NIR-Light-Triggered Mild-Temperature Hyperthermia to Overcome the Cascade Cisplatin Resistance for Improved Resistant Tumor Therapy.

Currently, cisplatin resistance has been recognized as a multistep cascade process for its clinical chemotherapy failure. Hitherto, it remains challenging to develop a feasible and promising strategy to overcome the cascade drug resistance (CDR) issue for achieving fundamentally improved chemotherapeutic efficacy. Herein, a novel self-assembled nanoagent is proposed, which is constructed by Pt(IV) prodrug, cyanine dye (cypate), and gadolinium ion (Gd3+), for systematically conquering the cisplatin resistance by employing near-infrared (NIR) light activated mild-temperature hyperthermia in tumor targets. The proposed nanoagents exhibit high photostability, GSH/H+-responsive dissociation, preferable photothermal conversion, and enhanced cellular uptake performance. In particular, upon 785-nm NIR light irradiation, the generated mild temperature of ≈ 43 °C overtly improves the cell membrane permeability and drug uptake, accelerates the disruption of intracellular redox balance, and apparently enhances the formation of Pt-DNA adducts, thereby effectively overcoming the CDR issue and achieves highly improved therapeutic efficacy for cisplatin-resistant tumor ablation.

Protease-Mediated T1 Contrast Enhancement of Multilayered Magneto-Gadolinium Nanostructures for Imaging and Magnetic Hyperthermia.

In this work, we constructed a multifunctional composite nanostructure for combined magnetic hyperthermia therapy and magnetic resonance imaging based on T1 and T2 signals. First, iron oxide nanocubes with a benchmark heating efficiency for magnetic hyperthermia were assembled within an amphiphilic polymer to form magnetic nanobeads. Next, poly(acrylic acid)-coated inorganic sodium gadolinium fluoride nanoparticles were electrostatically loaded onto the magnetic nanobead surface via a layer-by-layer approach by employing a positively charged enzymatic-cleavable biopolymer. The positive-negative multilayering process was validated through the changes occurring in surface ζ-potential values and structural characterization by transmission electron microscopy (TEM) imaging. These nanostructures exhibit an efficient heating profile, in terms of the specific absorption rates under clinically accepted magnetic field conditions. The addition of protease enzyme mediates the degradation of the surface layers of the nanostructures with the detachment of gadolinium nanoparticles from the magnetic beads and exposure to the aqueous environment. Such a process is associated with changes in the T1 relaxation time and contrast and a parallel decrease in the T2 signal. These structures are also nontoxic when tested on glioblastoma tumor cells up to a maximum gadolinium dose of 125 µg mL-1, which also corresponds to a iron dose of 52 µg mL-1. Nontoxic nanostructures with such enzyme-triggered release mechanisms and T1 signal enhancement are desirable for tracking tumor microenvironment release with remote T1-guidance and magnetic hyperthermia therapy actuation to be done at the diseased site upon verification of magnetic resonance imaging (MRI)-guided release.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy.

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10-13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. STATEMENT OF SIGNIFICANCE: Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM-1s-1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

Effective mitigation of gadolinium deposition using the bidentate hydroxypyridinone ligand Me-3,2-HOPO.

With the extensive usage of gadolinium-based contrast agents (GBCAs) in magnetic resonance imaging (MRI), gadolinium deposition has been observed in the brain, kidneys, liver, etc., and this is also closely related to the development of nephrogenic systemic fibrosis (NSF) in patients with renal dysfunction. Chelation, thereby promoting the elimination of deposited Gd(III), seems to be promising for alleviating these problems. Despite many ligands suitable for chelation therapy having been studied, the decorporation of transition metals (e.g. iron, copper, lead, etc.) and actinides (e.g. uranium, plutonium, etc.) has long been a primary concern, whereas the study of Gd(III) has been extremely limited. Due to their excellent metal binding abilities in vivo and therapeutic effects toward neurodegenerative diseases, bidentate hydroxypyridinone ligands are expected to be able to remove Gd(III) from the brain, kidneys, bones, and liver. Herein, the Gd(III) decorporation efficacy of a bidentate hydroxypyridinone ligand (Me-3,2-HOPO) has been evaluated. The complexation behavior between Me-3,2-HOPO and Gd(III) in solution and solid states was characterized with the assistance of potentiometric titration and X-ray diffraction techniques, respectively. Solution-based thermodynamic studies illustrate that the dominant species of complex between Gd(III) and Me-3,2-HOPO (HL) is GdL2+ (log ß120 = 11.8 (3)) at pH 7.4. The structure of the Gd-Me-3,2-HOPO crystal obtained from a room temperature reaction reveals the formation of a Gd(III) dimer that is chelated by four ligands as a result of metal ion hydration and ligand complexation. Cellular Gd(III) removal assays illustrate that Me-3,2-HOPO could effectively reduce final amounts of gadolinium by 77.6% and 66.1% from rat renal proximal tubular epithelial (NRK-52E) cells and alpha mouse liver 12 (AML-12) cells, respectively. Our current results suggest the potential of bidentate HOPO ligands as an effective approach to treat patients suffering from Gd(III) toxicity.

A natural anthocyanin-based multifunctional theranostic agent for dual-modal imaging and photothermal anti-tumor therapy.

Nowadays, cancer is one of the most serious diseases threatening the health of human beings, and imaging-guided photothermal therapy (PTT) is rapidly emerging as a potent oncotherapy strategy due to its unique advantages of high efficiency, noninvasiveness, visualization, and accuracy. In this study, a multifunctional nanoplatform based on gadolinium ion chelated natural anthocyanins (ACNs) is reported, which can be used not only as an excellent photoacoustic/magnetic resonance (PA/MR) dual-modal contrast agent but also for imaging-guided tumor PTT. The nanoparticles obtained have a suitable size, good dispersity, and physiological stability. The excellent biocompatibility and remarkable photothermal effect of the nanoparticles in vitro were demonstrated by CCK-8 assays and co-staining experiments. Moreover, the magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) results obtained in vivo showed that the nanoparticles were ideal dual-modal contrast agents whether given by intravenous or intratumoral injection. After intratumoral injection, the dual-modal PAI/MRI was used for determining the maximum diffusion time of the probe in the tumor site to guide laser treatment, achieving complete tumor elimination without normal tissue injury. Importantly, ACN is a natural compound extracted from black carrots, possessing native biocompatibility and biodegradability, which was further proved by the results of the detailed safety evaluation. Overall, the as-prepared nanoparticles displayed significant tumor diagnosis and treatment effects while mitigating biosafety concerns, and thus this was found to be a promising nanotherapeutic method for cancer treatment.

Near-Infrared Photothermal/Photodynamic-in-One Agents Integrated with a Guanidinium-Based Covalent Organic Framework for Intelligent Targeted Imaging-Guided Precision Chemo/PTT/PDT Sterilization.

Phototherapy holds great promise in the treatment of bacterial infections, especially the multidrug resistant bacterial infections. However, most therapeutic agents are based on the integration of individual photothermal agents and photosensitizers, always in the activated state, and generally lack bacterial specificity, resulting in uncertain pharmacokinetics and serious nonspecific damage to normal tissues. Herein, we report a pH-responsive nanoplatform with synergistic chemo-phototherapy function for smart fluorescence imaging-guided precision sterilization. pH reversible activated symmetric cyanine was designed and prepared as a bacterial-specific imaging unit and PTT/PDT-in-one agent. Meanwhile, a guanidinium-based covalent organic framework (COF) was employed as a nanocarrier and chemotherapy agent to build the intelligent nanoplatform via electrostatic self-assembly. The self-assembly of the PTT/PDT-in-one agent and the COF greatly improves the stability and blood circulation of the PTT/PDT-in-one agent and provides charge-reversed intelligent targeting ability. The developed smart nanoplatform not only enables bacterial-targeted imaging but also possesses chemo/PTT/PDT synergetic high-efficiency bactericidal effects with little side effects, showing great potential in practical applications.

A supramolecular complex based on a Gd-containing polyoxometalate and food-borne peptide for MRI/CT imaging and NIR-triggered photothermal therapy.

A multifunctional supramolecular complex is reported for the integrated multiple magnetic resonance imaging/computed X-ray tomography (MRI/CT) imaging and photothermal therapy, wherein a gadolinium-substituted paramagnetic polyoxometalate cluster and food-borne antioxidant peptides identified from the trepang protein hydrolysates are introduced. The as-prepared complex maintained an uniform particle size and much better biocompatibility, and is an ideal candidate for the in vivo applications. The complex allows for T1-weighted MR imaging and a high Hounsfield unit value for enhanced CT imaging. Interestingly, we demonstrate that the complex possesses outstanding photothermal cancer-killing effects due to its high photothermal conversion efficiency under the exposure of an NIR laser and enhanced antibacterial activity to avoid bacterial infection from the thermal therapeutic process. These results indicate that the supramolecular complex platform exhibit potential for accurate medical diagnosis at an early stage and effective eradication of the tumor cells.

NIR-laser-triggered gadolinium-doped carbon dots for magnetic resonance imaging, drug delivery and combined photothermal chemotherapy for triple negative breast cancer.

BACKGROUND: Owing to high genetic diversities of tumor cells and low response rate of standard chemotherapy, patients with triple negative breast cancer (TNBC) have short progression-free survivals and poor outcomes, which need to explore an effective approach to improve therapeutic efficacy. METHODS: Novel gadolinium doped carbon dots (Gd@CDs) have been designed and prepared through hydrothermal method with 3,4-dihydroxyhydrocinnamic acid, 2,2'-(ethylenedioxy)bis(ethylamine) and gadolinium chloride. The synthesized nanostructures were characterized. Taking advantage of good biocompatibility of Gd@CDs, a nanoplatform based on Gd@CDs has been developed to co-deliver chemotherapy drug doxorubicin hydrochloride (Dox) and a near-infrared (NIR) photothermal agent, IR825 for magnetic resonance imaging (MRI) guided photothermal chemotherapy for TNBC. RESULTS: The as-synthesized Dox@IR825@Gd@CDs displayed favorable MRI ability in vivo. Upon NIR laser irradiation, Dox@IR825@Gd@CDs could convert the NIR light to heat and efficiently inhibit tumor growth through photothermal chemotherapy in vitro and in vivo. Additionally, the impact of photothermal chemotherapy on the murine motor coordination was assessed by rotarod test. Dox@IR825@Gd@CDs presented low toxicity and high photothermal chemotherapy efficiency. CONCLUSION: A noble theranostic nanoplatform (Dox@IR825@Gd@CDs) was developed that could be tailored to achieve loading of Dox and IR825, intracellular delivery, favorable MRI, excellent combination therapy with photothermal therapy and chemotherapy to enhance therapeutic effect against TNBC cells. This study will provide a promising strategy for the development of Gd-based nanomaterials for MRI and combinational therapy for TNBC.

A Gd-doped polydopamine (PDA)-based theranostic nanoplatform as a strong MR/PA dual-modal imaging agent for PTT/PDT synergistic therapy.

Based on widely used photoacoustic imaging (PAI) and photothermal properties of polydopamine (PDA), a multifunctional Gd-PDA-Ce6@Gd-MOF (GPCG) nanosystem with a core-shell structure and strong imaging ability was constructed. Benefitting from the metal-organic framework (MOF) structure, GPCG nanoparticles (NPs) showed enhanced magnetic resonance imaging (MRI) ability with high relaxation rates (r1 = 13.72 mM-1 s-1 and r2 = 216.14 mM-1 s-1). The MRI effect of Gd ions combined with the PAI effect of PDA, giving GPCG NPs a dual-modal imaging ability. The core, mainly composed of PDA and photodynamic photosensitizer chlorin e6 (Ce6), achieved photothermal/photodynamic therapy (PTT/PDT) synergistic performance. Besides, to overcome the unexpected release of Ce6, the MOF shell realized pH-sensitive release and a high local concentration. Through in vivo studies, we concluded that GPCG NPs show a good inhibitory effect on tumor growth. In conclusion, we successfully obtained a GPCG theranostic nanoplatform and paved the way for subsequent design of imaging guided therapeutic nanostructures based on metal-doped PDA.

A GdW10@PDA-CAT Sensitizer with High-Z Effect and Self-Supplied Oxygen for Hypoxic-Tumor Radiotherapy.

Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2 self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2 to O2 and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2 self-supplement composites provide a promising radiosensitizer for the radiotherapy field.

Late Onset Nephrogenic Systemic Fibrosis in a Patient with Stage 3 Chronic Kidney Disease: a Case Report.

Nephrogenic systemic fibrosis (NSF) is a progressive systemic fibrosing disease that may occur after gadolinium contrast exposure. It can lead to severe complications and even death. NSF is highly prevalent among patients with advanced chronic kidney disease (CKD). In this report, however, we describe the case of a patient with NSF that occurred during early CKD. A 65-year-old man with stage 3a CKD was transferred to our hospital because of lower extremity edema. The medical history revealed that he was exposed to gadolinium 185 days earlier, and the result of his tibial skin biopsy was consistent with NSF. The patient underwent a combined therapy with ultraviolet-A1 phototherapy and methotrexate and steroid therapy for 6 months. The combined therapy stopped the systemic progression of NSF.

Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?

Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.

Dual-Stimuli-Responsive Multifunctional Gd2Hf2O7 Nanoparticles for MRI-Guided Combined Chemo-/Photothermal-/Radiotherapy of Resistant Tumors.

The design and synthesis of a novel generation of a nanoscaled platform with imaging-guided therapy remain a real challenge. It can not only improve the imaging sensitivity of tumor tissues for guiding all kinds of treatments but also reduce the harm for healthy tissues. Here, polydopamine (PDA), polyethylene glycol (PEG), and c(RGDyK) peptide (RGD)-modified and cisplatin-loaded Gd2Hf2O7 nanoparticles (Gd2Hf2O7@PDA@PEG-Pt-RGD NPs) are designed for magnetic resonance imaging (MRI)-guided combined chemo-/photothermal-/radiotherapy of resistant tumors. The as-prepared NPs display high relaxivity (r1 = 38.28 mM-1 s-1) as an MRI contrast agent because of their ultrasmall size and surface modification with polyacrylic acid and PDA. Gd2Hf2O7@PDA@PEG-Pt-RGD NPs exhibit pH and NIR dual-stimuli responsiveness for cisplatin release. Based on competent NIR absorption and high X-ray attenuation efficiency, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs show potential photothermal effect by exposing to an 808 nm NIR laser and significantly improve the generation of reactive oxygen species after X-ray radiation. Combined chemo-/photothermal-/radiotherapy can effectively treat the resistant A549R cells, providing the enhanced therapeutic efficiency to cancer tissues and the reduced side effect to healthy tissues. Furthermore, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs present no obvious toxicity during the treatment, which demonstrates the potential as an efficient MRI-guided combined chemo-/photothermal-/radiotherapy nanoplatform for drug-resistant tumors.

Oxygen Vacancy Defect-Induced Activity Enhancement of Gd Doping Magnetic Nanocluster for Oxygen Supplying Cancer Theranostics.

This work finds that Fe3O4 nanoclusters can rearrange by Gd doping and then self-assemble to a hollow magnetic nanocluster (HMNC), providing larger magnetic moments to obtain an excellent MRI capability and increasing the number of oxygen vacancies in HMNC. The hollow structure makes platinum(IV) prodrugs effectively load into HMNC. Second, plenty of oxygen vacancy defects can capture oxygen molecules, enhance the catalytic activity of HMNC, and then promote intracellular ROS generation. On the basis of this, a targeting iRGD-labeled HMNC nanosystem (iHMNCPt-O2) is developed through loading oxygen molecules and platinum(IV) prodrugs for chemo- and chemodynamic therapy of cancer. This nanosystem shows an excellent response ability to weak acid and GSH, which can cause a series of cascade reactions in a cell. These cascade reactions are dramatically enhanced at the intracellular ROS level, cause mitochondria and DNA damage, and then induce cancer cell death. Besides, systemic delivery of iHMNCPt-O2 significantly enhanced the MRI contrast signal of tumors and improved the quality of MR images, accurately diagnosing tumors. Therefore, this work provides a novel method for accelerating the Fenton-like reaction and enhancing the MRI capability and fabricates a promising "all-in-one" system to overwhelm the problems of cancer theranostic.

Selective Decoating-Induced Activation of Supramolecularly Coated Toxic Nanoparticles for Multiple Applications.

In spite of the rapid emergence of numerous nanoparticles (NPs) for biomedical applications, it is often challenging to precisely control, or effectively tame, the bioactivity/toxicity of NPs, thereby exhibiting limited applications in biomedical areas. Herein, we report the construction of hyaluronic acid (HA)-laminated, otherwise toxic methylviologen (MV), NPs via ternary host-guest complexation among cucurbit[8]uril, trans-azobenzene-conjugated HA, and MV-functionalized polylactic acid NPs (MV-NPs). The high, nonspecific toxicity of MV-NPs was effectively shielded (turned off) by HA lamination, as demonstrated in cells, zebrafish, and mouse models. The supramolecular host-guest interaction-mediated HA coating offered several HA-MV-NP modalities, including hyaluronidase locally and photoirradiation remotely, to precisely remove HA lamination on demand, thereby endowing materials with the capability of selective decoating-induced activation (DIA) for applications as a user-friendly herbicide, a selective antibacterial agent, or an anticancer nanomedicine. This work offers facile supramolecular coating and DIA strategies to effectively tame and precisely control the bioactivity and toxicity of functional nanomaterials for diverse applications.

NaGdF4:Yb,Er-Ag nanowire hybrid nanocomposite for multifunctional upconversion emission, optical imaging, MRI and CT imaging applications.

The effect of novel silver nanowire encapsulated NaGdF4:Yb,Er hybrid nanocomposite on the upconversion emission and bioimaging properties has been investigated. The upconvension nanomaterials were synthesised by polyol method in the presence of ethylene glycol, PVP and ethylenediamine. The NaGdF4:Yb,Er-Ag hybrid was formed with upconverting NaGdF4:Yb,Er nanoparticles of size ~ 80 nm and silver nanowires of thickness ~ 30 nm. The surface plasmon induced by the silver ion in the NaGdF4:Yb,Er-Ag nanocomposite resulted an intense upconversion green emission at 520 nm and red emission at 660 nm by NIR diode laser excitation at 980 nm wavelength. The UV-Vis-NIR spectral absorption at 440 nm and 980 nm, the intense Raman vibrational modes and the strong upconversion emission results altogether confirm the localised surface plasmon resonance effect of silver ion in the hybrid nanocomposite. MRI study of both NaGdF4:Yb,Er nanoparticle and NaGdF4:Yb,Er-Ag nanocomposite revealed the T1 relaxivities of 22.13 and 10.39 mM-1 s-1, which are larger than the commercial Gd-DOTA contrast agent of 3.08 mM-1 s-1. CT imaging NaGdF4:Yb,Er-Ag and NaGdF4:Yb,Er respectively showed the values of 53.29 HU L/g and 39.51 HU L/g, which are higher than 25.78 HU L/g of the CT contrast agent Iobitridol. The NaGdF4:Yb,Er and NaGdF4:Yb,Er-Ag respectively demonstrated a negative zeta potential of 54 mV and 55 mV, that could be useful for biological application. The in vitro cytotoxicity of the NaGdF4:Yb,Er tested in HeLa and MCF-7 cancer cell line by MTT assay demonstrated a cell viability of 90 and 80 %, respectively. But, the cell viability of NaGdF4:Yb,Er-Ag slightly decreased to 80 and 78%. The confocal microscopy imaging showed that the UCNPs are effectively up-taken inside the nucleolus of the cancer cells, and it might be useful for NIR laser-assisted phototherapy for cancer treatment. Graphical abstract.

Gadolinium-Rose Bengal Coordination Polymer Nanodots for MR-/Fluorescence-Image-Guided Radiation and Photodynamic Therapy.

Combination therapy based on nanomedicine has gained momentum in oncology in recent years, offering superior safety and efficacy over monotherapies. It is critical to design theranostics that are composed of imaging and therapeutic agents already approved. Herein, gadolinium (Gd)-rose bengal coordination polymer nanodots (GRDs) are reported. The GRDs exhibit a unique absorption property and 7.7-fold luminescence enhancement, as well as a 1.9-fold increase in singlet oxygen generation efficiency over free rose bengal. Meanwhile, GRDs exhibit a twofold increase in r1 relaxivity over gadopentetic acid (Gd-DTPA) and have better X-ray absorption ability than rose bengal alone. These excellent properties of the GRDs are verified both in vitro and in vivo. The combination of photodynamic therapy (PDT) and radiation therapy (RT) more significantly inhibits tumor growth than monotherapies (i.e., PDT or RT). This work offers a new route to designing and synthesizing Gd-based nanotheranostics for image-guided cancer therapy.

NIR-Driven Water Splitting H2 Production Nanoplatform for H2-Mediated Cascade-Amplifying Synergetic Cancer Therapy.

As a newly emerging treatment strategy for many diseases, hydrogen therapy has attracted a lot of attention because of its excellent biosafety. However, the high diffusivity and low solubility of hydrogen make it difficult to accumulate in local lesions. Herein, we develop a H2 self-generation nanoplatform by in situ water splitting driven by near-infrared (NIR) laser. In this work, core-shell nanoparticles (CSNPs) of NaGdF4:Yb,Tm/g-C3N4/Cu3P (UCC) nanocomposites as core encapsulated with zeolitic imidazolate framework-8 (ZIF-8) modified with folic acid as shell are designed and synthesized. Due to the acid-responsive ZIF-8 shell, enhanced permeability and retention (EPR) effect, and folate receptor-mediated endocytosis, CSNPs are selectively captured by tumor cells. Upon 980 nm laser irradiation, CSNPs exhibit a high production capacity of H2 and active oxygen species (ROS), as well as an appropriate photothermal conversion temperature. Furthermore, rising temperature increases the Fenton reaction rate of Cu(I) with H2O2 and strengthens the curative effect of chemodynamic therapy (CDT). The excess glutathione (GSH) in tumor microenvironment (TME) can deplete positive holes produced in the valence band of g-C3N4 in the g-C3N4/Cu3P Z-scheme heterojunction. GSH also can reduce Cu(II) to Cu(I), ensuring a continuous Fenton reaction. Thus, a NIR-driven H2 production nanoplatform is constructed for H2-mediated cascade-amplifying multimodal synergetic therapy.

Gd-/CuS-Loaded Functional Nanogels for MR/PA Imaging-Guided Tumor-Targeted Photothermal Therapy.

The second near-infrared (NIR-II, 1000-1700 nm) light-based diagnosis and therapy have received extensive attention for neoplastic disease treatments because of the fact that light in the NIR-II window possesses less photon scattering along with deeper tissue penetration than that in the NIR-I (700-950 nm) window. Herein, we present a Gd- and copper sulfide (CuS)-integrated nanogel (NG) platform for magnetic resonance (MR)/photoacoustic (PA) imaging-guided tumor-targeted photothermal therapy (PTT). In our approach, we prepared cross-linked polyethylenimine (PEI) NGs via an inverse emulsion method, modified the PEI NGs with Gd chelates, targeting ligand folic acid (FA) through a polyethylene glycol (PEG) spacer and 1,3-propanesultone, and finally loaded CuS nanoparticles (NPs) within the functional NGs. The as-synthesized Gd/CuS@PEI-FA-PS NGs with a mean size of 85 nm exhibit a good water dispersibility and protein resistance property, admirable r1 relaxivity (11.66 mM-1 s-1), excellent NIR-II absorption feature, high photothermal conversion efficiency (26.7%), and FA-mediated targeting specificity to cancer cells overexpressing FA receptor (FAR). With these properties along with the good cytocompatibility, the developed Gd/CuS@PEI-FA-PS NGs enable MR/PA dual-mode imaging-guided targeted PTT of FAR-overexpressing tumors under the irradiation of an NIR-II (1064 nm) laser. The designed Gd/CuS@PEI-FA-PS NGs may be used as a promising theranostic agent for MR/PA dual-mode imaging-guided PTT of other FAR-expressing tumors.