Fast Recovery Double-Network Hydrogels Based on Particulate Macro-RAFT Agents.

Synthetic hydrogels struggle to match the high strength, toughness, and recoverability of biological tissues under periodic mechanical loading. Although the hydrophobic polymer chain of polystyrene (PS) may initially collapse into a nanosphere upon contact with water, it has the ability to be elongated when it is subjected to an external force. To address this challenge, we employ the reversible addition-fragmentation chain transfer (RAFT) method to design a carboxyl-substituted polystyrene (CPS) which can form a covalently cross-linked network with four-armed amino-terminated polyethylene glycol (4-armed-PEG-NH2), and a ductile polyacrylamide network is introduced in order to prepare a double-network (DN) hydrogel. Our results demonstrate that the DN hydrogel exhibits exceptional mechanical properties (0.62 kJ m-2 fracture energy, 2510.89 kJ m-3 toughness, 0.43 MPa strength, and 820% elongation) when a sufficient external force is applied to fracture it. Moreover, when the DN hydrogel is subjected to a 200% strain, it displays superior recoverability (94.5%). This holds a significant potential in enhancing the mechanical performance of synthetic hydrogels and can have wide-ranging applications in fields such as tissue engineering for hydrophobic polymers.

Enhancing the targeting ability of nanoparticles via protected copolymers.

It is important to maintain the balance between therapeutic efficiency and cytotoxicity when using nanomaterials for biomedical applications. Here, we propose a new method (i.e., non-covalent coating of protected copolymers onto the nanoparticle surface) to enhance the active targeting of nanoparticles to the cancer cells by combining the dissipative particle dynamics simulation and in vitro experiments. When coating the protected copolymer onto the nanoparticle surface, the uptake efficiency could be greatly altered due to the competition between the copolymer-ligand interaction and the receptor-ligand interaction-the non-covalent coating is more efficient than the covalent coating. Furthermore, the effect of the physicochemical properties of the protected copolymer on the targeting ability of nanoparticles was also investigated. This study offers useful insight into the optimal design of nanocarriers in biomedicine.

Neutrophil membranes coated, antibiotic agent loaded nanoparticles targeting to the lung inflammation.

Natural cellular membranes, with the outstanding qualities of biocompatibility and specificity, have gained growing attentions in the system of drug delivery. Nanoparticles coated with cellular membranes are starting to be applied as drug-loaded-vehicles to target tumors. Here, neutrophil membranes were selected to apply in the treatment of inflammation because neutrophils can participate in various inflammatory responses and accumulate at inflammatory sites to eliminate pathogens. Through extracting neutrophil membranes from natural neutrophils without affecting their biological properties, nanoparticles loaded with sparfloxacin (SPX) were coated with these membranes and disguised as neutrophils. Compared with traditional nano-medicines, the neutrophil membrane-coated nanoparticles (NM-NP-SPX) possessed precise targeting ability just like the neutrophils could accumulate at inflammatory sites when inflammation burst. In addition, NM-NP-SPX could prolong the circulation time and had the property of controlled-release. Through in vivo experiments, we found that the concentration of three representative inflammatory cytokines in blood, bacteria and inflammatory cells in lungs of the mice with pneumonia reduced significantly in the initial 24 h after the injection of NM-NP-SPX, which meant that NM-NP-SPX could greatly reduce the risk of death for the patients with inflammation. Moreover, the infected lungs could recover rapidly without any side effects to other organs due to the low cytotoxicity of NM-NP-SPX against normal cells. Therefore, our developed drug delivery system has enormous advantages in treating inflammations. Not only that, this kind of bionic method may have greater value and application prospects in curing the inflammations arisen from cancers.

A tumor-microenvironment-responsive nanomaterial for cancer chemo-photothermal therapy.

Taxol (TAX) is a typical anticancer drug that is widely used in clinical treatment of cancer, while gold nanorods (AuNRs) are a kind of well-known material applied for photothermal therapy (PTT). The therapeutic outcome of TAX in chemotherapy is however limited by drug resistance, while AuNRs often show poor accuracy in PTT. To optimize the functions of TAX and AuNRs, we developed a hydrogen peroxide (H2O2)-triggered nanomaterial (LV-TAX/Au@Ag) for combined chemo-photothermal therapy. In normal tissues, TAX is protected in the lipid bilayer and isolated from the surrounding normal cells, while AuNRs are coated with silver shells and show low photothermal capacity. However, after reaching the tumor tissues, the silver shells can be etched by endogenous H2O2 in the tumor microenvironment, and the photothermal properties of AuNRs are then recovered. Meanwhile, the generated oxygen destabilizes the LV, which makes the 100 nm sized nanosystems disassemble into the smaller sized TAX and AuNRs, leading to the deep penetration and direct interaction with tumor tissues. The related in vitro experiments proved the validity of this "turn off/on" effect. Extensive necrosis and apoptosis were observed in the tumor tissues and the proliferation of solid tumor was greatly suppressed due to this combined chemo-photothermal therapy. In addition, no significant damage was found in normal tissues after the treatment of LV-TAX/Au@Ag. Therefore, the strategy to achieve environmental response by modifying the photothermal agents enhanced the efficiency and safety of nanomedicine, which may help improve cancer treatment.

Combinational phototherapy and hypoxia-activated chemotherapy favoring antitumor immune responses.

Background: Tumor metastasis is responsible for most cancer death worldwide, which lacks curative treatment. Purpose: The objective of this study was to eliminate tumor and control the development of tumor metastasis. Methods: Herein, we demonstrated a smart nano-enabled platform, in which 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2h-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) and tirapazamine (TPZ) were co-loaded in poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL) to form versatile nanoparticles (PEG-PCL-IR780-TPZ NPs). Results: The intelligence of the system was reflected in the triggered and controlled engineering. Specially, PEG-PCL not only prolonged the circulation time of IR780 and TPZ but also promoted tumor accumulation of nanodrugs through enhanced permeability and retention (EPR) effect. Moreover, reactive oxygen species (ROS) generated by IR780 armed by an 808 nm laser irradiation evoked a cargo release. Meanwhile, IR780, as a mitochondria-targeting phototherapy agent exacerbated tumor hypoxic microenvironment and activated TPZ for accomplishing hypoxia-activated chemotherapy. Most significantly, IR780 was capable of triggering immunogenic cell death (ICD) during the synergic treatment. ICD biomarkers as a "danger signal" accelerated dendritic cells (DCs) maturation, and subsequently activated toxic T lymphocytes. Conclusion: Eventually, antitumor immune responses stimulated by combinational phototherapy and hypoxia-activated chemotherapy revolutionized the current landscape of cancer treatment, strikingly inhibiting tumor metastasis and providing a promising prospect in the clinical application.

Tailor-made PEG-DA-CuS nanoparticles enriched in tumor with the aid of retro Diels-Alder reaction triggered by their intrinsic photothermal property.

INTRODUCTION: In recent years, near-infrared laser-induced photothermal therapy is being considered as a promising approach to kill tumors owing to its noninvasive nature and excellent antitumor efficiency. However, the lack of ideal photothermal agents hinders further development of this technology. MATERIALS AND METHODS: Aiming at solving this long-standing obstacle, we report here about the polyethylene glycol (PEG)-DA modified copper sulfide (CuS) nanoparticles (NPs) (PEG-DA-CuS NPs), a kind of semiconductor photothermal agents that show excellent photothermal stability and high heat conversion efficiency. RESULTS AND DISCUSSION: Owing to the surrounding PEG, the water solubility of CuS NPs was significantly improved when circulating in blood in the body. When the NPs reached the tumors and were irradiated by a 1,064 nm laser (1 W/cm2, 10 minutes), the local temperature increased above 90°C, triggering the retro Diels-Alder reaction. After the release of PEG chain, CuS NPs soon formed aggregates and enriched the tumor via the enhanced permeability and retention effect, promoting the efficacy of photothermal therapy. CONCLUSION: Therefore, we believe PEG-DA-CuS NPs are able to serve as a kind of cytotoxic and efficient photothermal agent to kill cancer.

Fluorescence guided photothermal/photodynamic ablation of tumours using pH-responsive chlorin e6-conjugated gold nanorods.

Photothermal/photodynamic therapies (PTT/PDT) have been widely accepted as non-invasive therapeutic modalities to erase tumours. However, both therapies face the problem of precisely locating tumours and reducing their side effects. Herein, chlorin e6 conjugated gold nanorod, (Ce6-PEG-AuNR), a type of gold nanorod-photosensitizer conjugate, is designed as a kind of nano-therapeutic agent to simultaneously realize combined PTT/PDT. Compared to free Ce6, the fluorescence of Ce6 adhered to the conjugate is effectively quenched by the longitudinal surface plasmon resonance (LSPR) of in the Ce6-PEG-AuNR. However, the specific fluorescence of Ce6 can be recovered in tumour tissue when Ce6 is separated from the conjugate owing to the cleavage of hydrazone bond between Ce6 and PEG caused by intracellular acidic conditions in tumour tissue. Based on this effect, we can precisely locate tumours and further kill cancer cells by combined PTT/PDT. In addition, the combined therapy (PTT/PDT) function is more efficient in cancer treatment than that of PTT or PDT alone. Therefore, Ce6-PEG-AuNR can serve as a promising dual-modal phototherapeutic agent as well as a tumour-sensitive fluorescent probe to diagnose and treat cancer.

Preservation of Supported Lipid Membrane Integrity from Thermal Disruption: Osmotic Effect.

Preservation of structural integrity under various environmental conditions is one major concern in the development of the supported lipid membrane (SLM)-based devices. It is common for SLMs to experience temperature shifts from manufacture, processing, storage, and transport to operation. In this work, we studied the thermal adaption of the supported membranes on silica substrates. Homogenous SLMs with little defects were formed through the vesicle fusion method. The mass and fluidity of the bilayers were found to deteriorate from a heating process but not a cooling process. Fluorescence characterizations showed that the membranes initially budded as a result of heating-induced lipid lateral area expansion, followed by the possible fates including maintenance, retraction, and fission, among which the last contributes to the irreversible compromise of the SLM integrity and spontaneous release of the interlipid stress accumulated. Based on the mechanism, we developed a strategy to protect SLMs from thermal disruption by increasing the solute concentration in medium. An improved preservation of the membrane mass and fluidity against the heating process was observed, accompanied by a decrease in the retraction and fission of the buds. Theoretical analysis revealed a high osmotic energy penalty for the fission, which accounts for the depressed disruption. This osmotic-based protection strategy is facile, solute nonspecific, and long-term efficient and has little impact on the original SLM properties. The results may help broaden SLM applications and sustain the robustness of SLM-based devices under multiple thermal conditions.

Paclitaxel-Loaded ß-Cyclodextrin-Modified Poly(Acrylic Acid) Nanoparticles through Multivalent Inclusion for Anticancer Therapy.

A nanoassembled drug delivery system for anticancer treatment, formed by the host-guest interactions between paclitaxel (PTX) and ß-cyclodextrin (ß-CD) modified poly(acrylic acid) (PCDAA), is successfully prepared. After such design, the aqueous solubility of PTX is greatly increased from 0.34 to 36.02 µg mL(-1), and the obtained PCDAA-PTX nanoparticles (PCDAA-PTX NPs) exhibit a sustained PTX release behavior in vitro. In vitro cytotoxicity finds that PCDAA-PTX NPs can accumulate significantly in tumor cells and remain the pharmacological activity of PTX. The in vivo real-time biodistribution of PCDAA-PTX NPs is investigated using near-infrared fluorescence imaging, indicating that the PCDAA-PTX NPs can effectively target to the tumor site by the enhanced permeability and retention effect in H22 tumor-bearing mice. Through in vivo antitumor examination, PCDAA-PTX NPs exhibit superior efficacy in impeding the tumor growth compared to the commercially available Taxol®.

Thickness dependent effective viscosity of a polymer solution near an interface probed by a quartz crystal microbalance with dissipation method.

The solution viscosity near an interface, which affects the solution behavior and the molecular dynamics in the solution, differs from the bulk. This paper measured the effective viscosity of a dilute poly (ethylene glycol) (PEG) solution adjacent to a Au electrode using the quartz crystal microbalance with dissipation (QCM-D) technique. We evidenced that the effect of an adsorbed PEG layer can be ignored, and calculated the zero shear rate effective viscosity to remove attenuation of high shear frequency oscillations. By increasing the overtone n from 3 to 13, the thickness of the sensed polymer solution decreased from ~70 to 30 nm. The zero shear rate effective viscosity of the polymer solution and longest relaxation time of PEG chains within it decrease with increasing solution thickness. The change trends are independent of the relation between the apparent viscosity and shear frequency and the values of the involved parameter, suggesting that the polymer solution and polymer chains closer to a solid substrate have a greater effective viscosity and slower relaxation mode, respectively. This method can study the effect of an interface presence on behavior and phenomena relating to the effective viscosity of polymer solutions, including the dynamics of discrete polymer chains.

Comparison of the different responses of surface plasmon resonance and quartz crystal microbalance techniques at solid-liquid interfaces under various experimental conditions.

A molecular level understanding of the phenomena taking place at solid-liquid interfaces, ranging from changes in mass to conformation changes, is the key to developing and improving many chemical and biological systems and their scientific and medical applications. Surface plasmon resonance (SPR) and quartz crystal microbalance (QCM) techniques are often coupled to achieve this understanding. We divided various experimentally relevant scenarios into the following six categories: boundary solutions; surface modifications; conformation; viscoelastic properties; molecular ruler; and mass sensitivity. For each case, based on theoretical analyses, we discuss the following four points with respect to discrete adsorbates at solid-liquid interfaces: (1) the different types of information that can be obtained, why it can be obtained and how to obtain it; (2) the origins of many current approaches and why they are imperfect; (3) guidelines for experimental design; and (4) possible studies, such as the effect of dimensional confinement and adsorption forces on the ability of conformational changes to occur on the receipt of external stimuli and the hysteresis in these changes.

Effect of osmotic stress on membrane fusion on solid substrate.

There is currently a lack of comprehensive understanding of osmotic effect on lipid vesicle fusion on solid oxide surface. The question has both biological and biomedical implications. We studied the effect by quartz crystal microbalance with dissipation monitoring using NaCl, sucrose as osmolytes, and two different osmotic stress imposition methods, which allowed us to separate the osmotic effects from the solute impacts. Osmotic stress was found to have limited influence on the fusion kinetics, independently of the direction of the gradient. Further atomic force microscopy experiments and energy consideration implied that osmotic stress spends the majority of chemical potential energy associated in directed transport of water across membrane. Its contribution to vesicle deformation and fusion on substrate is therefore small compared to that of adhesion.

Lipid exchange between membranes: effects of membrane surface charge, composition, and curvature.

Intermembrane lipid exchange is critical to membrane functions and pharmaceutical applications. The exchange process is not fully understood and it is explored by quartz crystal microbalance with dissipation monitor method in this research. It is found that intermembrane lipid exchange is accelerated with the decrease of vesicle size and the increase of charge and liquid crystalline lipid composition ratio. Vesicle adsorption rate, membrane lateral pressure gradient, and lipid lateral diffusion coefficient are inferred to be critical in deciding the lipid exchange kinetics between membranes. Besides that, the membrane contact situation during lipid exchange is also studied. The maximum total membrane contact area is found to increase with the decrease of vesicle size, charged and liquid crystalline lipid composition ratio. A competition mechanism between the vesicle adsorption rate and the intermembrane lipid exchange rate was proposed to control the maximum total membrane contact area.

Effect of calcium cation on lipid vesicle deposition on silicon dioxide surface under various thermal conditions.

Calcium cation (Ca(2+)) is a key element to the cell membrane functions. Its effects on liquid crystal vesicle deposition have already been learnt. In this study, it is found that Ca(2+) can also influence the gel vesicle deposition by controlling the vesicle rupture and fusion on SiO(2) at temperatures lower than the main transition temperature. Particular analyses were given to the vesicle-SiO(2) and inter-vesicle attractions that are originated from the Ca(2+) bridging effect. It is concluded that the aggregate condition of vesicles should be taken into consideration when dealing with vesicle deposition on a solid substrate.

Radioactivity concentrations in soils of the Xiazhuang granite area, China.

The natural radioactivity of soils at the Xiazhuang granite massif of Southern China has been studied. The radioactivities of 55 samples have been measured with a low-background HPGe detector. The radioactivity concentrations of (238)U and (40)K ranged from 40.2 to 442 and from 442 to 913 Bq/kg, respectively, while the radioactivity concentration of (232)Th varied only slightly. In order to evaluate the radiological hazard of the natural radioactivity, the radium equivalent activity (Ra(eq)), the absorbed dose rate (D ), the annual effective dose rate and the external hazard index (H(ex)) have been calculated and compared with the internationally approved values. The study provides background radioactivity concentrations in a granite area, specifically, the area in the vicinity of a uranium mine in Southern China. The data can be used in exploring granite-type uranium deposits.