Silver–titanium dioxide nanocomposites as effective antimicrobial and antibiofilm agents

Recent studies have revealed the existence of liver cancer stem cells (CSCs). Therefore, there is an urgent need for new and effective treatment strategies specific to liver CSCs. In this work, the poly(d,l-lactide-coglycolide) nanoparticles containing paclitaxel were prepared by emulsification-solvent evaporation method. The nanoparticles decorated with anti-CD133 antibody, termed targeted nanoparticles, were prepared by carbodiimide chemistry for liver CSCs. The physicochemical characteristics of the nanoparticles (i.e., encapsulation efficiency, particle size distribution, morphology, and in vitro release) were investigated. Cellular uptake and accumulation in tumor tissue of nanoparticles were observed. To assess anti-tumor activity of nanoparticles in vitro and in vivo, cell survival assay and tumor regression study were carried out using liver cancer cell lines (Huh7 and HepG2) and their xenografts. Particle size of targeted nanoparticles was 429.26 ± 41.53 nm with zeta potential of ?11.2 mV. Targeted nanoparticles possessed spherical morphology and high encapsulation efficiency (87.53 ± 5.9 %). The accumulation of targeted nanoparticles depends on dual effects of passive and active targeting. Drug-loaded nanoparticles showed cytotoxicity on the tumor cells in vitro and in vivo. Targeted nanoparticles resulted in significant improvement in therapeutic response through selectively eliminating CD133 positive subpopulation. These results suggested that the novel nanoparticles could be a promising candidate with excellent therapeutic efficacy for targeting liver CSCs.     

Bioconjugated Fluorescent Polymeric Nanoparticles for Imaging and Targeted Therapy of HER2-Overexpressing Cancer Cells

We report the development of Herceptin-conjugated fluorescent polymeric nanoparticles (PNp) probes. Synthesis of fluorescent conjugated polymer as the core, preparation of the core/shell PNp, the ability of immobilizing Herceptin on PNp, targeting and imaging of bioconjugated PNp toward HER2-overexpressing cancer cells, and therapeutic effect on cell cycle, together with the expression of apoptosis related proteins, were investigated. We have achieved active tumor targeting by rapid PNp-antibody binding to tumor-specific antigens. Besides, Herceptin-conjugated PNp can suppress the growth of HER2-overexpressing cancer cells.     

Colloid electrostatic self-assembly synthesis of SnO2/graphene nanocomposite for supercapacitors

Journal of Nanoparticle Research - Most anticancer drugs cannot kill cancer stem cells (CSCs) effectively, which lead to the failure of anticancer chemotherapy, such as relapse and metastasis. In...     

物理学在肿瘤细胞的极性及迁移研究中的应用

肿瘤细胞和所处微环境的物理性质, 以及它们之间的相互物理作用对于肿瘤的产生、发展与转移都有极大的影响, 这使得从物理学角度探索肿瘤研究成为了必然趋势. 肿瘤转移是癌症致死的最大因素, 而肿瘤细胞迁移中的极化是肿瘤转移的重要一步. 本文总结了物理学实验和模型在揭示细胞迁移和极化机理方面的贡献. 实验上应用最新的微流控芯片技术与表面微模型化技术等手段, 研究空间维度、黏附行为、机械力等物理信号对于细胞极性的建立与保持以及细胞迁移行为的影响后, 发现物理信号与生化反应之间的相互耦合对于细胞迁移有着至关重要的作用; 理论上基于扩散反应方程, 已经建立了一系列表征细胞极化的模型. 今后的研究将结合物理实验建立肿瘤细胞迁移中的极化模型, 进而发展针对肿瘤细胞感知物理信号的新的治疗肿瘤转移方法.     

Triple-combination therapy assisted with ultrasound-active gold nanoparticles and ultrasound therapy against 3D cisplatin-resistant ovarian cancer model

Cancer chemotherapy suffers from drug resistance and side effects of the drugs. Combination therapies have been attracted attention to overcome these limitations of traditional cancer treatments. Recently, increasing in intracellular chemotherapeutic concentration in the presence of ultrasonic waves (US) has been shown in the preclinical stage. In addition, some recent studies have shown that nanoparticles increase the effectiveness of ultrasound therapy. In this study, the US-active property of gold nanocones (AuNCs) was utilized for combinational US and cisplatin (Cis) to overcome drug resistance. The effect of the triple combination therapy US + AuNCs + Cis with low-dose Cis on 2/3D models of cisplatin-resistant ovarian cancer cell line (A2780cis) were investigated. In the 2D cell culture, 60% of the A2780cis cell population was suppressed with triple combination therapy; and the long-term therapeutic efficacy of the US + AuNCs + Cis with the low-dose drug was demonstrated by suppressing 83% of colony formation. According to the results in the 3D cell model, 60% of the spheroid formation was suppressed by the triple combination therapy with low-dose Cis. These results not only demonstrate the success of the US + AuNCs + Cis triple combination therapy for its long-term therapeutic effect on resistant cancer cells but also verified that it might enable effective cancer therapy in vivo and clinical stages based on the 3D tumor models. In addition, enhanced anti-cancer activity was demonstrated at the low-dose Cis on drug-resistant cancer cells indicating the triple-combination therapy successfully overcame drug resistance and this is a promising strategy to reduce the side effects of chemotherapy. This work exhibits a novel US and AuNCs-mediated combination cancer therapy, which demonstrates the role of ultrasound-active AuNCs to combat drug resistance with low-dose chemotherapy.     

Amphiphilic Core–Shell Nanocomposite Particles for Enhanced Magnetic Resonance Imaging

A scalable synthesis of magnetic core–shell nanocomposite particles, acting as a novel class of magnetic resonance (MR) contrast agents, has been developed. Each nanocomposite particle consists of a biocompatible chitosan shell and a poly(methyl methacrylate) (PMMA) core where multiple aggregated γ‐Fe₂O₃ nanoparticles are confined within the hydrophobic core. Properties of the nanocomposite particles including their chemical structure, particle size, size distribution, and morphology, as well as crystallinity of the magnetic nanoparticles and magnetic properties were systematically characterized. Their potential application as an MR contrast agent has been evaluated. Results show that the nanocomposite particles have good stability in biological media and very low cytotoxicity in both L929 mouse fibroblasts (normal cells) and HeLa cells (cervical cancer cells). They also exhibited excellent MR imaging performance with a T₂ relaxivity of up to 364 mM_Fe^?1 s^?1. An in vivo MR test performed on a naked mouse bearing breast tumor indicates that the nanocomposite particles can localize in both normal liver and tumor tissues. These results suggest that the magnetic core–shell nanocomposite particles are an efficient, inexpensive and safe T₂‐weighted MR contrast agent for both liver and tumor MR imaging in cancer therapy.     

Therapeutic siRNA targeting the cancer cell stemness regulator PRDI-BF1 and RIZ domain zinc finger protein 14

PRDI-BF1 and RIZ (PR) domain zinc finger protein 14 (PRDM14), first reported in 2007 to be overexpressed in breast cancer, plays an important role in breast cancer proliferation. Subsequent studies reported that PRDM14 is expressed in embryonic stem cells, primordial germ cells, and various cancers. PRDM14 was reported to confer stemness properties to cancer cells. These properties induce cancer initiation, cancer progression, therapeutic resistance, distant metastasis, and recurrence in refractory tumors. Therefore, PRDM14 may be an ideal therapeutic target for various types of tumors. Silencing PRDM14 expression using PRDM14-specific siRNA delivered through an innovative intravenous drug delivery system reduced the size of inoculated tumors, incidence of distant metastases, and increased overall survival in nude mice without causing adverse effects. Therapeutic siRNA targeting PRDM14 is now being evaluated in a human phase I clinical trial for patients with refractory breast cancer, including triple-negative breast cancer.     

Synergistic Effect of Thermo‐Radiotherapy Using Au@FeS Core–Shell Nanoparticles as Multifunctional Therapeutic Nanoagents

Imaging guided combined therapy has attracted great attention in recent years. This study develops core–shell Au@FeS nanoparticles with polyethylene glycol (PEG) coating as multifunctional nanotheranostic agent for tumor imaging and combined photothermal therapy (PTT) and radiotherapy (RT). In this Au@FeS nanostructure, the gold core can act as a radiosensitizer for enhanced RT, while FeS shell offers contrast for T2‐weighted magnetic resonance imaging and endows the nanoparticles with strong high near‐infrared (NIR) for photoacoustic imaging and PTT. As demonstrated by both in vitro and in vivo experiments, Au@FeS‐PEG can act as excellent therapeutic agent for cancer synergistic treatment. More importantly, mild PTT boosts the blood flow into tumor and increases oxygenation to overcome the tumor hypoxia microenvironment, further enhancing the efficacy of RT. Moreover, Au@FeS‐PEG induces on obvious toxicity at a high dose (20 mg kg^?1) to the treated mice as evidenced by blood biochemistry. Therefore, this study brings an excellent strategy for cancer enhanced RT through NIR‐triggered mild PTT to overcome hypoxia‐associated radioresistance.     

Toward understanding of the role of reversibility of phenotypic switching in the evolution of resistance to therapy

Reversibility of state transitions is intensively studied topic in many scientific disciplines over many years. In cell biology, it plays an important role in epigenetic variation of phenotypes, known as phenotypic plasticity. More interestingly, the cell state reversibility is probably crucial in the adaptation of population phenotypic heterogeneity to environmental fluctuations by evolving bet-hedging strategy, which might confer to cancer cells resistance to therapy. In this article, we propose a formalization of the evolution of highly reversible states in the environments of periodic variability. Two interrelated models of heterogeneous cell populations are proposed and their behavior is studied. The first model captures selection dynamics of the cell clones for the respective levels of phenotypic reversibility. The second model focuses on the interplay between reversibility and drug resistance in the particular case of cancer. Overall, our results show that the threshold dependencies are emergent features of the investigated model with eventual therapeutic relevance. Presented examples demonstrate importance of taking into account cell to cell heterogeneity within a system of clones with different reversibility quantified by appropriately chosen genetic and epigenetic entropy measures.     

Cytotoxic effects and in vitro reversal of multidrug resistance by therapeutic ultrasound in human hepatocarcinoma cell line (HepG2)

Multidrug resistance (MDR) is one of the major obstacles to successful chemotherapy of human malignancies. Although many strategies have been explored to overcome MDR, none of them have been proven to be clinically useful until now. The aim of this study was to investigate whether a novel therapeutic ultrasound (US) approach would have useful effects on the reversal of MDR in cancer cells. Wild-type and MDR phenotype (HepG2/ADM) cells of the human hepatocarcinoma cell line HepG2 were exposed to 0.8 MHz US at an intensity of 0.43 W/cm² for a 9 s exposure (total energy density: 3.87 J/cm²). After US exposure, cell number and viability were counted immediately, and flow cytometry was performed to measure retention of rhodamine 123 and adriamycin in HepG2 and HepG2/MDR cells. Both cell lines were then incubated in suspension with adriamycin, vincristine, etoposide, cisplatin and 5-fluorouracil, respectively, and the MTT assay was used to determine cytotoxicity. The results showed that US exposure could significantly increase the uptake of Rh123 and ADM by HepG2/ADM tumor cells. The resistant index for the chemotherapeutic drugs was significantly lower in the US-exposed HepG2/ADM cells than in those not exposed to US. It was therefore concluded that US exposure could enhance the sensitivity of HepG2/ADM tumor cells to these chemotherapeutic agents, and the functional and structural changes induced by previous US exposure in MDR tumor cells may be responsible for it. However, further study is needed to investigate the mechanism behind US-mediated reversal of MDR.     

Effect of the Semiconductor Quantum Dot Shell Structure on Fluorescence Quenching by Acridine Ligand

The main line of research in cancer treatment is the development of methods for early diagnosis and targeted drug delivery to cancer cells. Fluorescent semiconductor core/shell nanocrystals of quantum dots (e.g., CdSe/ZnS) conjugated with an anticancer drug, e.g., an acridine derivative, allow real-time tracking and control of the process of the drug delivery to tumors. However, linking of acridine derivatives to a quantum dot can be accompanied by quantum dot fluorescence quenching caused by electron transfer from the quantum dot to the organic molecule. In this work, it has been shown that the structure of the shell of the quantum dot plays the decisive role in the process of photoinduced charge transfer from the quantum dot to the acridine ligand, which is responsible for fluorescence quenching. It has been shown that multicomponent ZnS/CdS/ZnS shells of CdSe cores of quantum dots, which have a relatively small thickness, make it possible to significantly suppress a decrease in the quantum yield of fluorescence of quantum dots as compared to both the classical ZnS thin shell and superthick shells of the same composition. Thus, core/multicomponent shell CdSe/ZnS/CdS/ZnS quantum dots can be used as optimal fluorescent probes for the development of systems for diagnosis and treatment of cancer with the use of anticancer compounds based on acridine derivatives.     

Platelet aggregation in the formation of tumor metastasis

Metastasis is the major cause of death from cancer, yet the optimal strategy against it remains uncertain. The pathogenesis of hematogenous metastasis is dynamic and consists of the following steps: 1) detachment of tumor cells from the primary site, 2) invasion into the host's blood vessels, 3) migration in the host's blood stream, 4) transport along the circulation, 5) arrest in or adhesion to the capillary in a distant organ, 6) extravasation, and 7) proliferation within the foreign tissues. A key to successful hematogenous metastasis is tumor survival in the bloodstream because most circulating tumor cells are rapidly destroyed by the shear forces or are attacked by the immune system. Less than 0.01% of these cells result in metastasis. Tumor cell-induced platelet aggregation has been reported to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microcirculation. Platelet aggregation is also believed to protect tumor cells from immunological assault in the circulation. We have identified Aggrus as a platelet-aggregating factor expressed on a number of human cancers. Because hematogenous metastasis is reduced when neutralizing antibodies or eliminating carbohydrates attenuates Aggrus function, Aggrus's main contribution to hematogenous metastasis of Aggrus-expressing cells, then, is by promoting platelet aggregation. Aggrus could serve as an ideal target for drug development to block metastasis.     

A cellular automata model for avascular solid tumor growth under the effect of therapy

Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.     

Detection of circulating tumor cells via an X‐ray imaging technique

Detailed information on the location and the size of tumor cells circulating through lymphatic and blood vessels is useful to cancer diagnosis. Metastasis of cancers to other non‐adjacent organs is reported to cause 90% of deaths not from the primary tumors. Therefore, effective detection of circulating tumors cells (CTCs) related to metastasis is emphasized in cancer treatments. With the use of synchrotron X‐ray micro‐imaging techniques, high‐resolution images of individual flowing tumor cells were obtained. Positively charged gold nanoparticles (AuNPs) which were inappropriate for incorporation into human red blood cells were selectively incorporated into tumor cells to enhance the image contrast. This approach enables images of individual cancer cells and temporal movements of CTCs to be captured by the high X‐ray absorption efficiency of selectively incorporated AuNPs. This new technology for in vivo imaging of CTCs would contribute to improve cancer diagnosis and cancer therapy prognosis.     

Detection of Binding of a Synthetic Granzyme B-like Peptide Fluorescent Conjugate within Platelet-like Structures in Cancer-related Peripheral Blood Specimens and Tissue Sections

Platelets and cytotoxic T lymphocytes (CTL) are important whole blood components in peripheral blood. Studies have shown that platelets, from precursor megakaryocytes, are significant factors in cancer prognosis, cancer progression, and metastasis; but a direct platelet-cancer relationship remains unclear. CTL play an essential role in cancer surveillance by inducing cancer cell death with granzyme B. A recent report has shown the presence of binding targets with binding affinity to a synthetic granzyme B-like peptide fluorescent conjugate (GP1R) in different types of cancer cells grown in vitro. It suggests that these binding targets may serve as a “universal-pathologic-biomarker”. It is not known if similar biomarkers may be present in platelets of cancer patients. We show with fluoroscopic images that GP1R can bind to binding targets: 1) within platelets in methanol-fixed whole blood smears of patients with breast cancer and lung cancer, and 2) within platelet-like structures in formalin-fixed-paraffin-embedded (FFPE) nude mouse xenogeneic breast tumor tissues. Samples without cancer-association displayed no discernible GP1R-binding in platelet-like structures. Our data demonstrate for the first time that a similar “universal-pathologic-biomarker” detectable by GP1R-binding is present in circulating platelets of cancer patients. The data depict a co-existence of animal-platelets and human-breast cancer cells, both have a common pathologic biomarker detectable by GP1R, in the tumor growth. The fluoroscopic images indicate a visual direct connection between pathologic platelets and cancer. These preliminary results may lead to developments of novel platelet-based cancer diagnostics and therapeutics and a better understanding of the potential multifunction of GP1R and its relationship to megakaryocytes and PD1.     

Pulsed-wave low-dose ultrasound hyperthermia selectively enhances nanodrug delivery and improves antitumor efficacy for brain metastasis of breast cancer

The clinical application of chemotherapeutics for brain tumors remains a challenge due to limitation of blood-brain barrier/blood-tumor barrier (BBB/BTB). In this study, we investigated the effects of low-dose focused ultrasound hyperthermia (UH) on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer cells (4T1-luc2) expressing firefly luciferase were implanted into mouse striatum as a brain tumor model. The mice were intravenously injected with PLD with/without transcranial pulsed-wave/continuous-wave UH (pUH/cUH) treatment on day-6 after tumor implantation. pUH (frequency: 500 kHz, PRF: 1000 Hz, duty cycle: 50%) was conducted under equal acoustic power (2.2-Watt) and sonication duration (10-min) as cUH. The amounts of doxorubicin accumulated in the normal brain and tumor tissues were measured with fluorometry. The tumor growth responses for the control, pUH, PLD, PLD + cUH, and PLD + pUH groups were evaluated with IVIS. The PLD distribution and cell apoptosis were assessed with immunofluorescence staining. The results showed that pUH significantly enhanced the PLD delivery into brain tumors and the tumor growth was further inhibited by PLD + pUH without damaging the sonicated normal brain tissues. This indicates that low-dose transcranial pUH is a promising method to selectively enhance nanodrug delivery and improve the brain tumor treatment.     

Folate Conjugated Chitosan Grafted Thiazole Orange Derivative with High Targeting for Early Breast Cancer Cells Diagnosis

The folate receptor (FR) is over-expressed on many solid tumors and has been exploited for targeted delivery of folic acid linked liposomes to cancer cells in vitro. In the present study, we developed a novel folic acid (FA) conjugated chitosan (CTS) grafted thiazole orange (TO) complex (FA-CTS-TO), and the formation can be used to label tumor cells. The structure of TO derivatives was confirmed by ¹H NMR and MS, and the fluorescence probe of FA-CTS-TO complex was confirmed by Fourier transform infrared analysis and Differential thermal analysis. The in vitro and in vivo of FA-CTS-TO complex were tested in breast cancer cells and the results showed a high targeting specificity in tumor cells with FR over-expressed. Such prominent fluorescence properties demonstrate again that FA-CTS-TO complex as a tumor targeting fluorescence probe is appropriate for breast cancer cells.     

Photo-activated pheophorbide a inhibits the growth of prostate cancer cells

Pheophorbide a (PhA) was identified as a photosensitizer to exert cytotoxicity on tumor cells. However, the efficacy of this compound on the treatment of prostate cancer remains unknown. The aim of this study was to evaluate the photodynamic effect of PhA on prostate cancer cells. Cellular uptake of PhA and cell viability after photo-activation was studied in LNCaP prostate cancer cells. The corresponding production of reactive oxygen species within cells was determined after photodynamic therapy (PDT). Our results showed that the uptake of PhA into LNCaP cells was in a time-dependent manner and the cytotoxicity of PhA-PDT was photosensitizer dose- and light dose-dependent. The intracellular reactive oxygen species was remarkably induced after PDT treatment, which was responsible for the inhibition effect on prostate cancer cells. This is the first report to evaluate the photodynamic effect of PhA on prostate cancer. Our findings demonstrate that PhA-PDT may be a potentially promising treatment for localized prostate cancer, which can be a therapeutic option after the failures of radiotherapy and hormone therapy.     

A Functionalized Hollow Mesoporous Silica Nanoparticles‐Based Controlled Dual‐Drug Delivery System for Improved Tumor Cell Cytotoxicity

Multifunctional nanoparticles for selectively targeting tumor cells and effectively delivering multiple drugs are urgently needed in cancer therapy. Here, a dual‐drug delivery system is prepared, based on functionalized hollow mesoporous silica nanoparticles (HMSNs). Doxorubicin (DOX) hydrochloride is loaded into the hollow core, and dichloro(1,2‐diaminocyclohexane)platinum (II) (DACHPt) is stored in the pores of the shell by the coordination interaction with the carboxyl groups modified on the pore walls, which also serves as barriers to control the DOX release. Detailed studies in vitro indicate that the DACHPt release is triggered by Cl^? through the cleavage of the coordination interaction, and the DOX release depends on the release rate of DACHPt and the environmental pH value. The surface of the mechanized nanoparticles is also modified by transferrin (Tf) to achieve the tumor specificity. Compared with individual drug delivery systems, the dual‐drug delivery system shows synergistic efficacy on the cell cytotoxicity (combination index = 0.30), resulting in improved tumor cell killing. The present dual‐drug delivery system provides a promising strategy to develop controlled and targeted combination therapies for efficient cancer treatment.     

Quiescent cells: A natural way to resist chemotherapy

Most chemotherapeutic treatments use drugs that target proliferating cancer cells. Therefore, they do not affect quiescent cells which are naturally resistant. Surviving cancer cells can reactivate their cell cycles in the intervals between doses, becoming proliferative again and thus restarting tumor growth. In this work, we present a mathematical model to study the impact of quiescent cells on chemotherapy effectiveness. Our simulations show that, although tumor growth is delayed after the beginning of each dose, the resistance of quiescent cells is enough to reactivate it due to accelerated repopulation, eventually causing therapy failure even in the absence of acquired resistance.