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This work studied the effect of kissing bond defects on the fatigue strength of friction stir welded (FSW) specimens and assessed fatigue life prediction approaches for the fatigue strength evaluation of friction stir welded specimens. For specimens with inherent kissing bond defects prepared by friction stir welding process made of AA5083 aluminum alloy thin sheets, constant amplitude fatigue tests under different loading levels were carried out on MTS test frame. Profiles of kissing bond defects at weld toes as well as the fatigue fracture morphologies were observed with scanning electron microscopy. According to the experimental observations, finite element models based on both the virtual notch radius theory and the crack propagation conception were built, respectively, to calculate the stress and strain in the weld zone. Correspondingly, fatigue lives were predicted by these two methods and compared with experimental results.

The growing characteristics of metallic iron particles during reductive roasting of boron-bearing magnetite concentrate under different conditions were investigated. The size of the metallic iron particles was quantitatively measured via optical image analysis with consideration of size calibration and weighted ratio of image numbers in the core, middle and periphery zones of cross-section of pellets. In order to guarantee the measurement accuracy 54 images were captured in total for each specimen, with a weighted ratio of 1:7:19 with respect to the core, middle and periphery section of the cross-section of pellets. Increasing reduction temperature and time is favorable to the growth of metallic iron particles. Based on the modification of particle size measurement, in terms of time (t) and temperature (T) a predicting model of metallic iron particle size (D), was established as: D=125-0.112t-0.2352T-5.355×10-4t2+2.032× 10-4tT +1.134×10-4T2.

Endo/lysosomal escape and gene release are two critical bottlenecks in gene delivery. Herein, a novel photo-controllable metal-organic frameworks (MOFs) nanoswitch is rationally designed for enhancing small interfering RNA (siRNA) delivery. One single laser triggers the “off-to-on” switching of MOFs nanocomplexes, inducing significant siRNA release accompanied by rapid MOFs dissociation into protonatable 2-methylimidazalo and osmotic rupturing Zn2+ ions, which cooperatively contribute to remarkable endo/lysosomal rupture (∼ 90%). The simultaneous endo/lysosomal rupture and release enable a high spatio-temporal control on RNA interference for effective cancer therapy. Notably, the “off-to-on” switching also activates fluorescence recovery for real-time monitoring siRNA delivery. The nanoswitch could easily be extended to deliver other therapeutic agents (e.g., DNA, protein, anticancer drug) for overcoming endo/lysosomal entrapment.

Efficient intracellular delivery of bioactive compounds into cancer cells is critically important for treatment, as some compounds only validate for therapy after entering cancer cells. The boron neutron capture therapy (BNCT) applies thermal neutron irradiation to react with 10B-compounds that existed inside cancer cells to generate secondary killing irradiations to eradicate cancer cells. The effective distance of the emitted secondary killing irradiations is as long as a cellular diameter, which requires the cellular uptake of 10B-compounds for efficient tumor BNCT. However, current clinical approved 10B-compound of sodium borocaptate (BSH) exhibits low cellular uptake by cancer cells, which limits the therapeutic efficacy. Herein, the multifunctional polymeric micelles with endosome escape and redox-responsive functions have been developed by self-assembly from the BSH-conjugated block copolymers for enhanced delivery of BSH into cancer cells. The BSH-loaded polymeric micelles (BSH/micelle) showed a hydrodynamic diameter around 50 nm, and the size distribution was monodisperse. The BSH/micelle were stable in normal physiological environment, while the BSH could be released in responding to high level of redox-potential in cancer cells. Besides, intracellular delivery of BSH was highly promoted by BSH/micelle through the endosome escape function of micelles, which further increased the tumor therapeutic efficacy by BNCT.

The use of nanoscale metal–organic frameworks (MOFs) as drug delivery vehicles has attracted considerable attention in tumor therapy. In this study, novel biocompatible MOF-based nanocarriers were used as part of a facile and reproducible strategy for precision cancer theranostics. Both diagnostic (Mn2+) and therapeutic compounds (doxorubicin, DOX) were incorporated into the multifunctional MOF-based nanocarriers, which exhibited high colloidal stability and promoted T1-weighted proton relaxivity and low-pH-activated drug release. The obtained MOF-based nanocarriers exhibited significantly high cellular uptake and efficient intracellular drug delivery into cancer cells, which resulted in high apoptosis and cytotoxicity, in addition to effectively inhibiting the migration of 4T1 breast cancer cells. Moreover, the MOF-based nanocarriers could intensively deliver diagnostic and therapeutic agents to tumors to enable precise visualization of the nanocarrier accumulation and accurate tumor positioning, diagnosis, and imaging-guided therapy using magnetic resonance imaging (MRI). In addition, the functional MOF-based nanocarriers exhibited effective ablation of the primary breast cancer, as well as significant inhibition of lung metastasis with a high survival rate. Therefore, the developed nanocarriers represent a viable platform for cancer theranostics.

Rationale: Cationic nanocarriers present with well-known toxicities, including inflammatory toxicity, which limit their clinical application. How the cationic nanocarrier-induced inflammatory response is negatively regulated is unknown. Herein, we found that following a sublethal dose of cationic nanocarriers, the induced inflammatory response is characterized by early neutrophil infiltration and spontaneous resolution within 1 week. Methods: C57BL/6 mice were intravenously injected with a dosage of 1-100 mg/kg cationic DOTAP liposomes as well as other cationic materials. Cell necrosis was detected by flow cytometry. Release of mitochondrial DNA was quantified by qPCR via Taqman probes. Signal proteins were detected by Western blotting. PGE2 production in the supernatant was quantitated using an enzyme immunoassay (EIA). The infiltrated inflammatory cells were observed in WT mice, Ccr2-/- mice, Sting-/- mice and Tlr9-/- mice. Results: The early stage (24-48 h) inflammatory neutrophil infiltration was followed by an increasing percentage of monocytes; and, compared with WT mice, Ccr2-/- mice presented with more severe pulmonary inflammation. A previously uncharacterized population of regulatory monocytes expressing both inflammatory and immunosuppressive cytokines was identified in this model. The alteration in monocyte phenotype was directly induced by mtDNA release from cationic nanocarrier-induced necrotic cells via a STING- or TLR9-dependent pathway. Neutrophil activation was specifically inhibited by PGE2 from Ly6C+ inflammatory monocytes, and intravenous injections of dual-phenotype monocytes beneficially modified the immune response; this inhibitory effect was abolished after treatment with indomethacin. Moreover, we provide clear evidence that mitochondrial DNA activated Ly6C+ monocytes and increased PGE2 production through TLR9- or STING-mediated MAPK-NF-κB-COX2 pathways. Conclusion: Our findings suggest that Ly6C+ monocytes and mtDNA-induced Ly6C+ monocyte PGE2 production may be part of a feedback mechanism that contributes to the resolution of cationic nanocarrier-induced inflammatory toxicity and may have important implications for understanding nanoparticle biocompatibility and designing better, safer drug delivery systems.

Calcium phosphate (CaP) was engineered as a drug delivery nanocarrier nearly 50 years ago due to its biocompatibility and biodegradability. In recent years, several approaches have been developed for the preparation of size-controllable, stable and multifunctional CaP nanocarriers, and several targeting moieties have also been decorated on the surface of these nanocarriers for active targeting. The CaP nanocarriers have been utilized for loading probes, nucleic acids, anticancer drugs and photosensitizers for cancer imaging, therapy and theranostics. Herein, we reviewed the recent advances in the preparation strategies of CaP nanocarriers and the applications of these nanocarriers in tumor diagnosis, gene delivery, drug delivery and theranostics and finally provided perspectives.

Tracking of cells in biological systems is critically important for monitoring disease treatment, such as in stem cell therapy. This report prepared new types of biocompatible gadolinium hybrid iron oxide (GdIO) nanocomposites, which demonstrated high sensitivity for dual T1- and T2-weighted magnetic resonance imaging (MRI). The GdIO nanocomposites could efficiently label mesenchymal stem cells (MSCs) by incubation for 24 h at a safe dose, as they did not affect the cell viability, proliferation or differentiation capacity. There was high contrast enhancement in the GdIO-labeled stem cells for dual T1- and T2-weighted MR imaging. In addition, the GdIO nanocomposites were injected into adult mouse lateral ventricles, where cells could be labeled to monitor their biological behaviors by MRI. These GdIO nanocomposites with dual-imaging functions are a good platform for cell labeling and other diagnostic applications.

Engineered nanoparticles that respond to pathophysiological parameters, such as pH or redox potential, have been developed as contrast agents for the magnetic resonance imaging (MRI) of tumours. However, beyond anatomic assessment, contrast agents that can sense these pathological parameters and rapidly amplify their magnetic resonance signals are desirable because they could potentially be used to monitor the biological processes of tumours and improve cancer diagnosis. Here, we report an MRI contrast agent that rapidly amplifies magnetic resonance signals in response to pH. We confined Mn2+ within pH-sensitive calcium phosphate (CaP) nanoparticles comprising a poly(ethylene glycol) shell. At a low pH, such as in solid tumours, the CaP disintegrates and releases Mn2+ ions. Binding to proteins increases the relaxivity of Mn2+ and enhances the contrast. We show that these nanoparticles could rapidly and selectively brighten solid tumours, identify hypoxic regions within the tumour mass and detect invisible millimetre-sized metastatic tumours in the liver. A magnetic resonance imaging contrast agent that amplifies its signal in response to pH is used to rapidly identify tumours, report hypoxic regions in the tumour and detect millimetre-sized metastatic tumours in the liver of animals.

Zn0.997WO4: Pr3 +0.003 and different concentrations (0.1 mol% to 0.9 mol%) of Pr, Li co-doped ZnWO4 red phosphors were prepared by means of solid-state reaction process. The crystalline, surface morphology and luminescent properties of Zn0.997WO4: Pr3 +0.003 and Zn1 − x − yWO4: xPr3 +, yLi+ phosphors were investigated by the X-ray diffraction patterns (XRD), scanning electron microscope (SEM) and fluorescent measurements. From powder XRD analysis, the formation of monoclinic structure with C2/h point-group symmetry and P2/c space group of the as-synthesized samples is confirmed. The SEM image showed that surface morphology of the phosphor powder is irregular cylindricality. The luminescent spectra are dominated by the red emission peaks at 607, 621 and 643 nm, respectively, radiated from the 1D2 → 3H4, 3P0 → 3H6 and 3P0 → 3F2 transitions of Pr3 + ions. The concentrations of the highest luminescent intensity is determined at 0.3 mol% Pr3 + and 0.3 mol% Li co-doped ZnWO4 powder crystal, and the peak intensity is improved more than 3 times in comparison with that of 0.3 mol% Pr3 + single-doped ZnWO4. The enhanced luminescence comes from the improved crystalline and from the charge compensation of Li+ ions. The decay curve and CIE chromaticity coordinates of as-prepared samples are also studied in detail.

Polymeric micelles that self-assembled from amphiphilic block copolymers have attracted much attention for drug delivery and cancer theranostics, while several candidates are under clinical trial. Polymeric micelles are generally constructed to be 10–100 nm in diameter, and composited with a hydrophilic shell which usually is composed of poly(ethylene glycol) (PEG) and a hydrophobic core. Polymeric micelles provide a good platform for cancer therapy and diagnosis (theranostics), which could co-load nucleic acids, anticancer drugs, and antibodies inside the core for therapy, while incorporating contrast agents (CAs) inside the core or conjugating on the surface for imaging. The PEG shell could protect the drugs inside the core from degradation by enzymes. Some targeting moieties, such as sugar, growth factors, phenylboronic acid, antibodies, and aptamer could be decorated on their surface to selectively interact with receptors that are highly expressed on tumor cells to increase the targeting ability. The polymeric micelles are stable in the blood circulation, which could enable delivery of drugs/CAs to tumor tissues through the enhanced permeability and retention effect. The targeting moieties of micelles could specifically interact with the epitopes that are overexpressed on cancer cells to increase the diagnostic selectivity and break down therapeutic limitations, which could also reduce their distribution in normal regions. Polymeric micelles with theranostic functions could be utilized for cancer diagnosis, image-guided therapy, tracing polymeric micelles in the body, and monitoring the therapeutic effects. In this chapter we focus on recent advances of polymeric micelles for tumor optical imaging, MRI, multifunctional imaging, image-guided therapy, and theranostics.

The severe mortality and morbidity of myocardial infarction requests appropriate and accurate detection. Considering pathological profile of the acidic myocardial infarction microenvironments, herein, the low pH-sensitive albumin nanocomposites with MnO2 motifs (MnO2@BSA) have been engineered for T1-weighted MR imaging of myocardial infarction, while using non-pH-responsive Gd2O3@BSA nanocomposites as control. The nanocomposites were 20–30 nm in diameter with spheroid morphology. Besides, the MnO2@BSA have exhibited pH-triggered releasing of Mn2+, demonstrating approximately 38-fold and 55-fold increased molecular relaxivity at acute myocardial infarction-mimicking pH 6.5 (13.08 mM−1s−1) and macrophage intracellular pH 5.0 (18.76 mM−1s−1) compared to the extremely low relaxivity (0.34 mM−1s−1) at normal physiological conditions (pH 7.4). However, the Gd2O3@BSA with molecular relaxivity approximately 10 mM−1s−1 were without pH-sensitive properties. Furthermore, the MnO2@BSA have demonstrated high accumulation in the acute myocardial infarction regions and fast metabolism from the body after systemic injection, accounting high contrast enhancement for accurate MR imaging of acute myocardial infarction in rabbit models, demonstrating better diagnostic performance over the controls.

International audience; Cancer stem-like cells (CSCs) treatment is a plausible strategy for enhanced cancer therapy. Here we report a glucose-installed sub-50-nm nanocarrier for the targeted delivery of small interfering RNA (siRNA) to CSCs through selective recognition of the glucose ligand to the glucose transporter 1 (GLUT1) overexpressed on the CSC surface. The siRNA nanocarrier was constructed via a two-step assembling process. First, a glucose-installed poly(ethylene glycol)-block-poly(l-lysine) modified with lipoic acid (LA) at the omega-end (Glu-PEG-PLL-LA) was associated with a single siRNA to form a unimer polyion complex (uPIC). Second, a 20nm gold nanoparticle (AuNP) was decorated with ~65 uPICs through AuS bonding. The glucose-installed targeted nanoparticles (Glu-NPs) exhibited higher cellular uptake of siRNA payloads in a spheroid breast cancer (MBA-MB-231) cell culture compared with glucose-unconjugated control nanoparticles (MeO-NPs). Notably, the Glu-NPs became more efficiently internalized into the CSC fraction, which was defined by aldehyde dehydrogenase (ALDH) activity assay, than the other fractions, probably due to the higher GLUT1 expression level on the CSCs. The Glu-NPs elicited significantly enhanced gene silencing in a CSC-rich orthotopic MDA-MB-231 tumor tissue following systemic administration to tumor-bearing mice. Ultimately, the repeated administrations of polo-like kinase 1 (PLK1) siRNA-loaded Glu-NPs significantly suppressed the growth of orthotopic MDA-MB-231 tumors. These results demonstrate that Glu-NP is a promising nanocarrier design for CSC-targeted cancer treatment.

Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors in a light-selective manner. To improve the PDT efficacy, numerous kinds of nanocarriers have been developed to deliver photosensitizers (PSs) selectively into the tumor through leaky tumor-associated vasculature. However, the corresponding prolonged retention of the nanocarrier in the bloodstream may lead to unfavorable photochemical damage to normal tissues such as skin. Here, we report an organic-inorganic hybrid nanocarrier with a pH-responsive on/off switch of PDT efficacy. This hybrid nanocarrier is constructed by hydrothermal synthesis after simple mixing of calcium/phosphate ions, chlorin e6 (amphiphilic low molecular weight PS), and poly(ethylene glycol)-b-poly(aspartic acid) (PEG-PAsp) copolymers in an aqueous solution. The hybrid nanocarrier possesses a calcium phosphate (CaP) core encapsulating the PSs, which is surrounded by a PEG shielding layer. Under physiological conditions (pH 7.4), the nanocarrier suppressed the photochemical activity of PS by lowering the access of oxygen molecules to the incorporated PS, while PDT efficacy was restored in a pH-responsive manner because of the dissolution of CaP and eventual recovery of access between the oxygen and the PS. Owing to this switch, the nanocarrier reduced the photochemical damage in the bloodstream, while it induced effective PDT efficacy inside the tumor cell in response to the acidic conditions of the endo-/lysosomes.

A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent.In vivo evaluation was performed on colon carcinoma Col-26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 × 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice.The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate-based nanoparticles was suppressed up to four times higher compared to the non-treated group, supported by the results of histopathological analysis.The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment.

Gadolinium (Gd) chelates-loaded nanocarriers have high potential for achieving magnetic resonance imaging (MRI)-guided Gd neutron capture therapy (GdNCT) of tumors. Herein, we developed calcium phosphate micelles hybridized with PEG-polyanion block copolymers, and incorporated with the clinical MRI contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA/CaP). The Gd-DTPA/CaP were nontoxic to cancer cells at the concentration of 100 μM based on Gd-DTPA, while over 50% of the cancer cells were killed by thermal neutron irradiation at this concentration. Moreover, the Gd-DTPA/CaP showed a dramatically increased accumulation of Gd-DTPA in tumors, leading to the selective contrast enhancement of tumor tissues for precise tumor location by MRI. The enhanced tumor-to-blood distribution ratio of Gd-DTPA/CaP resulted in the effective suppression of tumor growth without loss of body weight, indicating the potential of Gd-DTPA/CaP for safe cancer treatment.

Smart drug delivery systems that are based on environmental-responsive polymers have been developed to specifically deliver cargos to desired disease sites and controlled drug release in response to pathophysiological stimuli. Owing to the high selectivity, sensitivity, and rate enhancement of enzymes, particularly in biological processes, certain disease-associated enzymes have recently become an emerging bioresponsive trigger for smart drug delivery and diagnostic applications. In this chapter, we summarize the general strategies for designing enzyme-responsive drug delivery systems with functional polymers, focus on the enzyme-responsive polymers for therapeutic and diagnostic applications, and discuss the future directions of enzyme-responsive polymeric systems.

For systemic delivery of siRNA to solid tumors, a size-regulated and reversibly stabilized nanoarchitecture was constructed by using a 20 kDa siRNA-loaded unimer polyion complex (uPIC) and 20 nm gold nanoparticle (AuNP). The uPIC was selectively prepared by charge-matched polyionic complexation of a poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) copolymer bearing ∼40 positive charges (and thiol group at the ω-end) with a single siRNA bearing 40 negative charges. The thiol group at the ω-end of PEG-PLL further enabled successful conjugation of the uPICs onto the single AuNP through coordinate bonding, generating a nanoarchitecture (uPIC-AuNP) with a size of 38 nm and a narrow size distribution. In contrast, mixing thiolated PEG-PLLs and AuNPs produced a large aggregate in the absence of siRNA, suggesting the essential role of the preformed uPIC in the formation of nanoarchitecture. The smart uPIC-AuNPs were stable in serum-containing media and more resistant against heparin-induced counter polyanion exchange, compared to uPICs alone. On the other hand, the treatment of uPIC-AuNPs with an intracellular concentration of glutathione substantially compromised their stability and triggered the release of siRNA, demonstrating the reversible stability of these nanoarchitectures relative to thiol exchange and negatively charged AuNP surface. The uPIC-AuNPs efficiently delivered siRNA into cultured cancer cells, facilitating significant sequence-specific gene silencing without cytotoxicity. Systemically administered uPIC-AuNPs showed appreciably longer blood circulation time compared to controls, i.e., bare AuNPs and uPICs, indicating that the conjugation of uPICs onto AuNP was crucial for enhancing blood circulation time. Finally, the uPIC-AuNPs efficiently accumulated in a subcutaneously inoculated luciferase-expressing cervical cancer (HeLa-Luc) model and achieved significant luciferase gene silencing in the tumor tissue. These results demonstrate the strong potential of uPIC-AuNP nanoarchitectures for systemic siRNA delivery to solid tumors.

Boron neutron capture therapy is a promising tumor treatment method, though its wide application has been limited due to the poor tumor selectivity and intracellular delivery of 10B-compounds. Here, block copolymer-boron cluster conjugate based on the clinically used sodium borocaptate (BSH) and poly(ethylene glycol)-b-poly(glutamic acid) copolymer have been developed for effectively penetrating tumor tissues and homogeneously delivering the boron clusters into cancer cells towards safe and efficient boron neutron capture therapy. The PEGylated block copolymer-boron cluster (BSH) conjugate has demonstrated significant higher cellular uptake and tumor accumulation when compared to the non-PEGylated formulations and BSH. Moreover, the enhanced delivery to tumors of the conjugates, as well as their superior intratumoral penetration, which facilitated reaching the intracellular space of most cells in tumors, allowed the effective ablation of tumors after neutron irradiation.

Ludwigite ore has not yet been utilized on an industrial scale due to its complex mineralogy and fine mineral dissemination. In this study, sodium salts were employed to enhance the separation of iron and boron by reductive roasting-magnetic separation. It was found that the separation of iron and boron as well as the iron grade and recovery were significantly improved by the addition of Na2SO4 or Na2CO3. Under the reduction temperature of 1050 °C, reduction time of 60 min and magnetic intensity of 0.1T. Compared with the inexistence of sodium salts, the iron grade and recovery of the magnetic concentrate increased from 83.3% and 88.6% to 93.2% and 95.1%, respectively, by adding 6% Na2CO3. The XRD and microstructure analyses indicated that the iron oxides were transformed into metallic iron and the average metallic iron grains were grown to over 40 m which was beneficial for separation of metallic iron from gangue.

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

An intelligent theranostic nanoplatform based on nanovalve operated metal-organic framework (MOF) core-shell hybrids, incorporating tumorous microenvironment-triggered drug release, magnetic resonance imaging (MRI) guidance, sustained release, and effective chemotherapy in one pot is reported. The core-shell hybrids are constructed by an in situ growth method, in which Fe3 O4 particles with superior abilities of MRI and magnetic separation form the core and UiO-66 MOF with high loading capacity compose the shell, and then are surface-installed with pillararene-based pseudorotaxanes as tightness-adjustable nanovalves. This strategy endows the system with the ability of targeted, multistimuli responsive drug release in response to pH changes, temperature variations, and competitive agents. Water-soluble carboxylatopillar[6]arene system achieved sustained drug release over 7 days due to stronger host-guest binding, suggesting that the nanovalve tightness further reinforces the desirable release of anticancer agent over a prolonged time at the lesion site.

A novel family of stimuli-responsive smart hydrogel is developed in this study for K + -induced self-regulated controlled-release, which is featured with isothermally K + -induced pulse-release mode at a certain temperature due to the isothermally K + -induced shrinking behavior of the hydrogel by recognizing the increase of K + concentration in the environment. The proposed poly( N -isopropylacrylamide- co -benzo-15-crown-5-acrylamide) hydrogel is composed of crown ether 15-crown-5 as ion-signal sensing receptor and poly( N -isopropylacrylamide) as actuator. The selective formation of stable 2:1 “host-guest” complexation between the crown ether 15-crown-5 and potassium ion drives the polymeric network of the hydrogel to shrink; as a result, the hydrogel exhibits especial and selective response to potassium ions. A K + -recognition pulse-release performance of loaded drug from the fabricated hydrogel is achieved by using the K + -induced isothermal shrinkage property of the hydrogel. The proposed hydrogel provides a new mode of K + -recognition volume change for stimuli-responsive smart actuators, which is highly attractive for targeting drug delivery systems, biomedical devices, and sensors and so on.

A novel thermo-responsive smart copolymer that can selectively respond to specific ions, poly[(N-isopropylacrylamide)-co-(benzo-15-crown-5-acrylamide)], has been synthesized and characterized. The copolymer exhibits a negative shift of the lower critical solution temperature (LCST) for phase transition that is specifically responsive to certain alkali metal ions. The order of significance of the LCST shift that is induced by ions is K + > Cs + > Na + > Li + . The greater the number of crown ether units in the copolymer, or the larger the ion concentration, the higher the sensitivity and selectivity of the copolymer for cation recognition. Because of its novel ion-responsive characteristics, the proposed smart copolymer is a promising new candidate material for sensors, actuators, switches, and so on.

Superparamagnetic iron oxide nanoparticles (SPIONs) are highly cytotoxic and target cancer cells with high specificity; however, the mechanism by which SPIONs induce cancer cell-specific cytotoxicity remains unclear. Herein, the molecular mechanism of SPION-induced cancer cell-specific cytotoxicity to cancer cells is clarified through DNA microarray and bioinformatics analyses. SPIONs can interference with the mitochondrial electron transport chain (METC) in cancer cells, which further affects the production of ATP, mitochondrial membrane potential, and microdistribution of calcium, and induces cell apoptosis. Additionally, SPIONs induce the formation of reactive oxygen species in mitochondria; these reactive oxygen species trigger cancer-specific cytotoxicity due to the lower antioxidative capacity of cancer cells. Moreover, the DNA microarray and gene ontology analyses revealed that SPIONs elevate the expression of metallothioneins in both normal and cancer cells but decrease the expression of METC genes in cancer cells. Overall, these results suggest that SPIONs induce cancer cell death by targeting the METC, which is helpful for designing anti-cancer nanotheranostics and evaluating the safety of future nanomedicines.

A series of novel, thermo-sensitive copolymers with different molar ratios of N-isopropylacrylamide (NIPAM) and hydrophobic cis-dibenzo-18-crown-6-diacryl-amide (cis-DBCAm) were prepared via free-radical copolymerization. cis-DBCAm with polymerizable end groups was successfully synthesized by reacting the corresponding amino crown ether with acryloyl chloride. The copolymers were characterized by FT-IR and elemental analysis, and the thermo-sensitivities of the copolymers were evaluated by measuring their lower critical solution temperatures (LCSTs) in the absence or presence of various metal ions. The results indicated that incorporation of cis-DBCAm lowered LCSTs, and that the LCSTs of the copolymers decreased with the increase in cis-DBCAm content in the copolymers. When the cavities of the crown ether units captured either K + or Cs + ions, the LCST of the respective copolymer-metal ion complex was further decreased, whereas the capture of Na + or Li + ions did not have a significant influence on the LCSTs of the copolymers.

Nanocarriers have been used for specific delivery of therapeutic agents to solid tumors based on the enhanced permeability and retention in cancerous tissues. Despite metastasis is the main reason of cancer-related death and a priority for nanocarrier-based therapies, the targeting ability of nanocarriers to the metastatic disease is poorly understood, especially for preangiogenic micrometastases as nanocarriers usually use the malignant neovasculature for enhancing their accumulation. Thus, herein, we studied the ability of micellar nanocarriers incorporating (1,2-diaminocyclohexane)platinum(II) (DACHPt) for treating liver metastases of bioluminescent murine colon adenocarcinoma C-26, during overt and preangiogenic metastatic stages. After intravenous injection, DACHPt-loaded micelles (DACHPt/m) effectively inhibited the tumor growth in both metastatic tumor models. While the anticancer activity of the micelles against overt metastases was associated with their selective accumulation in cancerous tissues having neovasculature, the ability of DACHPt/m to target preangiogenic metastases was correlated with the inflammatory microenvironment of the niche. This targeting capability of polymeric micelles to preangiogenic metastasis may provide a novel approach for early diagnosis and treatment of metastases.

In the past decades, polymeric nanocarriers have emerged as a biocompatible platform for delivering therapeutic compounds to tumor sites in a cancer-selective manner, and some polymeric nanocarriers have already been approved for clinical application while more are under clinical trial, demonstrating their promises for cancer therapy. In this chapter, the concept of polymeric nanocarriers, structure design, and preparation methods are introduced and summarized firstly. Besides, the applications of polymeric nanocarriers delivering cargoes to the tumor tissues in a passive way by enhanced permeability and retention (EPR) effects and parameters that may influence this procedure have been summarized and discussed. Moreover, the polymeric nanoparticles could actively target tumor tissues through the interaction of targeting moieties on their surfaces with cancer cell-specific receptors, and several types of targeting ligands could be used for active targeting. Furthermore, polymeric nanocarriers have been functionalized to release encapsulated drugs at specific sites or time intervals controlled by environmental triggers, such as pH, temperature, and enzyme. Finally, the application of polymeric nanocarriers for primary cancer and metastatic cancer diagnosis and treatment are described. Polymeric nanocarriers have demonstrated some success in the field of cancer diagnosis and therapy, and with the progress in chemistry, biology, oncology, and modern technologies, much powerful polymeric nanocarriers would be developed for cancer therapy.

Efficient systems for delivery of small interfering RNA (siRNA) are required for clinical application of RNA interference (RNAi) in cancer therapy. Herein, we developed a safe and efficient nanocarrier comprising poly(ethylene glycol)-block-charge-conversional polymer (PEG-CCP)/calcium phosphate (CaP) hybrid micelles for systemic delivery of siRNA and studied their efficacy in spontaneous bioluminescent pancreatic tumors from transgenic mice. PEG-CCP was engineered to provide the siRNA-loaded hybrid micelles with enhanced colloidal stability and biocompatibility due to the PEG capsule and with endosome-disrupting functionality due to the acidic pH-responsive CCP segment where the polyanionic structure could be converted to polycationic structure at acidic pH through cis-aconitic amide cleavage. The resulting hybrid micelles were confirmed to have a diameter of

E‐cadherin/catenin complex is crucial for cancer cell migration and invasion. The histidine‐alanine‐valine (HAV) sequence has been shown to inhibit a variety of cadherin‐based functions. In this study, by fusing HAV and the classical tumor‐targeting Arg‐Gly‐Asp (RGD) motif and Asn‐Gly‐Arg (NGR) motif to the apoptosis‐inducing peptide sequence‐AVPIAQK, a bifunctional peptide has been constructed with enhanced tumor targeting and apoptosis effects. This peptide is further processed as a nanoscale vector to encapsulate the hydrophobic drug docetaxel (DOC). Bioimaging analysis shows that peptide nanoparticles can penetrate into xenograft tumor cells with a significantly long retention in tumors and high tumor targeting specificity. In vivo, DOC/peptide NPs are substantially more effective at inhibiting tumor growth and prolonging survival compared with DOC control. Together, the findings of this study suggest that DOC/peptide NPs may have promising applications in pulmonary carcinoma therapy.

Nanodevices for magnetic resonance imaging of cancer were self-assembled to core-shell micellar structures by metal complex formation of K(2)PtCl(6) with diethylenetriaminepentaacetic acid gadolinium (III) dihydrogen (Gd-DTPA), a T(1)-contrast agent, and poly(ethylene glycol)-b-poly{N-[N'-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-b-PAsp(DET)) copolymer in aqueous solution. Gd-DTPA-loaded polymeric micelles (Gd-DTPA/m) showed a hydrodynamic diameter of 45 nm and a core size of 22 nm. Confining Gd-DTPA inside the core of the micelles increased the relaxivity of Gd-DTPA more than 13 times (48 mM(-1) s(-1)). In physiological conditions Gd-DTPA/m sustainedly released Gd-DTPA, while the Pt(IV) complexes remain bound to the polymer. Gd-DTPA/m extended the circulation time in plasma and augmented the tumor accumulation of Gd-DTPA leading to successful contrast enhancement of solid tumors. μ-Synchrotron radiation-X-ray fluorescence results confirmed that Gd-DTPA was delivered to the tumor site by the micelles. Our study provides a facile strategy for incorporating contrast agents, dyes and bioactive molecules into nanodevices for developing safe and efficient drug carriers for clinical application.

A novel thermoresponsive hydrogel with ion-recognition property was prepared via free-radical cross-linking copolymerization of N-isopropylacrylamide (NIPAM) with benzo-18-crown-6-acrylamide (BCAm) as host receptor. Both chemical structures and stimuli-sensitive properties of the prepared poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) P(NIPAM-co-BCAm) hydrogel were characterized. The smart hydrogel could respond to both temperature and ion stimuli. When the crown ether units captured Ba2+ and formed stable BCAm/Ba2+ host-guest complexes, the lower critical solution temperature (LCST) of the hydrogel increased due to the repulsion among charged BCAm/Ba2+ complex groups and osmotic pressure within the hydrogel. Whereas crown ethers captured Cs+, the LCST shifted to a lower temperature because of the formation of 2:1 sandwich complexes. Unexpectedly, the LCST of the cross-linked P(NIPAM-co-BCAm) hydrogel in K+ solution did not shift to a higher temperature, which was definitely different from the previously reported linear P(NIPAM-co-BCAm) copolymer in K+ solution. The results of this work provide valuable information for development of dual thermo- and ion-responsive hydrogels which have potential applications in drug controlled-release systems or biomedical fields.