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The keys to the prevention of tumor recurrence after operation are the elimination of residual tumor cells and the reversal of microenvironments that induce recurrence. In the formulation of a treatment scheme, building an appropriate drug delivery system is essential. An in-situ drug delivery system (ISDDS) is regarded as an effective treatment route for postoperative use that increases drug delivery efficiency and mitigates side-effects. ISDDS technology has been considerably improved through a clearer understanding of the mechanisms of postoperative recurrence and the development of drug delivery materials. This paper describes the initiation and characteristics of postoperative recurrence mechanisms. Based on this information, design principles for ISDDS are proposed, and a variety of practical drug delivery systems that fulfil specific therapeutic needs are presented. Challenges and future opportunities related to the application of in-situ drug carriers for inhibiting cancer recurrence are also discussed. Unlabelled Image • In-situ drug delivery system (ISDDS) is effective for postoperative drug delivery. • The mechanisms of microenvironment promoting tumor recurrence are summarized. • ISDDSs based on the mechanism of postoperative tumor recurrence • Perspectives of ISDDS for preventing postoperative tumor recurrence [ABSTRACT FROM AUTHOR]

Conclusion: Fas ligand (FasL) gene therapy may provide a new efficient therapeutic model for head and neck squamous cell cancer (HNSCC). Acid ceramidase (AC) may not play an important role in the sensitivity of HNSCC cell lines to Fas-induced apoptosis. Objectives: The aims of this study were to investigate the efficacy of FasL gene therapy for HNSCC in vitro and to determine whether the expression of AC in different kinds of HNSCC cell lines is related to the sensitivity of HNSCC cell lines to Fas-mediated apoptotic induction. Methods: Three HNSCC cell lines (Hep-2, MMSI, and SCCVII) were transfected with pEGFP-FasL, a plasmid containing a modified human FasL gene fused to enhanced green fluorescent protein (GFP). pEGFP-C1, a plasmid containing the GFP gene alone, was used as a control. Cell death was observed by fluorescence imaging and quantified using a tetrazolium-based (MTS) assay. SCCVII cells were analyzed by flow cytometry to determine the presence of apoptotic induction. Hep-2 and MMSI cells were evaluated by quantitative real-time PCR to evaluate the expression of AC. Results: Transfection of pEGFP-FasL plasmid was shown to be able to induce cell death, the sensitivity of Fas-mediated apoptosis in HNSCC was different, and the level of AC did not correlate with the sensitivity of HNSCC cells to Fas-induced apoptosis. [ABSTRACT FROM AUTHOR]

BODIPY-based amphiphilic dye with enhanced donor–acceptor-donor structure (BDP-AP) was synthesized, which could self-assemble into stable nanoparticles (BDP-AP NPs) for synergistic NIR-triggered PDT/PTT therapy. [Display omitted] • BODIPY-based amphiphilic dye with enhanced D-A-D structure was synthesized. • BDP-AP could self-assemble into stable nanoparticles BDP-AP NPs. • BDP-AP NPs synchronously generated 1O 2 and performed photothermal conversion. • BDP-AP NPs was used for the synergistic NIR-triggered PDT/PTT therapy. Near‐infrared (NIR) responsive nanoparticles are an important platform for multimodal phototherapy. Importantly, the simultaneous NIR-triggered photodynamic (PDT) and photothermal (PTT) therapy is a powerful approach to increase the antitumor efficiency of phototherapic nanoparticles due to the synergistic effect. Herein, a boron dipyrromethene (BODIPY)-based amphiphilic dye with enhanced electron donor–acceptor-donor (D-A-D) structure (BDP-AP) was designed and synthesized, which could self-assemble into stable nanoparticles (BDP-AP NPs) for the synergistic NIR-triggered PDT/PTT therapy. BDP-AP NPs synchronously generated singlet oxygen (1O 2) and achieved preeminent photothermal conversion efficiency (61.42%). The in vitro and in vivo experiments showed that BDP-AP NPs possessed negligible dark cytotoxicity and infusive anticancer performance. BDP-AP NPs provide valuable guidance for the construction of PDT/PTT-synergistic NIR nanoagents to improve the efficiency of photoinduced cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent form of cell death accompanied by iron and lipid peroxidase accumulation and has drawn substantial attentions since its first discovery in 2012. Various studies have shown that tumor cells with high tumorigenicity, invasiveness, and metastatic potential are sensitive to ferroptosis. Consequently, many strategies to induce ferroptosis have been used in the design of antitumor nanodrug delivery systems (NDDSs). Prior reviews have thoroughly summarized the mechanism underlying ferroptosis, related pathways, and NDDSs materials. Recent studies have demonstrated that ferroptosis is interacted with several metabolic pathways, and these pathways have provided a basis for designing strategies for NDDSs-induced ferroptosis. Therefore, this review summarizes NDDSs designs for ferroptosis driven by different metabolic pathways, emphasizes the feasibility of inducing ferroptosis in cancer treatment, and finally discusses limitations of NDDSs and future developments in the field. [Display omitted] • Ferroptosis is involved in multiple metabolic pathway, such as iron, amino acids, lipid and mitochondria metabolism. • Working of different strategies to induce ferroptosis are discussed. • The application of nanodrug delivery systems (NDDSs) in ferroptosis-basic cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. Patients and methods: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. Results: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70–0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63–0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. Conclusion: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Chelating Cu from tumors has been verified as an effective and promising strategy for cancer therapy through antiangiogenesis. However, systematic removal Cu by injecting with Cu chelators will result unavoidable side effects, since Cu is indispensable to the body. In this work, a micelle targeting to tumors' newborn vessels based on a polypeptide was developed to co-load DOX and Probe X, which can go through an "OFF-to-ON" procedure to report the Cu+-capture events in vivo in a real-time way by giving near infrared (NIR) fluorescence and photoacoustic signal. By co-delivering antiangiogenesis and chemotherapeutic reagents, the tumor can be significantly suppressed, meanwhile with a low systematic toxicity. Hopefully, this work can offer new insights in designing sophisticated antitumor strategy. Unlabelled Image • A theranostic specific Cu+ chelator was proposed. • Targeting micelle co-loaded with Cu+-chelator and chemotherapeutic reagents was fabricated. • Antiangiogenesis and tumor's oxygen saturation reduction were reduced. • Fine antitumor efficacy was achieved with low side effect. [ABSTRACT FROM AUTHOR]

Abstract Targeted delivery and accumulation of chemotherapeutics to tumor sites is in high demand and extremely challenging for anticancer therapy. Studies show that albumin is actively recruited into tumor tissue overexpressing albumin-binding proteins including secreted protein acidic and rich in cysteine (SPARC) and gp60. Herein, a novel redox-responsive paclitaxel-loaded micelle system with the modification of ABD035, which specifically and strongly binds to albumin, is designed to combine the strengths of albumin and micelles together for antitumor drug biomimetic delivery. The ABD035-modified micelle has a strong binding response to albumin and co-localization of BODIPY-labeled ABD035-modified micelle and SPARC is observed in tumor tissues. Furthermore, the ABD035-modified micelle significantly improves the therapeutic effect in the animal model bearing triple negative breast cancer by increasing drug accumulation in tumor tissue, enhancing cell uptake efficiency, rapidly releasing prototype drug under intracellular reductive conditions and increasing tumor cell apoptosis. These results together vote the biomimetic delivery of ABD035-modified micelle as a promising strategy for cancer therapy. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Background: In this study scales and items for the Oral Cancer Quality-of-life Questionnaire (QOL-OC) were designed and the instrument was evaluated.Methods: The QOL-OC was developed and modified using the international definition of quality of life (QOL) promulgated by the European Organization for Research and Treatment of Cancer (EORTC) and analysis of the precedent measuring instruments. The contents of each item were determined in the context of the specific characteristics of oral cancer. Two hundred thirteen oral cancer patients were asked to complete both the EORTC core quality of life questionnaire (EORTC QLC-C30) and the QOL-OC. Data collected was used to conduct factor analysis, test-retest reliability, internal consistency, and construct validity.Results: Questionnaire compliance was relatively high. Fourteen of the 213 subjects accepted the same tests after 24 to 48 h demonstrating a high test-retest reliability for all five scales. Overall internal consistency surpasses 0.8. The outcome of the factor analysis coincides substantially with our theoretical conception. Each item shows a higher correlation coefficient within its own scale than the others which indicates high construct validity.Conclusions: QOL-OC demonstrates fairly good statistical reliability, validity, and feasibility. However, further tests and modification are needed to ensure its applicability to the quality-of-life assessment of Chinese oral cancer patients. [ABSTRACT FROM AUTHOR]

Chemoresistance remains a formidable hurdle against cancer therapy. Seeking for novel therapy strategies is an urgent need for those who no longer benefit from chemotherapy. Chemoresistance is usually associated with the dysfunction of intrinsic apoptosis. Targeting extrinsic apoptosis via TRAIL signaling and the death receptors could be a potential solution to treat chemoresistant cancer. A highly biocompatible nano system for codelivery of the TRAIL DNA and the death receptor sensitizer monensin was developed, in which low-molecular-weight PEI (LMW-PEI) was crosslinked by the sulfhydryl cyclodextrin via disulfide bonds, and then bound with DNA, thus forming the bioreducible polyplex cores. In addition, the cyclodextrin also functioned as a carrier for the hydrophobic monensin via host-guest inclusion. Poly-γ-glutamic acid (γ-PGA) was used to modify the polyplex core via charge interaction. The γ-PGA corona can specifically bind with the tumor-associated gamma-glutamyl transpeptidase (GGT) overexpressed on the tumor cells, and achieve tumor-targeting delivery. Moreover, the tumor-homing peptide RGD-modified γ-PGA was also prepared as the surface coating materials for further improving gene delivery efficiency. This gene delivery system was characterized by the dual ligand-targeting, dual stimuli-responsive features. The ligands of RGD and γ-PGA can target the tumor-associated receptors (i.e., integrin and GGT). The conformation of γ-PGA is pH-sensitive, and the tumor acidic micro environments could trigger the detachment of surface-coating γ-PGA. The disulfide crosslinking LMW-PEI is redox-sensitive, and its fast disassembling in the tumor cells could favor the efficient gene delivery. The anti-tumor efficacy was demonstrated both in vitro and in vivo. Moreover, MYC-mediated synthetic lethality could be an important mechanism for overcoming the drug resistance. An important finding of our studies is the demonstration of the in vivo treatment efficacy of TRAIL/monensin, thus providing a potential novel therapeutic strategy for overcoming drug-resistant cancer. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP)‑based chemotherapy is the most widely used therapy for non‑small cell lung cancer (NSCLC). However, the existence of chemoresistance has become a major limitation in its efficacy. Long non‑coding RNAs (lncRNAs) have been shown to be involved in chemotherapy drug resistance. The aim of the present study was to investigate the biological role of lncRNA AK001796 in cisplatin‑resistant NSCLC A549/DDP cells. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis was performed to monitor the differences in the expression of AK001796 in cisplatin‑resistant (A549/DDP) cells and parental A549 cells. Cellular sensitivity to cisplatin and cell viability were examined using an MTT assay. Cell apoptosis and cell cycle distribution were measured using flow cytometry. The expression levels of cell cycle proteins cyclin C (CCNC), baculoviral IAP repeat containing 5 (BIRC5), cyclin‑dependent kinase 1 (CDK1) and G2 and S phase‑expressed 1 (GTSE1) were assessed using RT‑qPCR and western blot analyses. It was found that the expression of AK001796 was increased in A549/DDP cells, compared with that in A549 cells. The knockdown of AK001796 by small interfering RNA reduced cellular cisplatin resistance and cell viability, and resulted in cell‑cycle arrest, with a marked increase in the proportion of A549/DDP cells in the G0/G1 phase. By contrast, the knockdown of AK001796 increased the number of apoptotic cancer cells during cisplatin treatment. It was also shown that the knockdown of AK001796 positively induced the expression of cell apoptosis‑associated factors, CCNC and BIRC5, and suppressed the expression of cell cycle‑associated factors, CDK1 and GTSE5. Taken together, these findings indicated that lncRNA AK001796 increased the resistance of NSCLC cells to cisplatin through regulating cell apoptosis and cell proliferation, and thus provides an attractive therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-l-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood–brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system. [Copyright &y& Elsevier]

Abstract: Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood–brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors. [Copyright &y& Elsevier]

Abstract: A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dtACPP) that's dual-triggered by the lowered pHe and MMP2. In dtACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dtACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dtACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dtACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery. [Copyright &y& Elsevier]

Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17–92 cluster, was upregulated in the NPC samples and ell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3′ untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC. [ABSTRACT FROM PUBLISHER]

Abstract: Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in glioma, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG), yielding PAMAM–PEG–CTX. The cellular uptake of CTX itself was observed apparently in C6 glioma cells, almost not in 293 cells. The modification of CTX could significantly increase the cellular uptake of vectors and the DNA-loaded nanoparticles (NPs) in C6 cells. The in vivo distribution of PAMAM–PEG–CTX/DNA NPs in the brain was higher than that of PAMAM/DNA NPs and PAMAM–PEG/DNA NPs. Furthermore, the gene expression of PAMAM–PEG–CTX/DNA NPs was higher and broader in glioma than that of unmodified and PEG-modified counterparts. The TUNEL analysis showed a more wide-extended apoptosis in the CTX-modified group, compared to other groups including commercial temozolomide group. The median survival time of CTX-modified group and temozolomide group was 59.5 and 49 days, respectively, significantly longer than that of other groups. The results suggested that CTX could be exploited as a special glioma-targeting ligand, and PAMAM–PEG–CTX/DNA NPs is a potential non-viral delivery system for gene therapy of glioma via intravenous administration. [ABSTRACT FROM AUTHOR]

Abstract: A combination cancer therapy was investigated via co-delivery of therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL) and doxorubicin (DOX) using a tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG-T7). T7, a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. The result of fluorescence scanning showed that about 375 DOX molecules were bound to one pORF-hTRAIL molecule. The co-delivery system was constructed based on the electrostatic interactions between pORF-hTRAIL–DOX complex and cationic PAMAM-PEG-T7. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in human liver cancer Bel-7402 cells, and accumulated in tumor more efficiently in vivo. In comparison with single DOX or pORF-hTRAIL delivery system, co-delivery system induced apoptosis of tumor cells in vitro and inhibited tumor growth in vivo more efficiently. In mice bearing Bel-7402 xenografts, lower doses of co-delivery system (4 μg DOX/mouse, about 0.16 mg/kg) effectively inhibited tumor growth comparable to high doses (5 mg/kg) of free doxorubicin (77% versus 69%). These results suggested that T7-mediated co-delivery system of DOX and pORF-hTRAIL was a simply prepared, combined delivery platform which can significantly improve the anti-tumor effect. This co-delivery system might widen the therapeutic window and allow for the selective destruction of cancer cells. [ABSTRACT FROM AUTHOR]