Recovery of Gallium-68 and Zinc from HNO3-Based Solution by Liquid-Liquid Extraction with Arylamino Phosphonates.

The cyclotron production of gallium-68 via the 68Zn(p,n)68Ga nuclear reaction in liquid targets is gaining significant traction in clinics. This work describes (1) the synthesis of new arylamino phosphonates via the Kabachnik-Fields reaction, (2) their use for liquid-liquid extraction of 68Ga from 1 M Zn(NO3)2/0.01 M HNO3 in batch and continuous flow, and (3) the use of Raman spectroscopy as a process analytical technology (PAT) tool for in-line measurement of 68Zn. The highest extraction efficiencies were obtained with the extractants functionalized with trifluoromethyl substituents and ethylene glycol ponytails, which were able to extract up to 90% of gallium-68 in batch and 80% in flow. Only ppm amounts of zinc were co-extracted. The extraction efficiency was a function of pKa and the aqueous solubility of the extractant and showed marked concentration, solvent, and temperature dependence. Raman spectroscopy was found to be a promising PAT tool for the continuous production of gallium-68.

In vitro and in vivo MRI imaging and photothermal therapeutic properties of Hematite (α-Fe2O3) Nanorods.

Herein we report synthesis of hematite (α-Fe2O3) nanorods by calcinating hydrothermally synthesized goethite nanorods at 5000C. The structural, optical and MRI imaging guided cancer therapeutic properties of fabricated nanorods have been discussed in this manscript. FESEM and TEM imaging techniques were used to confirm the nanorod like morphology of as prepared materials. As we know that Fe2O3 nanorods with size in the range of 25-30 nm exhibit super magnetism. After coating with the PEG, the as prepared nanorods can be used as T2 MR imaging contrast agents. An excellent T2 MRI contrast of 38.763 mM-1s-1 achieved which is highest reported so far for α-Fe2O3. Besides the as prepared nanorods display an excellent photothermal conversion efficiency of 39.5% thus acts as an excellent photothermal therapeutic agent. Thus, we envision the idea of testing our nanorods for photothermal therapy and MR imaging application both in vitro and in vivo, achieving an excellent T2 MRI contrast and photothermal therapy effect with as prepared PEGylated nanorods.

In situ oxygenating and 808 nm light-sensitized nanocomposite for multimodal imaging and mitochondria-assisted cancer therapy.

The efficiency of photodynamic therapy (PDT) is severely constrained due to the innate hypoxic environment, besides the elevated level of glutathione (GSH). To get rid of the hypoxic environment and higher concentrations of GSH in the solid tumors, we propose an approach of oxygen self-sufficient multimodal imaging-guided nanocomposite CaO2-MnO2-UCNPs-Ce6/DOX (abbreviated as CaMn-NUC), in which CaO2 nanoparticles in the hydrophobic layer were seated on the hydrophilic MnO2 sheet and conjugated with chlorin e6 (Ce6) loaded upconversion nanoparticles (UCNPs-Ce6) via the click chemistry approach. CaMn-NUC was presented to overcome hypoxia and GSH-associated photodynamic resistance due to in situ oxygen generation and GSH reduction of MnO2 upon endocytosis, and a bulk amount of Mn2+ ions generated in the process under acidic tumor environment acts as the MRI contrast agent. Moreover, the MnO2 sheet protects Ce6 from self-degradation under irradiation; thus, it can be used to switch control of cellular imaging. Afterwards, in a regulated and targeted manner, the chemotherapeutic drug (doxorubicin hydrochloride, DOX) can be released with the degradation of CaMn-NUC in the acidic tumor microenvironment (TME). Thus, we testify a competent nanoplatform employing 808 nm-excited UCNPs-Ce6 for concurrent imaging and PDT in consideration of the large anti-Stokes shifts, deep penetration into biological tissues, narrow emission bands, and high spatial-temporal resolution of the UCNPs. Thus, our proposed nanoplatform postulates a strategy to efficiently kill cancer cells in a concentration- and time-dependent manner via the in situ oxygenation of solid tumor hypoxia to enhance the efficiency of multimodal imaging-guided chemo-photodynamic therapy.

Insight into the Luminescence Alternation of Sub-30 nm Upconversion Nanoparticles with a Small NaHoF4 Core and Multi-Gd3+ /Yb3+ Coexisting Shells.

It is absolutely imperative for development of material science to adjust upconversion luminescence (UCL) properties of highly doped upconversion nanoparticles (UCNPs) with special optical properties and prominent application prospects. In this work, featuring NaHoF4 @NaYbF4 (Ho@Yb) structures, sub-30 nm core-multishell UCNPs are synthesized with a small NaHoF4 core and varied Gd3+ /Yb3+ coexisting shells. X-ray diffraction, transmission electron microscopy, UCL spectrum, UCL lifetime, and pump power dependence are adhibited for characterization. Compared with the former work, except for a smaller total size, tunable emission in color from red to yellow to green, and intensity from low to stronger than that of traditional UCNPs is achieved for ≈10 nm NaHoF4 core size by means of changing number of layers and Gd3+ /Yb3+ concentration ratios in different layers. Besides, simultaneously doping Ho3+ into the shells will result in lowered UCL intensity and lifted green/red ratio. Surface energy loss and sensitizing energy supply, which can be modulated with inert shielding of Gd3+ and sensitization of Yb3+ , are proved to be the essential determinant. More UCL properties of these peculiar Ho@Yb UCNPs are uncovered and detailedly summarized, and the findings can help to expand the application scope of NaHoF4 into photoinduced therapy.

X-ray-triggered NO-released Bi-SNO nanoparticles: all-in-one nano-radiosensitizer with photothermal/gas therapy for enhanced radiotherapy.

Hypoxia in tumor cells is regarded as the most crucial cause of clinical drug resistance and radio-resistance; thus, relieving hypoxia of tumor cells is the key to enhancing the efficacy of anticancer therapy. As a gas signal molecule of vasodilatation factors, nitric oxide (NO) can relieve the hypoxia status of tumor cells, thereby, enhancing the sensitivity of tumor cells to radiotherapy. However, considering complications of vascular activity, the level of NO required for radiotherapy sensitization cannot be obtained in vivo. In view of this, we design and fabricate a multifunctional bismuth-based nanotheranostic agent, which is functionalized with S-nitrosothiol and termed Bi-SNO NPs. X-rays break down the S-N bond and simultaneously trigger large amount of NO-releasing (over 60 µM). Moreover, the as-prepared Bi-SNO NPs not only possess the capability of absorbing and converting 808 nm NIR photons into heat for photothermal therapy, but also have the ability to increase X-ray absorption and CT imaging sensitivity. In addition, the collaborative radio-, photothermal-, and gas-therapy of Bi-SNO in vivo was further investigated and remarkable synergistic tumor inhibition was realized. Finally, no obvious toxicity of Bi-SNO NPs was observed in the treated mice within 14 days. Therefore, the Bi-SNO developed in this work is an effective nano-agent for cancer theranostics with well-controlled morphology and uniform size (36 nm), which could serve as a versatile CT imaging-guided combined radio-, photothermal- and gas-therapy nanocomposite with negligible side effects.

Correction: Y2O3:Yb,Er@mSiO2-CuxS double-shelled hollow spheres for enhanced chemo-/photothermal anti-cancer therapy and dual-modal imaging.

Correction for 'Y2O3:Yb,Er@mSiO2-CuxS double-shelled hollow spheres for enhanced chemo-/photothermal anti-cancer therapy and dual-modal imaging' by Dan Yang et al., Nanoscale, 2015, 7, 12180-12191, DOI: 10.1039/C5NR02269J.

Correction: Nano-graphene oxide-UCNP-Ce6 covalently constructed nanocomposites for NIR-mediated bioimaging and PTT/PDT combinatorial therapy.

Correction for 'Nano-graphene oxide-UCNP-Ce6 covalently constructed nanocomposites for NIR-mediated bioimaging and PTT/PDT combinatorial therapy' by Arif Gulzar et al., Dalton Trans., 2018, 47, 3931-3939.

In vitro effects of cobalt nanoparticles on aspartate aminotransferase and alanine aminotransferase activities of wistar rats.

Cobalt nanoparticles (Co-NPs) have been extensively used in clinical practices and medical diagnosis. In this study, the potential toxicity effects of Co-NPs with special emphasis over the biochemical enzyme activities, such as aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) in serum, liver, and kidney of Wistar rats were investigated. This toxicity measurement of nanomaterials can support the toxicological data. The biochemical enzymatic variations are powerful tools for the assessment of toxicity. ASAT and ALAT enzymes have been widely used to predict tissue-specific toxicities associated with xenobiotic. The biochemical changes induced by Co-NPs have significance in their toxicological studies because the alterations in biochemical parameters before clinical symptoms indicate either their toxicant safety or detrimental effect. Herein, Co-NPs with particle size <50 nm significantly activated ASAT and ALAT enzymes in the serum, liver, and kidney of rats at concentration-dependent order.

An 808 nm Light-Sensitized Upconversion Nanoplatform for Multimodal Imaging and Efficient Cancer Therapy.

Photodynamic therapy (PDT) is commonly employed in clinics to treat the cancer, but because of the hypoxic tumor microenvironment prevalent inside tumors, PDT therapeutic efficiency is not adequate hence limiting the effectiveness of PDT. Therefore, we designed a nanocomposite consisting of reduced nanographene oxide (rGO) modified with polyethylene glycol (PEG), manganese dioxide (MnO2), upconversion nanoparticles (UCNPs), and Chlorin e6 (Ce6) to spark oxygen production from H2O2 with the aim of relieving the tumor hypoxic microenvironments. For in vivo tumor PDT and photothermal therapy (PTT), UCNPs-Ce6-labeled rGO-MnO2-PEG nanocomposites were used as a therapeutic agent, augmenting the therapeutic efficiency of PDT via redox progression through the catalytic H2O2 decomposition pathway and further achieving excellent tumor inhibition. It is important to mention that degradation of MnO2 in an acidic cellular microenvironment leads to the creation of a massive volume of Mn2+ which was employed as a contrast mediator for magnetic resonance imaging (MRI). Our research postulates an approach to spark O2 formation through an internal stimulus to augment the efficiency of MRI- and computerized tomography (CT)-imaging-guided PDT and PTT.

Tumor self-responsive upconversion nanomedicines for theranostic applications.

To date, malignant tumors continue to be the most lethal disease, causing more than 8.2 million deaths worldwide each year. In recent years, nanostructures based on rare-earth upconversion luminescent nanoparticles have shown significant advantages in the integration of multimodal imaging and therapy. Compared with normal tissues, the tumor microenvironment (TME) exhibits unique characteristics including high interstitial fluid pressure, abnormal blood vessels, a hypoxic and slightly acidic environment, and high levels of glutathione (GSH) and hydrogen peroxide (H2O2). According to these characteristics, increasing attention in the antitumor field has been given to designing nanomedicines with specific responses to the TME based on rare-earth upconversion nanoparticles (UCNPs) and to achieving efficient tumor diagnosis and treatment under the premise of reducing side effects. Nevertheless, a review that systematically summarizes TME-responsive upconversion nanomedicines (UCNMs) for realizing tumor self-enhanced theranostics has not been published to date. In this review, we summarize the recent progress made in UCNP-based nanotherapeutics by highlighting the increasingly developing trend of TME-responsive UCNMs. The general characteristics of the TME are introduced in detail and their utilization in designing TME-responsive UCNMs is systematically discussed. Based on NIR light-excited optical imaging, we discuss the superiority of UCNMs when applied in tumor theranostics with an emphasis on how to use them to realize TME-mediated multimodal imaging-guided therapy.

Redox-responsive UCNPs-DPA conjugated NGO-PEG-BPEI-DOX for imaging-guided PTT and chemotherapy for cancer treatment.

The disulfide bond (-S-S-) is an enormously valuable functional group in a variety of chemical and biological agents that display effective reactivity or biological activities (e.g., antitumor activities). The disulfide bonds prevalent in proteins are somewhat oxidizing in the extracellular space; however, such disulfide bonds can rarely be found inside cells because of disulfide cleavage reactions facilitated by abundant free cellular thiols, including glutathione (GSH), which is the most important common thiol-containing small molecule. Interestingly, intracellular GSH concentrations are considerably higher in cancer cells than in analogous normal cells; this feature may prove to be significant in the development of anticancer drug delivery systems (DDS). Moreover, upconversion nanoparticles (UCNPs) have been extensively investigated in multimodal imaging, photodynamic therapy (PDT) and photothermal therapy. UCNPs exploit near-infrared excitation instead of ultraviolet excitation and possess exclusive properties, which include greatly increased penetration depth in biological samples and reductions in background autofluorescence, photobleaching and photodamage to biological specimens. These fascinating optical features of UCNPs may broaden their prospects in the fields of imaging and therapy. Graphene has emerged as a flat monolayer of carbon atoms that are tightly embedded in a two-dimensional (2D) honeycomb lattice. Widespread research has been carried out on graphene in recent years owing to its exclusive shape and size, as well as innumerable fascinating physical and chemical properties. Owing to their high optical absorption in the near-infrared (NIR) region, graphene and GO have been extensively employed for photothermal therapy (PTT). In this study, we attempted to merge the properties of these compounds by conjugating UCNPs and NGO-PEG-BPEI-DOX into a single platform for chemotherapy and photothermal therapy.

Nano-graphene oxide-UCNP-Ce6 covalently constructed nanocomposites for NIR-mediated bioimaging and PTT/PDT combinatorial therapy.

NIR light-induced imaging-guided cancer therapy is an encouraging route in the cancer theranostic field. Herein, we describe a novel nanoscale proposal, which is established by covalently implanting core-shell structured upconversion nanoparticles (UCNPs) with nanographene oxide (NGO) by a process utilizing polyethylene glycol (PEG), and consequently loading Chlorin e6 (Ce6) onto the surface of NGO. The acquired NGO-UCNP-Ce6 (NUC) nanocomposites can not only be employed as upconversion luminescence (UCL) imaging probes of cells and whole-body animals with high contrast for diagnosis, but also can generate reactive oxygen species (ROS) under 808 nm light excitation for photodynamic therapy (PDT); over and above, they can swiftly and proficiently translate the 808 nm photon into thermal energy for photothermal therapy (PTT). An extraordinarily enhanced and synchronized therapeutic effect paralleled to the individual PTT or PDT is achieved, rendering extraordinary therapeutic effectiveness for cancer treatment. Consequently, profiting from this inimitable multifunctional nanohybrid, the NUCs synthesized here are encouraging as a cohesive theranostic probe for impending UCL imaging-guided combinatorial PDT/PTT.

Au Nanoclusters Sensitized Black TiO2-x Nanotubes for Enhanced Photodynamic Therapy Driven by Near-Infrared Light.

The low reactive oxygen species production capability and the shallow tissue penetration of excited light (UV) are still two barriers in photodynamic therapy (PDT). Here, Au cluster anchored black anatase TiO2-x nanotubes (abbreviated as Au25 /B-TiO2-x NTs) are synthesized by gaseous reduction of anatase TiO2 NTs and subsequent deposition of noble metal. The Au25 /B-TiO2-x NTs with thickness of about 2 nm exhibit excellent PDT performance. The reduction process increased the density of Ti3+ on the surface of TiO2 , which effectively depresses the recombination of electron and hole. Furthermore, after modification of Au25 nanoclusters, the PDT efficiency is further enhanced owing to the changed electrical distribution in the composite, which forms a shallow potential well on the metal-TiO2 interface to further hamper the recombination of electron and hole. Especially, the reduction of anatase TiO2 can expend the light response range (UV) of TiO2 to the visible and even near infrared (NIR) light region with high tissue penetration depth. When excited by NIR light, the nanoplatform shows markedly improved therapeutic efficacy attributed to the photocatalytic synergistic effect, and promotes separation or restrained recombination of electron and hole, which is verified by experimental results in vitro and in vivo.

Upconversion processes: versatile biological applications and biosafety.

Lanthanide-doped photon upconverting nanomaterials are evolving as a new class of imaging contrast agents, offering highly promising prospects in the area of biomedical applications. Owing to their ability to convert long-wavelength near-infrared excitation radiation into shorter-wavelength emissions, these nanomaterials are well suited to yield properties of low imaging background, large anti-Stokes shift, along with high optical penetration depth of NIR light for deep tissue optical imaging or light-activated drug release and therapy. Such materials have potential for significant advantages in analytical applications compared to molecular fluorophores and quantum dots. The use of IR radiation as an excitation source diminishes autofluorescence and scattering of excitation radiation, which leads to a reduction of background in optical experiments. The upconverting nanocrystals show exceptional photostability and are constituted of materials that are not significantly toxic to biological organisms. Excitation at long wavelengths also minimizes damage to biological materials. In this detailed review, various mechanisms operating for the upconversion process, and methods that are utilized to synthesize and decorate upconverting nanoparticles are investigated to elucidate by what means absorption and emission can be tuned. Up-to-date reports concerning cellular internalization, biodistribution, excretion, cytotoxicity and in vivo toxic effects of UCNPs are discussed. Specifically, studies which assessed the relationship between the chemical and physical properties of UCNPs and their biodistribution, excretion, and toxic effects are reviewed in detail. Finally, we also deliberate the challenges of guaranteeing the biosafety of UCNPs in vivo.

Integration of IR-808 Sensitized Upconversion Nanostructure and MoS2 Nanosheet for 808 nm NIR Light Triggered Phototherapy and Bioimaging.

Near infrared (NIR) light triggered phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) affords superior outcome in cancer treatment. However, the reactive oxygen species (ROS) generated by NIR-excited upconversion nanostructure is limited by the feeble upconverted light which cannot activate PDT agents efficiently. Here, an IR-808 dye sensitized upconversion nanoparticle (UCNP) with a chlorin e6 (Ce6)-functionalized silica layer is developed for PDT agent. The two booster effectors (dye-sensitization and core-shell enhancement) synergistically amplify the upconversion efficiency, therefore achieving superbright visible emission under low 808 nm light excitation. The markedly amplified red light subsequently triggers the photosensitizer (Ce6) to produce large amount of ROS for efficient PDT. After the silica is endowed with positive surface, these PDT nanoparticles can be easily grafted on MoS2 nanosheet. As the optimal laser wavelength of UCNPs is consistent with that of MoS2 nanosheet for PTT, the invented nanoplatform generates both abundant ROS and local hyperthermia upon a single 808 nm laser irradiation. Both the in vitro and in vivo assays validate that the innovated nanostructure presents excellent cancer cell inhibition effectiveness by taking advantages of the synergistic PTT and PDT, simultaneously, posing trimodal (upconversion luminescence/computed tomography (CT)/magnetic resonance imaging (MRI) imaging capability.

Lanthanide-doped bismuth oxobromide nanosheets for self-activated photodynamic therapy.

Low tissue penetration depth of the excited light and complicated synthetic procedures greatly hinder the clinical application of photodynamic therapy (PDT). Here we present a facile and mass production route to fabricate Yb3+/Tm3+ co-doped BiOBr nanosheets. In contrast to the complicated combination of photosensitizers (PSs) with up-conversion nanoparticles (UCNPs), which generates a PDT effect by a fluorescence resonance energy transfer process from UCNPs to PSs upon near-infrared light excitation, this as-synthesized material can be self-activated by deep-penetrating 980 nm laser light to produce a large amount of reactive oxygen species, giving rise to a high PDT efficiency which has been proven by in vitro and in vivo therapeutic assays. Surface modification of the BiOBr:Yb,Tm nanosheets with polyethylene glycol endows the system with improved biocompatibility. Through the combination of inherent fluorescence and CT imaging properties, an imaging-monitored therapeutic system has been realized. The system overcomes the problems of low tissue penetration depth, complicated structure-induced low efficiency, and potential safety concerns. Our finding presents the first demonstration of a self-activated nanoplatform for targeted and noninvasive deep-cancer therapy.

Bioapplications of graphene constructed functional nanomaterials.

Graphene has distinctive mechanical, electronic, and optical properties, which researchers have applied to develop innovative electronic materials including transparent conductors and ultrafast transistors. Lately, the understanding of various chemical properties of graphene has expedited its application in high-performance devices that generate and store energy. Graphene is now increasing its terrain outside electronic and chemical applications toward biomedical areas such as precise bio sensing through graphene-quenched fluorescence, graphene-enhanced cell differentiation and growth, and graphene-assisted laser desorption/ionization for mass spectrometry. In this Account, we evaluate recent efforts to apply graphene and graphene oxides (GO) to biomedical research and a few different approaches to prepare graphene materials designed for biomedical applications and a brief perspective on their future applications. Because of its outstanding aqueous processability, amphiphilicity, surface functionalizability, surface enhanced Raman scattering (SERS), and fluorescence quenching ability, GO chemically exfoliated from oxidized graphite is considered a promising material for biological applications. In addition, the hydrophobicity and flexibility of large-area graphene synthesized by chemical vapor deposition (CVD) allow this material to play an important role in cell growth and differentiation. Graphene is considered to be an encouraging and smart candidate for numerous biomedical applications such as NIR-responsive cancer therapy and fluorescence bio-imaging and drug delivery. To that end, suitable preparation and unique approaches to utilize graphene-based materials such as graphene oxides (GOs), reduced graphene oxides (rGOs), and graphene quantum dots (GQDs) in biology and medical science are gaining growing interest.

Doxorubicin-conjugated CuS nanoparticles for efficient synergistic therapy triggered by near-infrared light.

To integrate photothermal therapy (PTT) with chemotherapy for improving anticancer efficiency, we developed a novel and multifunctional doxorubicin (DOX) conjugated copper sulfide nanoparticle (CuS-DOX NP) drug delivery system using hydrazone bonds to conjugate carboxyl-functionalized copper sulfide nanoparticles (CuS NPs) and DOX. On the other hand, the hydrazone bonds could be used for improving the DOX release rate (88.0%) by cleavage in a mildly acidic environment irradiated by 808 nm laser light, which could greatly promote chemo-therapeutic efficacy. Simultaneously, CuS NPs which can absorb near infrared (NIR) light produce a clear thermal effect, giving rise to a synergistic therapeutic effect combined with enhanced chemo-therapy. The DOX-conjugated CuS NPs display an evident in vitro cytotoxicity to HeLa cancer cells under 808 nm light irradiation. High tumor inhibition efficacy has been achieved after 14 day in vivo treatment, performed with intravenous administration of CuS-DOX NPs with 808 nm laser irradiation on H22 tumor-bearing mice. The multifunctional system which was achieved by a facile route should be a potential candidate in the anti-cancer field due to the synergistic therapeutic effect, which is superior to any single approach.

Synthesis, luminescence, and anti-tumor properties of MgSiO3:Eu-DOX-DPP-RGD hollow microspheres.

In this report, MgSiO3:Eu-DOX-DPP-RGD hollow microspheres employed for simultaneous imaging and anti-cancer therapy have been designed by sequentially loading the anti-tumor drugs doxorubicin (DOX), light-activated platinum(iv) pro-drug PPD, and a targeted peptide of NH2-Gly-Arg-Gly-Asp-Ser (RGD) onto MgSiO3:Eu mesoporous hollow spheres, which were synthesized using solid SiO2 spheres as sacrificed template by a facile hydrothermal process based on the Kirkendall effect. The photoluminescence intensity of MgSiO3:Eu has been optimized, which can emit a recognized red signal in vitro and in vivo under modest ultraviolet (UV) irradiation. It was found that the platform has high biocompatibility and could become intracellular through fast and effective endocytosis with the aid of the targeted peptide RGD, and chemotherapeutic drugs DOX and light-activated platinum(iv) pro-drug DPP that can be released from the carrier to induce an obvious inhabitation effect to HeLa cancer cells (survival rate of only 17.4%), which has been verified by in vitro and in vivo results. Moreover, the in vitro result using a photosensitizer ZnPc loaded carrier shows that the system is not suitable for ZnPc induced photodynamic therapy. The apparent imaging effect and high anti-tumor efficacy of this functional system give it great potential in actual clinical applications.