A pH/GSH dual responsive nanoparticle with relaxivity amplification for magnetic resonance imaging and suppression of tumors and metastases.

Engineered magnetic nanoparticles combining diagnosis and therapy functions into one entity hold great potential to rejuvenate cancer treatment; however, they are still constrained by the "always on" signals and unsatisfactory therapeutic effect. Here, we report an intelligent theranostic probe based on Mn3O4 tetragonal bipyramids (MnTBs), which simultaneously respond to H+ and glutathione (GSH) with high sensitivity and quickly decompose to release Mn2+ in mild acidic and reductive intracellular environments. Mn2+ binds to the surrounding proteins to achieve a remarkable relaxivity amplification and selectively brighten the tumors. Particularly, this MR signal improvement is also effective in the detection of millimeter-sized liver metastases, with an ultrahigh contrast of 316%. Moreover, Mn2+ would trigger chemodynamic therapy (CDT) by exerting the Fenton-like activity to generate ˙OH from H2O2. Subsequently, a significant tumor suppression effect can be achieved by the GSH depletion-enhanced CDT. Besides, MnTBs manifest efficient urinary and hepatic excretions with biodegradability and minimal systemic toxicity. A pH/GSH dual responsive nanoprobe that integrates tumor diagnostic and therapeutic activities was developed to provide a new paradigm for precise diagnosis and treatment of tumors and metastases.

Fluorinated Ionic Liquid Based Multicolor 19 F MRI Nanoprobes for In Vivo Sensing of Multiple Biological Targets.

Multicolor imaging, which maps the distribution of different targets, is important for in vivo molecular imaging and clinical diagnosis. Fluorine 19 magnetic resonance imaging (19 F MRI) is a promising technique because of unique insights without endogenous background or tissue penetration limit. Thus multicolor 19 F MRI probes, which can sense a wide variety of molecular species, are expected to help elucidate the biomolecular networks in complex biological systems. Here, a versatile model of activatable probes based on fluorinated ionic liquids (ILs) for multicolor 19 F MRI is reported. Three types of ILs at different chemical shifts are loaded in nanocarriers and sealed by three stimuli-sensitive copolymers, leading to "off" 19 F signals. The coating polymers specifically respond to their environmental stimuli, then degrade to release the loaded ILs, causing 19 F signals recovery. The nanoprobes are utilized for non-invasive detection of tumor hallmarks, which are distinguished by their individual colors in one living mouse, without interference between each other. This multicolor imaging strategy, which adopts modular construction of various ILs and stimuli-responsive polymers, will allow more comprehensive sensing of multiple biological targets, thus, opening a new realm in mechanistic understanding of complex pathophysiologic processes in vivo.

A pH-Activatable MnCO3 Nanoparticle for Improved Magnetic Resonance Imaging of Tumor Malignancy and Metastasis.

Engineered magnetic nanoparticles have been extensively explored for magnetic resonance imaging (MRI) diagnosis of a tumor to improve the visibility. However, most of these nanoparticles display "always-on" signals without tumor specificity, causing insufficient contrast and false positives. Here, we provide a new paradigm of MRI diagnosis using MnCO3 nanorhombohedras (MnNRs) as an ultrasensitive T1-weighted MRI contrast agent, which smartly enhances the MR signal in response to the tumor microenvironment. MnNRs would quickly decompose and release Mn2+ at mild acidity, one of the pathophysiological parameters associated with cancer malignancy, and then Mn2+ binds to surrounding proteins to achieve a remarkable amplification of T1 relaxivity. In vivo MRI experiments demonstrate that MnNRs can selectively brighten subcutaneous tumors from the edge to the interior may be because of the upregulated vascular permeation at the tumor edge, where cancer cell proliferation and angiogenesis are more active. Specially, benefiting from the T2 shortening effect in normal liver tissues, MnNRs can detect millimeter-sized liver metastases with an ultrahigh contrast of 294%. The results also indicate an effective hepatic excretion of MnNRs through the gallbladder. As such, this pH-activatable MRI strategy with facility, biocompatibility, and excellent efficiency may open new avenues for tumor malignancy and metastasis diagnosis and holds great promise for precision medicine.

A Fluorinated Ionic Liquid-Based Activatable 19F MRI Platform Detects Biological Targets.

19F magnetic resonance imaging (19F MRI) is a promising technique for in vivo molecular imaging and clinical diagnosis, benefiting from its negligible background and unlimited tissue penetration depth. However, the development of 19F probes with good water solubility and versatile functions for bioresponsive and practical applications remains a challenge. Here, we report fluorinated ion liquids (ILs) as a new type of fluorine agents and build a fluorinated ionic liquid-based activatable 19F MRI platform (FILAMP), which relies on the phase transition of ILs. Upon exposure to environmental stimulation, coating polymer dissolves or degrades to release the fluorinated ILs payload, which rapidly enhances 19F signal. This "turn-on" response is verified by the successful detection of biological targets (for example, dysregulated pH and MMP overexpression) at the cellular level and in mice, demonstrating the potential of FILAMP as a robust activatable 19F probe for diagnosis and monitoring of biological and pathological processes.

Two-dimensional Pd-based nanomaterials for bioapplications.

Noble metal nanomaterials have been extensively explored in cancer diagnostic and therapeutic applications owing to their unique physical and chemical properties, such as facile synthesis, straightforward surface functionalization, strong photothermal effect, and excellent biocompatibility. Herein, we summarize the recent development of two-dimensional (2D) Pd-based nanomaterials and their applications in cancer diagnosis and therapy. Different synthetic strategies for Pd nanosheets and the related nanostructures, including Pd@Au, Pd@Ag nanoplates and mesocrystalline Pd nanocorolla, are first discussed. Together with their unique properties, the potential bioapplications of these 2D Pd nanomaterials are then demonstrated. With strong absorption in near-infrared (NIR) region, these nanomaterials have great potentials in cancer photothermal therapy (PTT). They also readily act as contrast agents in photoacoustic (PA) imaging or X-ray computed tomography (CT) to achieve image-guided cancer therapy. Moreover, significant efforts have been devoted to studying the combination of PTT and other treatment modalities (e.g., chemotherapy or photodynamic therapy) based on Pd nanomaterials. The remarkable synergistic or collaborative effects to achieve better therapeutic efficacy are discussed as well. Additionally, the biosafety of 2D Pd-based nanomaterials in vitro and in vivo was evaluated. Finally, challenges for the applications of Pd-based nanomaterials in cancer diagnosis and therapy, and future research prospects are highlighted.

Platinum(IV) prodrug conjugated Pd@Au nanoplates for chemotherapy and photothermal therapy.

Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(IV) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(IV) prodrug loading. Once injected into biological tissue, the Pt(IV) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(II) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(II) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.

An investigation of the mimetic enzyme activity of two-dimensional Pd-based nanostructures.

In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis.

Simultaneous Enhancement of Intracellular Optical Imaging and Photothermal Therapeutic Response by Octaarginine-Modified Fluorescent Dye Doped Pd@Ag@SiO2(RITC) Multifunctional Nanoparticles.

In the work, a novel multifunctional silica-based nanoplatform (Pd@Ag@SiO2(RITC)-R8) for bioimaging and photothermal therapy (PTT) of cancer cells has been developed. The Pd@Ag nanosheets encapsulated inside silica can act as effective near-infrared (NIR) absorbers for cancer photothermal therapy. Fluorescent dye, rhodamine B isothiocyanate (RITC), was covalently doped into the silica network to provide the capacity for optical imaging. After amine modification, the Pd@Ag@SiO2(RITC)-NH2 can be further conjugated with octaarginine (R8, a cell penetrating peptide) for enhancing the uptake of nanoparticles by cells. Confocal fluorescent images and flow cytometry analysis revealed that R8-conjugated nanoparticles (Pd@Ag@SiO2(RITC)-R8) were taken up by cells more efficiently. Correspondingly, the optical imaging and photothermal therapeutic efficiency of Pd@Ag@SiO2(RITC)-R8 upon cancer cells were also raised due to their higher cellular uptake when compared with that of Pd@Ag@SiO2(RITC)-NH2. Our results indicate that these multifunctional Pd@Ag@SiO2(RITC)-R8 may have great potential for applications in imaging-guided cancer photothermal therapy.

Optimization of Surface Coating on Small Pd Nanosheets for in Vivo near-Infrared Photothermal Therapy of Tumor.

Palladium nanosheets with strong near-infrared absorption have been recently demonstrated as promising photothermal agents for photothermal therapy (PTT) of cancers. However, systematic assessments of their potential risks and impacts to biological systems have not been fully explored yet. In this work, we carefully investigate how surface coatings affect the in vivo behaviors of small Pd nanosheets (Pd NSs). Several biocompatible molecules such as carboxymethyl chitosan (CMC), PEG-NH2, PEG-SH, and dihydrolipoic acid-zwitterion (DHLA-ZW) were used to coat Pd NSs. The blood circulation half-lives, biodistribution, potential toxicity, clearance, and photothermal effect of different surface-coated Pd NSs in mice after intravenous injection were compared. PEG-SH-coated Pd NSs (Pd-HS-PEG) were found to have ultralong blood circulation half-life and show high uptake in the tumor. We then carry out the in vivo photothermal therapeutic studies on the Pd-HS-PEG conjugate and revealed its outstanding efficacy in in vivo photothermal therapy of cancers. Our results highlight the importance of surface coatings to the in vivo behaviors of nanomaterials and can provide guidelines to the future design of Pd NSs bioconjugates for other in vivo applications.

Copper sulfide nanoparticles with phospholipid-PEG coating for in vivo near-infrared photothermal cancer therapy.

In this work, small sizes of hydrophobic copper sulfide nanoparticles (CuS NPs, ∼3.8 nm in diameter) have been successfully prepared from the reaction of copper chloride with sodium diethyldithiocarbamate (SDEDTC) inside a heated oleylamine solution. These CuS NPs displayed strong absorption in the 700-1100 nm near-infrared (NIR) region. By coating CuS NPs with DSPE-PEG2000 on the surface, the as-synthesized CuS@DSPE-PEG NPs exhibited good water solubility, significant stability and biocompatibility, as well as excellent photothermal conversion effects upon exposure to an 808 nm laser. After intravenous administration to mice, the CuS@DSPE-PEG NPs were found to passively target to the tumor site, and tumor tissues could be ablated efficiency under laser irradiation. In addition, CuS@DSPE-PEG NPs do not show significant toxicity by histological and blood chemistry analysis, and can be effectively excreted via metabolism. Our results indicated that CuS@DSPE-PEG NPs can act as an ideal photothermal agent for cancer photothermal therapy.

Simultaneous photodynamic and photothermal therapy using photosensitizer-functionalized Pd nanosheets by single continuous wave laser.

In this work, we prepared chlorin e6 (Ce6)-functionalized Pd nanosheets (Pd-PEI-Ce6) for the photodynamic and photothermal combined therapy that use a single laser. To fabricate the Pd-PEI-Ce6 nanocomposite, photosensitizer Ce6 were chemically conjugated to polyethylenimine (PEI) and the formed Ce6-PEI conjugates were then anchored onto Pd nanosheets by electrostatic and coordination interaction. The prepared Pd-PEI-Ce6 nanocomposite were about 4.5 nm in size, exhibited broad, and strong absorption from 450 to 800 nm, good singlet oxygen generation capacity and photothermal conversion efficiency, and excellent biocompability. Significantly greater cell killing was observed when HeLa cells incubated with Pd-PEI-Ce6 were irradiated with the 660 nm laser, attributable to both Pd nanosheets-mediated photothermal ablation and the photodynamic destruction effect of photosensitizer Ce6. The double phototherapy effect was also confirmed in vivo. It was found that the Pd-PEI-Ce6 treated tumor-bearing mice displayed the enhanced therapeutic efficiency compared to that of Pd-PEI, or Ce6-treated mice. Our work highlights the promise of using Pd nanosheets for potential multimode cancer therapies.

Photothermally enhanced photodynamic therapy based on mesoporous Pd@Ag@mSiO2 nanocarriers.

In this work, we have demonstrated that mesoporous silica-coated Pd@Ag nanoparticles (Pd@Ag@mSiO2) can be used as an excellent nanoplatform for photodynamic therapy (PDT) drug delivery. Photosensitizer molecules, Chlorin e6 (Ce6), are covalently linked to the mesoporous shell and the prepared Pd@Ag@mSiO2-Ce6 nanoparticles exhibit excellent water solubility, good stability against leaching and high efficiency in photo-generating cytotoxic singlet oxygen. More importantly, the photothermal effect of Pd@Ag nanoplates under the irradiation of a NIR laser can enhance the uptake of Pd@Ag@mSiO2-Ce6 nanoparticles by cells, further increasing the PDT efficiency toward cancer cells. The photothermally enhanced PDT effects were demonstrated both in vitro and in vivo. When the Pd@Ag@mSiO2-Ce6 nanoparticles were injected intratumorally into the S180 tumor-bearing mice, the tumors were completely destroyed without recurrence of tumors upon irradiation with both 808 nm and 660 nm lasers, while the irradiation with 808 nm or 660 nm alone did not. These results indicate that the Pd@Ag@mSiO2 nanoparticles may be a valuable new tool for application in cancer phototherapy.