Prognostic difference between surgery and external radiation in patients with stage I liver cancer based on competitive risk model and conditional survival rate.

PURPOSE: This study aimed to assess the difference in prognosis of patients with early-stage liver cancer after surgery or external radiation. METHODS: Between 2010 and 2015, 2155 patients with AJCC 7th stage I liver cancer were enrolled in the SEER database. Among these, 1972 patients had undergone surgery and 183 had undergone external beam radiation. The main research endpoints were overall survival (OS) and disease-specific survival (DSS). The competitive risk model was used to calculate the risk ratio of liver cancer-specific deaths when there was a competitive risk. Propensity Score Matching (PSM) method using a 1:1 ratio was used to match confounders such as sex, age, and treatment method. Conditional survival was dynamically assessed for patient survival after surgery or external radiation. RESULTS: Multivariate analysis of the competitive risk model showed that age, disease diagnosis time, grade, and treatment [surgery and external beam radiation therapy (EBRT)] were independent prognostic factors for patients with hepatocellular carcinoma. Surgery had a higher survival improvement rate than that of EBRT. As the survival of patients with liver cancer increased, the survival curve of surgery declined more slowly than that of radiotherapy patients and stabilized around 3 years after surgery. The survival curve of radiotherapy patients significantly dropped within 4 years and then stabilized. CONCLUSION: Surgery was better than EBRT for patients with stage I liver cancer. Close follow-up was required for 3 years after surgery or 4 years after external radiation. This study can help clinicians make better informed clinical decisions.

NIR-promoted ferrous ion regeneration enhances ferroptosis for glioblastoma treatment.

Ferroptosis, a unique iron-dependent mode of cell death characterized by lipid peroxide accumulation, holds significant potential for the treatment of glioblastoma (GBM). However, the effectiveness of ferroptosis is hindered by the limited intracellular ferrous ions (Fe2+) and hydrogen peroxide (H2O2). In this study, a novel near-infrared (NIR)-light-responsive nanoplatform (ApoE-UMSNs-GOx/SRF) based on upconversion nanoparticles (UCNPs) was developed. A layer of mesoporous silica and a lipid bilayer were coated on UCNPs sequentially and loaded with glucose oxidase (GOx) and sorafenib, respectively. Further attachment of the ApoE peptide endowed the nanoplatform with BBB penetration and GBM targeting capabilities. Our results revealed that ApoE-UMSNs-GOx/SRF could efficiently accumulated in the orthotopic GBM and induce amplified ferroptosis when combining with NIR irradiation. The UCNPs mediated the photoreduction of Fe3+ to Fe2+ by converting NIR to UV light, and excess H2O2 was produced by the reaction of glucose with the loaded GOx. These processes greatly promoted the production of ROS, which together with inhibition of system Xc- by the loaded sorafenib, leading to enhanced accumulation of lipid peroxides and significantly improved the antiglioma effect both in vitro and in vivo. Our strategy has the potential to enhance the effectiveness of ferroptosis as a therapeutic approach for GBM.

GBAP1 functions as a tumor promotor in hepatocellular carcinoma via the PI3K/AKT pathway.

Hepatocellular carcinoma (HCC) is common worldwide, and novel therapeutic targets and biomarkers are needed to improve outcomes. In this study, bioinformatics analyses combined with in vitro and in vivo assays were used to identify the potential therapeutic targets. Differentially expressed genes (DEG) in HCC were identified by the intersection between The Cancer Genome Atlas and International Cancer Genome Consortium data. The DEGs were evaluated by a gene set enrichment analysis as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A protein interaction network, univariate Cox regression, and Lasso regression were used to screen out hub genes correlated with survival. Increased expression of the long noncoding RNA GBAP1 in HCC was confirmed in additional datasets and its biological function was evaluated in HCC cell lines and nude mice. Among 121 DEGs, GBAP1 and PRC1 were identified as hub genes with significant prognostic value. Overexpression of GBAP1 in HCC was confirmed in 21 paired clinical tissues and liver cancer or normal cell lines. The inhibition of GBAP1 expression reduced HCC cell proliferation and promoted apoptosis by inactivating the PI3K/AKT pathway in vitro and in vivo. Therefore, GBAP1 has a pro-oncogenic function in HCC and is a candidate prognostic biomarker and therapeutic target.

Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.

Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.

Angiopep-2 Modified Exosomes Load Rifampicin with Potential for Treating Central Nervous System Tuberculosis.

Background: Central nervous system tuberculosis (CNS-TB) is the most devastating form of extrapulmonary tuberculosis. Rifampin (RIF) is a first-line antimicrobial agent with potent bactericidal action. Nonetheless, the blood-brain barrier (BBB) limits the therapeutic effects on CNS-TB. Exosomes, however, can facilitate drug movements across the BBB. In addition, exosomes show high biocompatibility and drug-loading capacity. They can also be modified to increase drug delivery efficacy. In this study, we loaded RIF into exosomes and modified the exosomes with a brain-targeting peptide to improve BBB permeability of RIF; we named these exosomes ANG-Exo-RIF. Methods: Exosomes were isolated from the culture medium of BMSCs by differential ultracentrifugation and loaded RIF by electroporation and modified ANG by chemical reaction. To characterize ANG-Exo-RIF, Western blot (WB), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were performed. Bend.3 cells were incubated with DiI labeled ANG-Exo-RIF and then fluorescent microscopy and flow cytometry were used to evaluate the targeting ability of ANG-Exo-RIF in vitro. Fluorescence imaging and frozen section were used to evaluate the targeting ability of ANG-Exo-RIF in vivo. MIC and MBC were determined through microplate alamar blue assay (MABA). Results: A novel exosome-based nanoparticle was developed. Compared with untargeted exosomes, the targeted exosomes exhibited high targeting capacity and permeability in vitro and in vivo. The MIC and MBC of ANG-Exo-RIF were 0.25 µg/mL, which were sufficient to meet the clinical needs. Conclusion: In summary, excellent targeting ability, high antitubercular activity and biocompatibility endow ANG-Exo-RIF with potential for use in future translation-aimed research and provide hope for an effective CNS-TB treatment.

A Prognostic Gene Signature for Hepatocellular Carcinoma.

Hepatocellular carcinoma is the third most common cause of cancer-related deaths in China and immune-based therapy can improve patient outcomes. In this study, we investigated the relationship between immunity-associated genes and hepatocellular carcinoma from the prognostic perspective. The data downloaded from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) and the Gene Expression Omnibus (GEO) was screened for gene mutation frequency using the maftools package. Immunity-associated eight-gene signature with strong prognostic ability was constructed and proved as an independent predictor of the patient outcome in LIHC. Seven genes in the immune-related eight-gene signature were strongly associated with the infiltration of M0 macrophages, resting mast cells, and regulatory T cells. Our research may provide clinicians with a quantitative method to predict the prognosis of patients with liver cancer, which can assist in the selection of the optimal treatment plan.

Fatty acid synthase (Fasn) inhibits the expression levels of immune response genes via alteration of alternative splicing in islet cells.

BACKGROUND: Increasing evidence has shown that fatty acid synthase (Fasn) is associated with diabetes mellitus (DM) and insulin resistance, however, it remains unclear how Fasn upregulation leads to dysregulation of energy homeostasis in islet cells. Consequently, uncovering the function of Fasn in islet cells. Consequently, uncovering the function of FASN in islet cells is immensely important for finding a treatment target. AIM: In this study, we elucidated the biological function of Fasn on the target genes in a rat insulinoma INS-1 cell line. METHODS: We created a Fasn overexpressing rat insulinoma cell line (Fasn-OE), and performed bulk RNA-sequencing (RNA-seq) experiments on Fasn-OE and INS-1 (control) cells. We first identified differentially expressed genes (DEGs) using Bioconductor package edgeR, and then discovered enriched gene ontology terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using the KEGG Orthology Based Annotation System (KOBAS) 2.0 web server. Furthermore, we identified alternative splicing events (ASEs) and regulated alternative splicing events (RASEs) by applying the ABLas pipeline. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used for validation of selected differentially expressed genes (DEGs) and Fasn-regulated alternative splicing genes (RASGs). RESULTS: In this study we found that Fasn overexpression led to significant changes of gene expression profiles, including downregulations of mRNA levels of immune related genes, including Bst2, Ddit3, Isg15, Mx2, Oas1a, Oasl, and RT1-S3 in INS-1 cell line. Furthermore, Fasn positively regulated the expression of transcription factors such as Fat1 and Ncl diabetes-related genes. Importantly, Fasn overexpression to result in alternative splicing events including in a metabolism-associated ATP binding protein mRNA Abcc5. In Gene Ontology analysis, the downregulated genes in Fasn-OE cells were mainly enriched in inflammatory response and innate immune response. In Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the downregulated genes were mainly enriched in TNF signaling pathway and cytokine-mediated signaling pathways. CONCLUSIONS: Our findings showed that upregulation of Fasn may play a critical role in islet cell immunmetabolism via modifications of immune/inflammatory related genes on transcription and alternative splicing level, which provide novel insights into characterizing the function of Fasn in islet cell immunity and for the development of chemo/immune therapies.

Immunogenic Cell Death Induced by Chemoradiotherapy of Novel pH-Sensitive Cargo-Loaded Polymersomes in Glioblastoma.

BACKGROUND: Inducing the immunogenic cell death of tumour cells can mediate the occurrence of antitumour immune responses and make the therapeutic effect more significant. Therefore, the development of treatments that can induce ICD to destroy tumour cells most effectively is promising. Previously, a new type of pH-sensitive polymersome was designed for the treatment of glioblastoma which represents a promising nanoplatform for future translational research in glioblastoma therapy. In this study, the aim of this work was to analyse whether chemoradiotherapy of the novel pH-sensitive cargo-loaded polymersomes can induce ICD. METHODS: Cell death in U87-MG and G422 cells was induced by Au-DOX@PO-ANG, and cell death was analysed by CCK-8 and flow cytometry. The release of CRT was determined by using laser scanning confocal microscopy and flow cytometry. ELISA kits were used to detect the release of HMGB1 and ATP. The dying cancer cells treated with different treatments were cocultured with bone-marrow-derived dendritic cells (BMDCs), and then flow cytometry was used to determine the maturation rate of BMDCs (CD11c+CD86+CD80+) to analyse the in vitro immunogenicity. Tumour vaccination experiments were used to evaluate the ability of Au-DOX@PO-ANG to induce ICD in vivo. RESULTS: We determined the optimal treatment strategy to evaluate the ability of chemotherapy combined with radiotherapy to induce ICD and dying cancer cells induced by Au-DOX@PO-ANG+RT could induce calreticulin eversion to the cell membrane, promote the release of HMGB1 and ATP, and induce the maturation of BMDCs. Using dying cancer cells induced by Au-DOX@PO-ANG+RT, we demonstrate the efficient vaccination potential of ICD in vivo. CONCLUSION: These results identify Au-DOX@PO-ANG as a novel immunogenic cell death inducer in vitro and in vivo that could be effectively combined with RT in cancer therapy.

Facile Assembly of Thermosensitive Liposomes for Active Targeting Imaging and Synergetic Chemo-/Magnetic Hyperthermia Therapy.

Cancer stem cells (CSCs) are thought to be responsible for the recurrence of liver cancer, highlighting the urgent need for the development of effective treatment regimens. In this study, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and thermosensitive magnetoliposomes (TMs) conjugated to anti-CD90 (CD90@17-AAG/TMs) were developed for temperature-responsive CD90-targeted synergetic chemo-/magnetic hyperthermia therapy and simultaneous imaging in vivo. The targeting ability of CD90@DiR/TMs was studied with near-infrared (NIR) resonance imaging and magnetic resonance imaging (MRI), and the antitumor effect of CD90@17-AAG/TM-mediated magnetic thermotherapy was evaluated in vivo. After treatment, the tumors were analyzed with Western blotting, hematoxylin and eosin staining, and immunohistochemical (IHC) staining. The relative intensity of fluorescence was approximately twofold higher in the targeted group than in the non-targeted group, while the T 2 relaxation time was significantly lower in the targeted group than in the non-targeted group. The combined treatment of chemotherapy, thermotherapy, and targeting therapy exhibited the most significant antitumor effect as compared to any of the treatments alone. The anti-CD90 monoclonal antibody (mAb)-targeted delivery system, CD90@17-AAG/TMs, exhibited powerful targeting and antitumor efficacies against CD90+ liver cancer stem cells in vivo.

Chitosan oligosaccharide decorated liposomes combined with TH302 for photodynamic therapy in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive tumor with extremely high mortality that results from its lack of effective therapeutic targets. As an adhesion molecule related to tumorigenesis and tumor metastasis, cluster of differentiation-44 (also known as CD44) is overexpressed in TNBC. Moreover, CD44 can be effectively targeted by a specific hyaluronic acid analog, namely, chitosan oligosaccharide (CO). In this study, a CO-coated liposome was designed, with Photochlor (HPPH) as the 660 nm light mediated photosensitizer and evofosfamide (also known as TH302) as the hypoxia-activated prodrug. The obtained liposomes can help diagnose TNBC by fluorescence imaging and produce antitumor therapy by synergetic photodynamic therapy (PDT) and chemotherapy. RESULTS: Compared with the nontargeted liposomes, the targeted liposomes exhibited good biocompatibility and targeting capability in vitro; in vivo, the targeted liposomes exhibited much better fluorescence imaging capability. Additionally, liposomes loaded with HPPH and TH302 showed significantly better antitumor effects than the other monotherapy groups both in vitro and in vivo. CONCLUSION: The impressive synergistic antitumor effects, together with the superior fluorescence imaging capability, good biocompatibility and minor side effects confers the liposomes with potential for future translational research in the diagnosis and CD44-overexpressing cancer therapy, especially TNBC.

LRP1-mediated pH-sensitive polymersomes facilitate combination therapy of glioblastoma in vitro and in vivo.

BACKGROUND: Glioblastoma (GBM) is the most invasive primary intracranial tumor, and its effective treatment is one of the most daunting challenges in oncology. The blood-brain barrier (BBB) is the main obstacle that prevents the delivery of potentially active therapeutic compounds. In this study, a new type of pH-sensitive polymersomes has been designed for glioblastoma therapy to achieve a combination of radiotherapy and chemotherapy for U87-MG human glioblastoma xenografts in nude mice and significantly increased survival time. RESULTS: The Au-DOX@PO-ANG has a good ability to cross the blood-brain barrier and target tumors. This delivery system has pH-sensitivity and the ability to respond to the tumor microenvironment. Gold nanoparticles and doxorubicin are designed as a complex drug. This type of complex drug improve the radiotherapy (RT) effect of glioblastoma. The mice treated with Au-DOX@PO-ANG NPs have a significant reduction in tumor volume. CONCLUSION: In summary, a new pH-sensitive drug delivery system was fabricated for the treatment of glioblastoma. The new BBB-traversing drug delivery system potentially represents a novel approach to improve the effects of the treatment of intracranial tumors and provides hope for glioblastoma treatment.

CRGDK-Functionalized PAMAM-Based Drug-Delivery System with High Permeability.

The low tumor permeability of nanomedicines is a major challenge for their application in tumor therapy. Reducing the size of nanomedicines or integrating penetrating peptides has been demonstrated to be very helpful to improve the tumor permeability of nanomedicines. In this paper, poly(amidoamine) (PAMAM) functionalized with the penetrating peptide CRGDK was designed as a drug carrier with a diameter of ∼5 nm. Paclitaxel (PTX) was used as a model drug and covalently linked to the carrier via a biocleavable ester bond. The CRGDK-functionalized drug-loaded nanoparticle exhibited a higher cellular uptake and a higher tumor accumulation and penetration than its nontargeted counterpart, which also endowed the functionalized nanomedicine with a higher antitumor efficiency than its nontargeted counterpart and the clinical Taxol formulation. The good performance of the peptide-bearing PAMAM-based nanomedicine indicates that our strategy is feasible to improve the tumor accumulation and penetration of nanomedicines.

Hydroxyapatite (HA) Modified Nanocoating Enhancement on AZ31 Mg Alloy by Combined Surface Mechanical Attrition Treatment and Electrochemical Deposition Approach.

Hydroxyapatite (HA) nanocoating was electrodeposited on the surface mechanical attrition treated (SMATed) AZ31 magnesium alloy. Phases, morphologies and the adhesion of coating were characterized by X-ray diffraction, scanning electron microscopy (SEM) and 3D optical profiler. The corrosion resistance of the HA coating was tested by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). The results showed that the HA coating on SMATed sample had a better crystallization than that on original one. The thickness of HA coating increased from 25 to 40 µm. The bonding strength between HA coating and SMATed substrate was higher than that between the coating and untreated counterpart. Potentiodynamic polarization and EIS demonstrated that the corrosion current density of HA coating on SMATed substrate decreased by 30.84% than that on original. The corrosion potential shifted 80.3 mV to the positive direction. The corrosion resistance of coatings on SMATed sample was significantly enhanced. The immersion experiments showed that the HA coatings on SMATed sample exhibited a better biological activity.

Antitumor Effect and Toxicity of an Albumin-Paclitaxel Nanocarrier System Constructed via Controllable Alkali-Induced Conformational Changes.

Various strategies have been developed to construct albumin nanomaterials via biophysical or chemical changes. In this work, a compound comprising albumin-paclitaxel nanoparticles (NPs-PTX) with a drug loading efficiency of 21% was constructed via manipulation of alkali induced conformation changes and hydrophilic-hydrophobicity transition. The toxicity of two PTX formulations (Taxol and NPs-PTX) in human umbilical vein endothelial cells (HUVECs), RAW264.7, K562, and HepG2 cells, and rats were determined. The half maximal inhibitory concentration (IC50) of Taxol was remarkably lower than that of NPs-PTX. Both PTX formulations promoted cell apoptosis, possibly via mitochondria-dependent (intrinsic) and mitochondria-independent pathways. The effect of PTX formulations (0.5 to 1 mg mL-1) on hemolysis and the median lethal dose (50% mortality, LD50) values of the PTX formulations were significantly different (p < 0.01). Reductions in the number of white blood cells (WBCs) and monocytes (MNCs) and obvious pathological changes in the spleen, thymus, and mesenteric lymph nodes were observed and may have been related to the bone marrow inhibition effect of PTX. The tumor inhibition rate of NPs-PTX (60.8%) was higher than that of Taxol (31.2%) (p < 0.05) when the dose of NPs-PTX (equivalent PTX) was 2.5 times as that of Taxol (30 vs 12 mg kg-1). Taxol is highly toxic, whereas NPs-PTX is moderately toxic. Thus, NPs-PTX has advantages over the commercially available Taxol formulation in terms of low toxicity and increased dosage, indicating NPs-PTX is a better option for safe and effective PTX delivery.

NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo.

Currently, glioma treatment is limited by two main factors: timely detection at onset or relapse and restriction of drugs by the blood-brain barrier (BBB) from entering the brain and influencing tumor growth. However, a safe BBB-traversing drug delivery system has brought new hope to glioma treatment. Exosomes have strong cargo-loading capacity and have the ability to cross the BBB. They can also be conferred with the ability for targeted delivery. Therefore, exosomes have great promise to be a targeted drug delivery vehicles. In this study, we firstly loaded superparamagnetic iron oxide nanoparticles (SPIONs) and curcumin (Cur) into exosomes and then conjugated the exosome membrane with neuropilin-1-targeted peptide (RGERPPR, RGE) by click chemistry to obtain glioma-targeting exosomes with imaging and therapeutic functions. When administered to glioma cells and orthotopic glioma models, we found that these engineered exosomes could cross the BBB smoothly and provided good results for targeted imaging and therapy of glioma. Furthermore, SPION-mediated magnetic flow hyperthermia (MFH) and Cur-mediated therapy also showed a potent synergistic antitumor effect. Therefore, the diagnostic and therapeutic effects on glioma were significantly improved, while reducing the side effects. We have designed a new type of glioma-targeting exosomes, which can carry nanomaterials and chemical agents for simultaneous diagnosis and treatment of glioma, thus providing a potential approach for improving the diagnosis and treatment effects of intracranial tumors.

Preparation of Folic Acid-Targeted Temperature-Sensitive Magnetoliposomes and their Antitumor Effects In Vitro and In Vivo.

BACKGROUND: Ovarian cancer is a common gynecologic malignancy with poor prognosis, requiring innovative new therapeutic strategies. Temperature-controlled drug delivery to cancer cells represents a novel, promising, targeted treatment approach. OBJECTIVE: We prepared folate receptor-targeted thermosensitive liposomes wrapped with the HSP90 inhibitor 17-AAG and superparamagnetic material (17-AAG/MTSLs-FA), and tested the efficacy of these targeted magnetoliposomes in vitro and in vivo. METHODS: Magnetic thermosensitive liposomes wrapped with 17-AAG were coprecipitated with Fe3O4 magnetic nanoparticles and prepared by a rotary evaporation method. Experiments were conducted with SKOV3 human ovarian cancer cells and MCF7 human breast carcinoma cells to evaluate the anti-tumor effects. RESULTS: 17-AAG/MTSLs-FA prepared in this study met the basic requirements for therapeutic application. The preparation method is relatively simple and the raw materials are readily available. The product exhibited strong magnetism, high encapsulation efficiencies, and satisfactory performance. The liposomes combined with hyperthermia significantly inhibited the proliferation of SKOV3 cells and induced apoptosis. Experiments using a mouse subcutaneous model as well as an ascites tumor xenograft model indicated that 17-AAG/MTSLs-FA was stable in vivo and effectively targeted tumor tissues expressing the folate receptor. CONCLUSIONS: Folic acid-conjugated 17-AAG magnetic thermosensitive liposomes in combination with an alternating magnetic field for heating can achieve a synergistic anti-tumor effect of chemotherapy and heat treatment, potentially offering a new method for ovarian cancer treatment.

Noninvasive evaluation of the migration effect of transplanted endothelial progenitor cells in ischemic muscle using a multimodal imaging agent.

BACKGROUND: Endothelial progenitor cells (EPCs) play an important role in repairing ischemia tissues. However, the survival, migration and therapeutic efficacy of EPCs after transplantation need to be better understood for further cell therapy. PURPOSE: This study investigated the migration effect of EPCs labeled with a multimodal imaging agent in a murine ischemic hindlimb model, using magnetic resonance imaging (MRI) and optical imaging after transplantation. METHODS: EPCs derived from mouse bone marrow were labeled with a multimodal imaging agent and were administered through intracardiac delivery to mice with ischemic hindlimbs. The injected EPCs and their migration effect were observed via MRI and optical imaging in vivo, and then compared to a reference standard based on histological data. The quantification of gadolinium in tissue samples was done using inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Using in vivo MRI and optical imaging, the labeled EPCs were observed to migrate to ischemic muscle on days 3-5 after injection, while ex vivo, the EPCs were observed in the capillary vessels of the injured tissue. There were significant linear correlations between the Gd contents measured using ICP-MS in samples from the ischemic hindlimbs and livers and T1 relaxation times calculated using MRI, as well as the average fluorescence signal intensities recorded in optical images (T1 relaxation time: r=0.491; average signal from optical imaging: r=0.704, P<0.01). EPC treatment upregulated the levels of C-X-C chemokine receptor 4 and vascular endothelial growth factor (VEGF) receptor 2 and enhanced the expression of stromal cell-derived factor-1 and VEGF. CONCLUSION: Transplanted EPCs can be monitored with noninvasive MRI and optical imaging in vivo and were found to enhance the paracrine secretion of angiogenic factors.

Theranostic micelles based on upconversion nanoparticles for dual-modality imaging and photodynamic therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is frequently metastatic once diagnosed and less likely to respond to curative surgery, emphasizing the need for the development of more sensitive and effective diagnostic and therapeutic strategies. Epithelial cell adhesion molecule (EpCAM) is deemed as the biomarker of cancer stem cells (CSCs), which are mainly responsible for the recurrence, metastasis and prognosis of HCC. In this study, we discuss the use of mitoxantrone (MX), an antitumor drug and a photosensitizer, for designing upconversion nanoparticle-based micelles grafted with the anti-EpCAM antibody, for dual-modality magnetic resonance/upconversion luminescence (MR/UCL)-guided synergetic chemotherapy and photodynamic therapy (PDT). The obtained micelles exhibit good biocompatibility, high specificity to HCC cells and superior fluorescent/magnetic properties in vitro. In vivo results demonstrate that the targeted micelles exhibited much better MR/UCL imaging qualities compared to the nontargeted micelles after the intravenous injection. More importantly, PEGylated UCNP micelles loaded with MX and grafted with anti-EpCAM antibody, denoted as anti-EpCAM-UPGs-MX, showcased the most effective synergetic antitumor efficacy compared with other treatment groups both in vitro and vivo. The remarkable antitumor effect, coupled with superior simultaneous dual-modality MR/UCL imaging as well as good biocompatibility and negligible toxicity, makes the UPG micelles promising for future translational research in HCC diagnosis and therapy.

Facile assembly of upconversion nanoparticle-based micelles for active targeted dual-mode imaging in pancreatic cancer.

BACKGROUND: Pancreatic cancer remains the leading cause of cancer-related deaths, the existence of cancer stem cells and lack of highly efficient early detection may account for the poor survival rate. Gadolinium ion-doped upconversion nanoparticles (UCNPs) provide opportunities for combining fluorescent with magnetic resonance imaging, and they can improve the diagnostic efficacy of early pancreatic cancer. In addition, as one transmembrane glycoprotein overexpressed on the pancreatic cancer stem cells, CD326 may act as a promising target. In this study, we developed a facile strategy for developing anti-human CD326-grafted UCNPs-based micelles and performed the corresponding characterizations. After conducting in vitro and vivo toxicology experiments, we also examined the active targeting capability of the micelles upon dual-mode imaging in vivo. RESULTS: We found that the micelles owned superior imaging properties and long-time stability based on multiple characterizations. By performing in vitro and vivo toxicology assay, the micelles had good biocompatibility. We observed more cellular uptake of the micelles with the help of anti-human CD326 grafted onto the micelles. Furthermore, we successfully concluded that CD326-conjugated micelles endowed promising active targeting ability by conducting dual-mode imaging in human pancreatic cancer xenograft mouse model. CONCLUSIONS: With good biocompatibility and excellent imaging properties of the micelles, our results uncover efficient active homing of those micelles after intravenous injection, and undoubtedly demonstrate the as-obtained micelles holds great potential for early pancreatic cancer diagnosis in the future and would pave the way for the following biomedical applications.

Targeting Early Apoptosis in Acute Ischemic Stroke with a Small-Molecule Probe.

Inhibiting apoptotic cells helps ameliorate ischemic injury. Actually, only the apoptotic cells in early stage could be rescued. Molecular imaging of the early apoptosis would make sense in ischemic stroke; however, few of apoptosis molecular probes could specifically target early apoptosis. This study developed a small-molecule early apoptosis targeting probe CYS-F, which was synthesized by cystine with fluorescein isothiocyanate dyes. And the final molecular weight of CYS-F was only 1013 Da, which was much smaller than the traditional apoptosis marker annexin V. CYS-F showed excellent early apoptosis targeting ability both in vitro and in vivo. And CYS-F was cleared rapidly from the circulation with a blood half-life of 1.325 h. A favorable match was obtained between the images in fluorescence imaging and magnetic resonance imaging in stroke models. The target-to-background ratio of the lesions on 0 h was negative, which reflected the decreased blood flow. Multimodal molecular imaging showed the therapeutic effect of cystamine was dose dependence and CYS-F could also predict the outcome of ischemic stroke at an early stage. The versatility of CYS-F provides a comprehensive and convenient route for clinical decision-making in acute ischemic stroke.