Microwave Responsive Nanoplatform via P-Selectin Mediated Drug Delivery for Treatment of Hepatocellular Carcinoma with Distant Metastasis.

Hepatocellular carcinoma (HCC) with metastatic disease is associated with a low survival in clinical practice. Many curative options including liver resection, transplantation, and thermal ablation are effective in local but limited for patients with distant metastasis. In this study, the efficacy, specificity, and safety of P-selectin targeted delivery and microwave (MW) responsive drug release is investigated for development of HCC therapy. By encapsulating doxorubicin (DOX) and MW sensitizer (1-butyl-3-methylimidazolium-l-lactate, BML) into fucoidan conjugated liposomal nanoparticles (TBP@DOX), specific accumulation and prominent release of DOX in orthotopic HCC and lung metastasis are achieved with adjuvant MW exposure. This results in orthotopic HCC growth inhibition that is not only 1.95-fold higher than found for nontargeted BP@DOX and 1.6-fold higher than nonstimuli responsive TP@DOX but is also equivalent to treatment with free DOX at a 10-fold higher dose. Furthermore, the optimum anticancer efficacy against distant lung metastasis and effective prevention of widespread dissemination with a prolonged survival is described. In addition, no adverse metabolic events are identified using the TBP@DOX nanodelivery system despite these events being commonly observed with traditional DOX chemotherapy. Therefore, administering TBP@DOX with MW exposure could potentially enhance the therapeutic efficacy of thermal-chemotherapy of HCC, especially those in the advanced stages.

Amplified intracellular Ca2+ for synergistic anti-tumor therapy of microwave ablation and chemotherapy.

BACKGROUND: Developing new strategies to reduce the output power of microwave (MW) ablation while keeping anti-tumor effect are highly desirable for the simultaneous achievement of effective tumor killing and avoidance of complications. We find that mild MW irradiation can significantly increase intracellular Ca2+ concentration in the presence of doxorubicin hydrochloride (DOX) and thus induce massive tumor cell apoptosis. Herein, we designed a synergistic nanoplatform that not only amplifies the intracellular Ca2+ concentration and induce cell death under mild MW irradiation but also avoids the side effect of thermal ablation and chemotherapy. RESULTS: The as-made NaCl-DOX@PLGA nanoplatform selectively elevates the temperature of tumor tissue distributed with nanoparticles under low-output MW, which further prompts the release of DOX from the PLGA nanoparticles and tumor cellular uptake of DOX. More importantly, its synergistic effect not only combines thermal ablation and chemotherapy, but also obviously increases the intracellular Ca2+ concentration. Changes of Ca2+ broke the homeostasis of tumor cells, decreased the mitochondrial inner membrane potential and finally induced the cascade of apoptosis under nonlethal temperature. As such, the NaCl-DOX@PLGA efficiently suppressed the tumor cell progression in vivo and in vitro under mild MW irradiation for the triple synergic effect. CONCLUSIONS: This work provides a biocompatible and biodegradable nanoplatform with triple functions to realize the effective tumor killing in unlethal temperature. Those findings provide reliable solution to solve the bottleneck problem bothering clinics about the balance of thermal efficiency and normal tissue protection.

A novel platform for enhanced biosensing based on the synergy effects of electrospun polymer nanofibers and graphene oxides.

A novel biosensing platform was developed by combining the advantages of electrospun poly(vinyl alcohol) (PVA)/chitosan nanofibers and graphene oxides (GO). Glucose oxidase (GOD) was employed as a model enzyme. By co-electrospinning the solution of PVA, chitosan, GOD and GO, the PVA/chitosan/GOD/GO nanofibers were directly modified on the platinum (Pt) electrode. The UV-vis spectra and the FTIR spectra were used to characterize the GO nanosheets. The morphologies of fabricated electrospun nanofibers were characterized by high resolution scanning electron microscopy. After a thin layer of nafion was modified on the surface of matrix, the as-prepared electrode was used to detect glucose. The electrode exhibited great advantages in high sensitivity, low detection limit and wide linear range. In the meantime, the electrode showed good stability, acceptable reproducibility, and excellent anti-interference capability for ascorbic acid, uric acid, lactose and sucrose. Moreover, the novel biosensor was successfully applied for the glucose determination in human serum samples. The mechanism of efficient biosensing of the nafion/PVA/chitosan/GOD/GO/Pt electrode was analyzed in detail and the results show that it can be due to the synergy effects of electrospun nanofibers and GO nanosheets.

High Biocompatible Poly(lactic-co-glycolic acid)-Based Nanosensitizer With Magnetic Resonance Imaging Capacity for Tumor Targeted Microwave Hyperthermia and Chemotherapy.

Microwave (MW) hyperthermia has been widely studied in tumor therapy, while the lack of specificity, and the potential toxicity induced by instability or difficulty in degradation of existed MW thermal sensitizers still limits the application. Herein, a new biocompatible Poly(lactic-co-glycolic acid) (PLGA)-based nanosensitizer of Dtxl-Gd@PLGA-PEG-TPP (DGPPT) with capacities of magnetic resonance (MR) imaging and mitochondrial targeting for MW hyperthermia combined with chemotherapy was constructed via a double emulsion solvent evaporation method. The modified TPP significantly enhanced the specificity of sensitizer for targeting mitochondria, a heat-sensitive energy supply plant in cells. Thus the MW thermal damage induced by the loaded Gd in PLGA nanospheres was also strengthened. Together, the system could also achieve MR imaging due to the existence of Gd. In addition, the encapsulated Dtxl performed the chemotherapy of inhibiting mitochondrial function for assisting with MW hyperthermia. In vivo experiments demonstrated that PLGA had high biocompatibility that no obvious damage occurred even the dose was up to 200 mg/kg. Meanwhile, DGPPT+MW representing the combination of mitochondrial targeting and MW hyperthermia-chemotherapy has also been proved to shrink tumor size effectively. This study provides a new direction for building biosafe and multifunctional MW sensitizer with active targeting ability to impede tumor growth.

Hollow nanospheres based on the self-assembly of alginate-graft-poly(ethylene glycol) and α-cyclodextrin.

This article studies the self-assembly of alginate-graft-poly(ethylene glycol) (Alg-g-PEG) and α-cyclodextrin (α-CD) in aqueous solution. It was found that they could form hollow spheres because of the formation of coil-rod Alg-g-PEG/α-CD inclusion complexes. In these Alg-g-PEG/α-CD complexes, the α-CDs are stacked along the PEG side chains to form a rod block, and alginate main chains act as a coil block. More rod-like blocks in Alg-g-PEG/α-CD favor the formation of small assemblies. The assemblies of Alg-g-PEG/α-CD show a dependence on concentration, temperature, pH, and salt concentration. At low concentration (below 0.125%) or high temperature (above 32 °C), Alg-g-PEG/α-CD particles were unstable and disrupted. Increasing the salt or decreasing the pH resulted in the aggregation of Alg-g-mPEG/α-CD particles, as detected by the increase in the recorded hydrodynamic diameter (D(h)).

Photothermal photodynamic therapy and enhanced radiotherapy of targeting copolymer-coated liquid metal nanoparticles on liver cancer.

The maximized therapeutic efficacy in tumor treatment can be achieved with combination therapy. Herein, a metronidazole (MN) and RGD peptides were linked with the copolymer chains of polyacrylic acid (PAA) and polyethylene glycol (PEG) by condensation and Michael addition reactions, respectively, named as RGD-PEG-PAA-MN. Subsequently, liquid-metal (LM) nanoparticles broken by ultrasonication were coated with modified copolymer, forming RGD-PEG-PAA-MN@LM nanoparticles. These nanoparticles with the degradation under an acidic condition could target to tumor cells, and LM of these composited nanoparticles could not only efficiently convert the photoenergy of near infrared (NIR) into thermal energy, but also produce more reactive oxygen species under NIR or X ray irradiation. Furthermore, MN in the composited nanoparticles could enhance their radiation sensitivity of tumor tissues with hypoxia condition. The synergic effect of these nanoparticles on cancer limitation after the sequential radiations of NIR and X ray was significantly higher than the single radiation. In the experiments of tumor bearing mice, the volume of the tumor in RGD-PEG-PAA-MN@LM group at 14th day after two radiations of NIR and X-ray were significantly smaller than LM group, and the tumor of RGD-PEG-PAA-MN@LM group at 14th day after two radiations almost disappeared, suggesting better synergistic effect of RGD-PEG-PAA-MN@LM nanoparticles on photothermal conversion, photodynamics under two irradiations and their enhanced sensitization of X-ray radiation. Our results indicated that the prepared nanoparticles would be applied in the combinational therapy of liver tumor by the photothermal, photodynamic and sensitized radiation.

l-Cysteine decorated nanoscale metal-organic frameworks delivering valproic acid/cisplatin for drug-resistant lung cancer therapy.

We design multifunctional CDDP-VPA@ZrMOF-Cys-PEG nanoparticles (CVZP NPs) based on the properties of valproic acid (VPA) that can downregulate the expression of vascular endothelial growth factor (VEGF) to reduce the drug resistance of tumor cells. In vivo experiments confirm that chemotherapy combined with microwave thermal therapy (MWTT) can significantly improve the therapeutic effect of cisplatin-resistant lung cancer.

Preparation and characterization of Keratin-PEG conjugate-based micelles as a tumor microenvironment-responsive drug delivery system.

Keratin-based drug carriers have attracted great interest due to their intrinsic biocompatibility and tumor micro-environmental responsiveness. In the study, keratin was first extracted from human hair with reduction method. The reduced keratin was successively conjugated with poly(ethylene glycol) (PEG) via thiol Michael addition reaction and iodoacetic acid (IAA) via substitution reaction to impart both physical stability and acidity responsiveness. Subsequently, the conjugated keratin was fabricated into micelles and loaded with doxorubicin (DOX) by self-assembly. The micelles exhibited pH, glutathione (GSH) and enzyme (trypsin) triple-responsiveness as well as charge reversibility under the simulated tumor microenvironment. These drug-loaded micelles exhibited high toxicity against A549 cells with low side effect on normal cells. Furthermore, anticancer efficacy in vivo revealed DOX-loaded micelles presented higher therapeutic efficiency than free DOX. Moreover, these micelles were stable under physiological conditions, and could be internalized through endocytosis without hemolysis. Based on the results, the drug-loaded micelles were satisfactory candidates for drug carriers.

High Biocompatible ZIF-8 Coated by ZrO2 for Chemo-microwave Thermal Tumor Synergistic Therapy.

The zeolitic imidazolate framework-8 (ZIF-8) is a specifically promising drug carrier due to its excellent intrinsic properties. However, the high toxicity of ZIF-8 nanoparticles severely limits their further research and clinical application. In this work, the biocompatibility of ZIF-8 nanoparticles is greatly improved by coating ZrO2 onto the surface. The survival rate of cells and mice in the ZIF-8@ZrO2 nanocomposite group is significantly increased compared with the undecorated ZIF-8 nanoparticle group. Doxorubicin (DOX) as a chemotherapeutic drug is deposited during the ZIF-8 growth by a facile one-pot method. Ionic liquid (IL) is loaded into the pore of the ZIF-8/DOX@ZrO2 nanocomposites for enhancing microwave thermal therapy. The tumor inhibition rate of ZIF-8/DOX@ZrO2@IL nanocomposites with synergistic microwave thermal therapy and chemotherapy is obviously higher than in other groups. In addition, the ZIF-8/DOX@ZrO2@IL nanocomposites are used for real-time monitoring of the therapeutic outcomes due to the excellent computed tomography contrast agent, ZrO2. Therefore, such a ZrO2 coating strategy shows great promise for overcoming high toxicity of ZIF-8 nanoparticles, which offers a new platform for tumor synergistic microwave thermal therapy and chemotherapy using the ZIF-8/DOX@ZrO2@IL nanocomposite as a theranostic nanocarrier.

Multifunctional and flexible ZrO2-coated EGaIn nanoparticles for photothermal therapy.

With extensive investigations involving liquid metals (LMs), Ga-based LMs have attracted increasing attention from biomedical researchers because of their good biocompatibility, ideal fluidity, and high thermal conductivity. LMs employed in cancer treatment suffer from high surface tension, thereby yielding unstable nanoparticles (NPs). Here, ZrO2 is coated onto LM NPs to form a stable core-shell nanostructure. In particular, LM NPs coated with ZrO2 and modified by PEG (LM@pZrO2 NPs) still maintain favorable flexibility, which is beneficial for cellular uptake. With regard to the photothermal properties of LM, LM@pZrO2 NPs rapidly warm up and emit the requisite amount of heat under NIR laser radiation. It is confirmed that LM@pZrO2 NPs are more effectively internalized by cells and are beneficial for tumor photothermal therapy. This research provides a coating strategy to fabricate a stable and flexible core-shell LM nanostructure, making it a promising vehicle for nanotheranostics.

Hydroxyapatite coating by electrophoretic deposition at dynamic voltage.

The aim of this study was to evaluate hydroxyapatite (HA) coatings produced by dynamic voltage during electrophoretic deposition (EPD). Dynamic voltages from 0 to 200 V were incrementally applied in three interims. The as-deposited coating was sintered at 800 degrees C and its properties evaluated. Structure and phase analyses of both as-deposited and sintered coatings were evaluated by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The HA coatings obtained by dynamic voltage consisted of two layers. While the inner layer was dense and firmly attached to the substrate and contained fine HA particles, the outer layer was porous and contained bigger particles. Repeated deposition was applied to increase the thickness of the coatings. SEM analysis showed that these coatings were free of cracks. In addition, decomposition of HA coatings was not observed until 800 degrees C.

Interlayer expansion of 2D MoS2 nanosheets for highly improved photothermal therapy of tumors in vitro and in vivo.

Interlayer-expanded MoS2 (E-MoS2) nanosheets with an interlayer spacing of 0.94 nm are demonstrated to show an high photothermal conversion efficiency of ∼62%. More importantly, such biocompatible E-MoS2 nanosheets show highly improved photothermal therapy (PTT) of tumors in vitro and in vivo under near-infrared light irradiation.

Biocompatible and biodegradable zeolitic imidazolate framework/polydopamine nanocarriers for dual stimulus triggered tumor thermo-chemotherapy.

Zeolitic imidazolate frameworks (ZIFs) have attracted great interest as pH-sensitive drug carrier because of high drug loading and intrinsic biodegradability. In this work, a biocompatible NIR and pH-responsive drug delivery nanoplatform based on ZIFs (PDA-PCM@ZIF-8/DOX) is synthesized for in vivo cancer therapy. The biocompatibility of ZIFs is greatly improved by polydopamine (PDA) modifying and proved by cytotoxicity and in vivo acute toxicity evaluation. The degradability is also regulated in an appropriate rate. Due to mild reaction condition of ZIFs, the synthesis and drug loading is achieved in one pot with high loading (37.86%) and encapsulation rate (78.76%). Meanwhile, PDA acts as a photothermal transfer agent to trigger thermal response switch of phase change materials for NIR controlled drug release. Under the dual stimulus of NIR and acid environment, the drug release is as high as 78%, while only 21% is released without stimulus, showing a remarkable effect of control release. In vivo anti-tumor experiments demonstrate the high tumor inhibition rate of photothermal-chemotherapy group with a significant synergistic effect. The biocompatible and biodegradable drug delivery platform based on ZIFs has shown great promise for future clinic cancer therapy.

Mitochondria-targeted zirconium metal-organic frameworks for enhancing the efficacy of microwave thermal therapy against tumors.

Although microwave (MW) thermal therapy has been widely studied for the treatment of tumors due to its less invasiveness, recurrence of tumors is still observed because of the relatively low bioavailability of MW sensitizers. For enhancing the bioavailability of MW sensitizers, triphenyl phosphate (TPP)-conjugated and doxorubicin (DOX)-loaded porous zirconium metal-organic framework nanocubes (ZrMOF NCs) modified with polyethylene glycol (PEG), ZrMOF-PEG-TPP@DOX NCs, were prepared as a MW sensitizer with mitochondrial-targeting ability. Moreover, the mitochondria are more susceptible to heat than the tumor tissues; this leads to improved tumor cell apoptosis. The results of this study indicate that ZrMOF NCs exhibit excellent heating effects due to the increased collisions of ions in the micropores of ZrMOFs under MW irradiation. In addition, ZrMOF-PEG-TPP@DOX NCs show preferential aggregation in the mitochondria, confirmed by confocal microscopy images. In vivo MW thermal therapeutic efficacy of ZrMOF-PEG-TPP@DOX NCs + MW is also better without recurrence during treatment than that of ZrMOF-PEG@DOX NCs + MW at a similar thermal therapeutic temperature; this reveals that the mitochondrial-targeting strategy can enhance the MW thermal therapeutic efficacy. This study provides a new biosafe MW sensitizer with mitochondrial-targeting ability for enhancing the efficacy of MW thermal therapy against tumors.

Imaging-guided synergetic therapy of orthotopic transplantation tumor by superselectively arterial administration of microwave-induced microcapsules.

It is an ambitious target to improve overall Hepatocellular Carcinoma therapeutic effects. Recently, MW ablation has emerged as a powerful thermal ablation technique, affording favorable survival with excellent local tumor control. To achieve better therapeutic effects of MW ablation, MW sensitizers are prepared for enhanced MW ablation to preferentially heat tumor territory. However, it is still not practicable for treatment of the orthotopic transplantation tumor. Herein, biocompatible and degradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) microcapsules with hierarchical structure have been designed for microwave-induced tumor therapy. Chemical drug doxorubicin hydrochloride (DOX·HCl), microwave (MW) sensitizers and CT imaging contrast MoS2 nanosheets and MR imaging contrast Fe3O4 nanoparticles are co-incorporated into the microcapsules. In vitro/vivo MR/CT dual-modal imaging results prove the potential application for guiding synergetic therapy and predicting post-therapy tumor progression in the orthotopic transplantation tumor model. After blocking the tumor-feeding arteries, these microcapsules not only exclude the cooling effect by cutting off the blood flow but also enhance MW heating conversion at tumor site. The focused MW heating makes microcapsules mollescent or ruptured and releases DOX·HCl from the microcapsules, achieving the controlled release of drugs for chemical therapy. Compared with MW ablation, 29.4% increase of necrosis diameter of normal liver in rabbit is obtained under MW ablation combined with transcatheter arterial blocking, and the average size of necrosis and inhibition rate of VX-2 liver orthotopic transplantation tumor in rabbit has increased by 129.33% and 73.46%. Moreover, it is proved that the superselectively arterial administration of the as-prepared microcapsules has no recognizable toxicity on the animals. Therefore, this research provides a novel strategy for the construction of MW-induced microcapsules for orthotopic transplantation tumor ablation with the properties of MW sensitizing, superselective arterial blocking, control release and enhanced accumulation of DOX·HCl, and MR/CT dual-modal imaging, which exhibits great potential applications in the field of HCC therapy.

Therapeutic efficacy of novel microwave-sensitized mPEG-PLGA@ZrO2@(DOX + ILS) drug-loaded microspheres in rabbit VX2 liver tumours.

The use of nanomaterials as drug delivery systems shows good effects in treating tumors. However, the effective dose of drugs targeted to tumor tissues is very low because of the effect of the reticuloendothelial system (RES) in removing such foreign substances. In order to eliminate the RES effect, we developed mPEG-PLGA@ZrO2@(DOX + ILS) (mPEG-PLGA@ZrO2@[DOX + ILS]) drug-loaded microspheres. These microwave (MW)-sensitized microspheres directly embolized the blood-supply vessels of tumors to induce tumor ischemia and hypoxia, as well as to aggregate drugs within tumor tissues in a long-lasting manner. Additionally, combination with MW ablation can triple the effects for the inhibition of tumor growth. The MW sensitive ionic liquid (ILS) in microspheres can rapidly produce a high temperature in a MW field on the basis of MW sensitization, thus accelerating the degradation of microspheres to release DOX-loaded ZrO2 into the lesions to kill tumors. Microspheres can also prolong the pharmacological time and effect of drugs through the enhanced permeability and retention (EPR) effect of nanocarriers, as well as the sustained release of nanomaterials. Studies performed in vivo revealed that mPEG-PLGA@ZrO2@(DOX + ILS) showed good biosafety. We undertook sensitized microsphere embolism therapy using novel mPEG-PLGA@ZrO2@(DOX + ILS) microspheres in a rabbit VX2 liver tumor model. Three, 6 and 9 d after treatment, computed tomography indicated no significant change in tumor size, and diffusion weighted imaging showed a marked decrease of residual tumor tissues. With the multiple functions of inducing embolisms, sensitization, and the sustained release of chemotherapeutics, novel mPEG-PLGA@ZrO2@(DOX + ILS) microspheres can achieve good therapeutic efficacy, in combination with MW ablation and chemotherapy, while embolizing the blood vessels of arterial tumors.

Effects of applied voltages on hydroxyapatite coating of titanium by electrophoretic deposition.

Hydroxyapatite (HA) coatings were deposited on titanium substrates by electrophoretic deposition (EPD) at constant voltage and dynamic voltage, respectively. Various surface morphologies were observed under different type of voltages. Under a constant voltage of 20 V, a dense HA coating could be prepared. Under a constant voltage of 200 V, big HA particles were deposited and the coating was porous. Under a dynamic voltage, a continuous gradient HA coating could be obtained. HA coatings were characterized with a field emission-scanning electron microscopy (FE-SEM) and an X-ray diffraction (XRD). XRD indicated no significant HA decomposition when the coatings were sintered for 2 h at 800 degrees C.

Biocompatible Hollow Polydopamine Nanoparticles Loaded Ionic Liquid Enhanced Tumor Microwave Thermal Ablation in Vivo.

Tumor microwave thermal therapy (MWTT) has attracted more attention because of the minimal damage to body function, convenient manipulation and low complications. Herein, a novel polydopamine (PDA) nanoparticle loading ionic liquids (ILs/PDA) as microwave susceptible agent is introduced for enhancing the selectivity and targeting of MWTT. ILs/PDA nanocomposites have an excellent microwave heating efficiency under an ultralow microwave power irradiation. Encouraging antitumor effect was observed when tumor bearing mice received ILs/PDA nanoparticles by intravenous injection and only single microwave irradiation. PDA nanoparticles with gold nanoparticles in core were constructed for tumor targeting study by ICP-MS and about 15% PDA nanoparticles were founded in tumor. Furthermore, the cytotoxicity and acute toxicity study in vivo of PDA showed the excellent biocompatibility of ILs/PDA nanocomposites. In addition, the degradation of ILs/PDA nanocomposites in simulated body fluid illustrated the low potential hazard when they entered the blood. The emergence of PDA as a novel and feasible platform for cancer thermal therapy will promote the rapid development of microwave therapy in clinics.

Using silver nanoparticle to enhance current response of biosensor.

In this paper, we present a simple procedure to increase the sensitivity of a glucose biosensor. The feasibility of an amperometric glucose biosensor based on immobilization of glucose oxidase (GOx) in silver (Ag) sol was investigated for the first time. GOx was simply mixed with Ag nanoparticles and cross-linked with a polyvinyl butyral (PVB) medium by glutaraldehyde. Then a platinum electrode was coated with the mixed solution. The effects of the amount of the Ag particles used, with respect to the current response for enzyme electrodes, were studied. A set of experimental results indicate that the current response for the enzyme electrode containing hydrophobic Ag sol increased from 0.531 to 31.17 microA in the solution of 10 mmol/L beta-D glucose. The time reaching the steady-state current response reduced from 60 to 20s, three times less than those without Ag particles involved.

One-pot synthesis of active copper-containing carbon dots with laccase-like activities.

Herein, an effective strategy for designing a new type of nanozyme, blue fluorescent laccase mimics, is reported. Active copper-containing carbon dots (Cu-CDs) were synthesized through a simple, nontoxic and one-pot hydrothermal method, which showed favorable photoluminescence properties and good photostability under high-salt conditions or in a broad pH range (3.0-13.5). The Cu-CDs possessed intrinsic laccase-like activities and could catalyze the oxidation of the laccase substrate p-phenylenediamine (PPD) to produce a typical color change from colorless to brown. Poly(methacrylic acid sodium salt) (PMAA) not only was used as the carbon source and reducing agent, but also provided carboxyl groups to assist flocculation between Cu-CDs and polyacrylamide, which facilitated the removal of PPD. Importantly, the intrinsic fluorescence of the as-prepared Cu-CDs could indicate the presence of hydroquinone, one of the substrates of laccases, based on laccase mimics and fluorescence quenching.