels in SCC VII cells after 24 hour treatment, suggesting that RRx-001 regulates global acetylation in cancer cells. These results demonstrate that, in contrast to the traditional "one drug one target" paradigm, RRx-001 has multi(epi)target features, which contribute to its anti-cancer activity and may rationalize the resensitization to previously effective therapies observed in clinical trials and serve as a unifying mechanism for its anticancer activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.6526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791224PMC
December 2015

Multifunctional nanosheets based on folic acid modified manganese oxide for tumor-targeting theranostic application.

Nanotechnology 2016 Jan 2;27(2):025101. Epub 2015 Dec 2.

School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan Province 450001, People's Republic of China.

It is highly desirable to develop smart nanocarriers with stimuli-responsive drug-releasing and diagnostic-imaging functions for cancer theranostics. Herein, we develop a reduction and pH dual-responsive tumor theranostic platform based on degradable manganese dioxide (MnO2) nanosheets. The MnO2 nanosheets with a size of 20-60 nm were first synthesized and modified with (3-Aminopropyl) trimethoxysilane (APTMS) to get amine-functionalized MnO2, and then functionalized by NH2-PEG2000-COOH (PEG). The tumor-targeting group, folic acid (FA), was finally conjugated with the PEGylated MnO2 nanosheets. Then, doxorubicin (DOX), a chemotherapeutic agent, was loaded onto the modified nanosheets through a physical adsorption, which was designated as MnO2-PEG-FA/DOX. The prepared MnO2-PEG-FA/DOX nanosheets with good biocompatibility can not only efficiently deliver DOX to tumor cells in vitro and in vivo, leading to enhanced anti-tumor efficiency, but can also respond to a slightly acidic environment and high concentration of reduced glutathione (GSH), which caused degradation of MnO2 into manganese ions enabling magnetic resonance imaging (MRI). The longitudinal relaxation rate r1 was 2.26 mM(-1) s(-1) at pH 5.0 containing 2 mM GSH. These reduction and pH dual-responsive biodegradable nanosheets combining efficient MRI and chemotherapy provide a novel and promising platform for tumor-targeting theranostic application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/0957-4484/27/2/025101DOI Listing
January 2016