Development of [18F]Thiazolylacylaminopyridine-Based Glycogen synthase Kinase-3ß ligands for positron emission tomography imaging.

Glycogen synthase kinase-3ß (GSK-3ß) regulates numerous of CNS-specific signaling pathways, and is particularly implicated in various pathogenetic mechanisms of Alzheimer's disease (AD). A noninvasive method for detecting GSK-3ß in AD brains via positron emission tomography (PET) imaging could enhance the understanding of AD pathogenesis and aid in the development of AD therapeutic drugs. In this study, an array of fluorinated thiazolyl acylaminopyridines (FTAAP) targeting GSK-3ß were designed and synthesized. These compounds showed moderate to high affinities (IC50 = 6.0 - 426 nM) for GSK-3ß in vitro. A potential GSK-3ß tracer, [18F]8, was successfully radiolabeled. [18F]8 had unsatisfactory initial brain uptake despite its suitable lipophilicity, molecular size and good stability. Further structural refinement of the lead compound is needed to develop promising [18F]-labeled radiotracers for the detection of GSK-3ß in AD brains.

A new class of CYP1B1 inhibitors derived from bentranil.

Cytochrome P450 1B1 (CYP1B1) is highly expressed in a variety of tumors and implicated to drug resistance. More and more researches have suggested that CYP1B1 is a new target for cancer prevention and therapy. Various CYP1B1 inhibitors with a rigid polycyclic skeleton have been developed, such as flavonoids, trans-stilbenes, and quinazolines. To obtain a new class of CYP1B1 inhibitors, we designed and synthesized a series of bentranil analogues, moreover, IC50 determinations were performed for CYP1B1 inhibition of five of these compounds and found that 6o and 6q were the best inhibitors, with IC50 values in the nM range. The selectivity index (SI) of CYP1B1 over CYP1A1 and CYP1A2 was 30-fold higher than that of α-naphthoflavone (ANF). The molecular docking results showed that compound 6q fitted better into the CYP1B1 binding site than other compounds, which was consistent with our experimental results. On the basis of 6o and 6q, it is expected to develop CYP1B1 inhibitors with stronger affinity, higher selectivity and better solubility.

Design, Synthesis, and Evaluation of 18F-Labeling CYP1B1 PET Tracer Based on 2-Phenylquinazolin.

Cytochrome P450 (CYP)1B1 has been identified to be specifically overexpressed in several solid tumors, thus it's a potential target for the detection of tumors. Based on the 2-Phenylquinazolin CYP1B1 inhibitors, we designed and synthesized several positron emission computed tomography (PET) imaging probes targeting CYP1B1. Through IC50 determinations, most of these probes exhibited good affinity and selectivity to CYP1B1. Considering their affinity, solubility, and their 18F labeling methods, we chose compound 5c as the best candidate. The 18F radiolabeling of [18F] 5c was easy to handle with good radiolabeling yield and radiochemical purity. In vitro and in vivo stability study indicated that probe [18F]5c has good stability. In cell binding assay, [18F]5c could be specifically taken up by tumor cells, especially HCT-116 cells. Although the tumor-blood (T/B) and tumor-muscle (T/M) values and PET imaging results were unsatisfied, it is still possible to develop PET probes targeting CYP1B1 by structural modification on the basis of 5c in the future.

Arsenite-loaded nanoparticles inhibit the invasion and metastasis of a hepatocellular carcinoma: in vitro and in vivo study.

Postoperative recurrence and metastasis are the major problems for the current treatment of hepatocellular carcinomas (HCC) in the clinic, including hepatectomy and liver transplantation. Here, we report that arsentic-loaded nanoparticles (ALNPs) are able to reduce the invasion of HCC cells in vitro, and, more importantly, can strongly suppress the invasion and metastasis of HCC in vivo without adverse side effects. Compared to free drug arsenic trioxide , ALNPs can deliver the drug into cancer cells more efficiently, destroy the structure of microtubules and reduce the aggregation of microfilaments in cell membranes more significantly. Furthermore, our results also reveal that tumor cells in murine blood were reduced remarkably after intravenous injection of ALNPs, indicating that this nano-drug may efficiently kill circulating tumor cells in vivo. In conclusion, our nano-drug ALNPs have great potential for the suppression of metastasis of HCC, which may open up a new avenue for the effective treatment of HCC without metastasis and recurrence.

Kinetic and sensitive analysis of tyrosinase activity using electron transfer complexes: in vitro and intracellular study.

Tyrosinase is an important marker of human diseases such as the neurodegeneration associated with Parkinson's disease and melanoma. Sensitive detection of tyrosinase activity in vitro and inside cells is of great significance to medical diagnostics and skin disorder treatments. With unique photophysical properties, semiconductor quantum dots (QDs) are employed as photoluminescent platforms for various biosensing, in particular for the detection of enzyme activities. In this work, QDs are functionalized with tyrosine and zwitterionic molecules to construct a nanometer-scale scaffold (QD-Tyr conjugate), and this is used to test tyrosinase activity in vitro and inside cells. Tyrosinase oxidizes tyrosine to dopachrome and switches on the electron-transfer access, which relates to fluorescence quenching. High quenching efficiency is achieved by shortening the distance between the electron donors and acceptors, which is attributed to the small size of the conjugated tyrosine. Enzymatic process curves reveal the enhanced enzymatic activity on the conjugated nanoparticle substrate, which leads to highly sensitive detection of tyrosinase (as low as 1 nM). It is also demonstrated that QD-Tyr conjugates can sensitively probe intracellular tyrosinase in melanoma cells, which promises great potential in disease monitoring and medical diagnostics.

Au-Fe3O4 Janus nanoparticles for imaging-guided near infrared-enhanced ferroptosis therapy in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is insensitive to conventional therapy due to its highly invasive nature resulting in poor therapeutic outcomes. Recent studies have shown multiple genes associated with ferroptosis in TNBC, suggesting an opportunity for ferroptosis-based treatment of TNBC. However, the efficiency of present ferroptosis agents for cancer is greatly restricted due to lack of specificity and low intracellular levels of H2O2 in cancer cells. Herein, we report a nano-theranostic platform consisting of gold (Au)-iron oxide (Fe3O4) Janus nanoparticles (GION@RGD) that effectively enhances the tumor-specific Fenton reaction through utilization of near-infrared (NIR) lasers, resulting in the generation of substantial quantities of toxic hydroxyl radicals (•OH). Specifically, Au nanoparticles (NPs) converted NIR light energy into thermal energy, inducing generation of abundant intracellular H2O2, thereby enhancing the iron-induced Fenton reaction. The generated •OH not only lead to apoptosis of malignant tumor cells but also induce the accumulation of lipid peroxides, causing ferroptosis of tumor cells. After functionalizing with the activity-targeting ligand RGD (Arg-Gly-Asp), precise synergistic treatment of TNBC was achieved in vivo under the guidance of Fe3O4 enhanced T2-weighted magnetic resonance imaging (MRI). This synergistic treatment strategy of NIR-enhanced ferroptosis holds promise for the treatment of TNBC.

Magnetic Field-Optimized Paramagnetic Nanoprobe for T2/T1 Switchable Histopathological-Level MRI.

Traditional magnetic resonance imaging (MRI) contrast agents (CAs) are a type of "always on" system that accelerates proton relaxation regardless of their enrichment region. This "always on" feature leads to a decrease in signal differences between lesions and normal tissues, hampering their applications in accurate and early diagnosis. Herein, we report a strategy to fabricate glutathione (GSH)-responsive one-dimensional (1-D) manganese oxide nanoparticles (MONPs) with improved T2 relaxivities and achieve effective T2/T1 switchable MRI imaging of tumors. Compared to traditional contrast agents with high saturation magnetization to enhance T2 relaxivities, 1-D MONPs with weak Ms effectively increase the inhomogeneity of the local magnetic field and exhibit obvious T2 contrast. The inhomogeneity of the local magnetic field of 1-D MONPs is highly dependent on their number of primary particles and surface roughness according to Landau-Lifshitz-Gilbert simulations and thus eventually determines their T2 relaxivities. Furthermore, the GSH responsiveness ensures 1-D MONPs with sensitive switching from the T2 to T1 mode in vitro and subcutaneous tumors to clearly delineate the boundary of glioma and metastasis margins, achieving precise histopathological-level MRI. This study provides a strategy to improve T2 relaxivity of magnetic nanoparticles and construct switchable MRI CAs, offering high tumor-to-normal tissue contrast signal for early and accurate diagnosis.

Polyethyleneimine-mediated assembly of DNA nanotubes for KRAS siRNA delivery in lung adenocarcinoma therapy.

Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.

Facile, sensitive, and ratiometric detection of mercuric ions using GSH-capped semiconductor quantum dots.

Glutathione (GSH) capped CdTe semiconductor quantum dots (QDs) are applied for detecting mercuric ions (Hg(2+)) of trace quantity. The synthesis of GSH-capped CdTe (CdTe@GSH) QDs is cost-efficient and straightforward. We observed that Hg(2+) can quantitatively quench the fluorescence of CdTe@GSH QDs and further induce the slight redshift of emission peaks due to the quantum confinement effect. Detailed studies by spectroscopy, dynamic light scattering (DLS), and electrospray ionization mass spectrometry (ESI-MS) demonstrated that the competitive Hg(2+) binding with GSH makes the surface of CdTe QDs exposed, results in gradual aggregation, and quantitatively changes the photophysical properties of QDs. The whole procedure for detecting Hg(2+) by this protocol took less than 10 min. The experimental limit of detection (LOD) of Hg(2+) can be as low as 5 nM using CdTe@GSH with a low concentration (0.5 nM) because of the excellent fluorescent properties of QDs. This strategy may become a promising means to simply detect Hg(2+) in water with high sensitivity.

Understanding the metabolic fate and assessing the biosafety of MnO nanoparticles by metabonomic analysis.

Recently, some types of MnO nanoparticle (Mn-NP) with favorable imaging capacity have been developed to improve the biocompatible profile of the existing Mn-based MRI contrast agent Mn-DPDP; however, the overall bio-effects and potential toxicity remain largely unknown. In this study, (1)H NMR-based metabolic profiling, integrated with traditional biochemical analysis and histopathological examinations, was used to investigate the absorption, distribution, metabolism, excretion and toxicity of Mn-NPs as candidates for MRI contrast agent. The metabolic responses in biofluids (plasma and urine) and tissues (liver, spleen, kidney, lung and brain) from rats could be divided into four classes following Mn-NP administration: Mn biodistribution-dependent, time-dependent, dose-dependent and complicated metabolic variations. The variations of these metabolites involved in lipid, energy, amino acid and other nutrient metabolism, which disclosed the metabolic fate and biological effects of Mn-NPs in rats. The changes of metabolic profile implied that the disturbance and impairment of biological functions induced by Mn-NP exposure were correlated with the particle size and the surface chemistry of nanoparticles. Integration of metabonomic technology with traditional methods provides a promising tool to understand the toxicological behavior of biomedical nanomaterials and will result in informed decision-making during drug development.

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.

Switchable ROS Scavenger/Generator for MRI-Guided Anti-Inflammation and Anti-Tumor Therapy with Enhanced Therapeutic Efficacy and Reduced Side Effects.

Photosensitizer in photodynamic therapy (PDT)  accumulates in both tumor and adjacent normal tissue due to low selective biodistribution, results in undesirable side effect with limited clinic application. Herein, an intelligent nanoplatform is reported that selectively acts as reactive oxygen species (ROS) scavenger in normal tissue but as ROS generator in tumor microenvironment (TME) to differentially control ROS level in tumor and surrounding normal tissue during PDT. By down-regulating the produced ROS with dampened cytokine wave in normal tissue after PDT, the nanoplatform reduces the inflammatory response of normal tissue in PDT, minimizing the side effect and tumor metastasis in PDT. Alternatively, the nanoplatform switches from ROS scavenger to generator through the glutathione (GSH) responsive degradation in TME, which effectively improves the PDT efficacy with reduced GSH level and amplified oxidative stress in tumor. Simultaneously, the released Mn ions provide real-time and in situ signal change of magnetic resonance imaging (MRI) to monitor the reversal process of catalysis activity and achieve accurate tumor diagnosis. This TME-responsive ROS scavenger/generator with activable MRI contrast may provide a new dimension for design of next-generation PDT agents with precise diagnosis, high therapeutic efficacy, and low side effect.

Multifunctional Droplets Formed by Interfacially Self-Assembled Fluorinated Magnetic Nanoparticles for Biocompatible Single Cell Culture and Magnet-Driven Manipulation.

The ability to encapsulate and manipulate droplets with a picoliter volume of samples and reagents shows great potential for practical applications in chemistry, biology, and materials science. Magnetic control is a promising approach for droplet manipulation due to its ability for wireless control and its ease of implementation. However, it is challenged by the poor biocompatibility of magnetic materials in aqueous droplets. Moreover, current droplet technology is problematic because of the molecule leakage between droplets. In the paper, we propose multifunctional droplets with the surface coated by a layer of fluorinated magnetic nanoparticles for magnetically actuated droplet manipulation. Multifunctional droplets show excellent biocompatibility for cell culture, nonleakage of molecules, and high response to a magnetic field. We developed a strategy of coating the F-MNP@SiO2 on the outer surface of droplets instead of adding magnetic material into droplets to enable droplets with a highly magnetic response. The encapsulated bacteria and cells in droplets did not need to directly contact with the magnetic materials at the outer surface, showing high biocompatibility with living cells. These droplets can be precisely manipulated based on magnet distance, the time duration of the magnetic field, the droplet size, and the MNP composition, which well match with theoretical analysis. The precise magnetically actuated droplet manipulation shows great potential for accurate and sensitive droplet-based bioassays like single cell analysis.

Recent advances in engineering iron oxide nanoparticles for effective magnetic resonance imaging.

Iron oxide nanoparticle (IONP) with unique magnetic property and high biocompatibility have been widely used as magnetic resonance imaging (MRI) contrast agent (CA) for long time. However, a review which comprehensively summarizes the recent development of IONP as traditional T 2 CA and its new application for different modality of MRI, such as T 1 imaging, simultaneous T 2/T 1 or MRI/other imaging modality, and as environment responsive CA is rare. This review starts with an investigation of direction on the development of high-performance MRI CA in both T 2 and T 1 modal based on quantum mechanical outer sphere and Solomon-Bloembergen-Morgan (SBM) theory. Recent rational attempts to increase the MRI contrast of IONP by adjusting the key parameters, including magnetization, size, effective radius, inhomogeneity of surrounding generated magnetic field, crystal phase, coordination number of water, electronic relaxation time, and surface modification are summarized. Besides the strategies to improve r 2 or r 1 values, strategies to increase the in vivo contrast efficiency of IONP have been reviewed from three different aspects, those are introducing second imaging modality to increase the imaging accuracy, endowing IONP with environment response capacity to elevate the signal difference between lesion and normal tissue, and optimizing the interface structure to improve the accumulation amount of IONP in lesion. This detailed review provides a deep understanding of recent researches on the development of high-performance IONP based MRI CAs. It is hoped to trigger deep thinking for design of next generation MRI CAs for early and accurate diagnosis.

Engineering manganese ferrite shell on iron oxide nanoparticles for enhanced T1 magnetic resonance imaging.

Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T1 relaxivity of IO nanoparticle in recent years; however, the high T2 relaxivity of MnIO nanoparticle hampers its T1 contrast efficiency and remains a hurdle when developing contrast agent for early and accurate diagnosis. Herein, we engineered the interfacial structure of IO nanoparticle coated with manganese ferrite shell (IO@MnIO) with tunable thicknesses. The Mn-doped shell significantly improve the T1 contrast of IO nanoparticle, especially with the thickness of ∼0.8 nm. Compared to pristine IO nanoparticle, IO@MnIO nanoparticle with thickness of ∼0.8 nm exhibits nearly 2 times higher T1 relaxivity of 9.1 mM-1s-1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T2 relaxivity to T1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T1 relaxation rates but obvious lower T2 relaxivities and r2/r1 ratios to MnIO nanoparticles with similar sizes. The desirable T1 contrast endows IO@MnIO nanoparticle to provide sufficient signal difference between normal and tumor tissue in vivo. This work provides a detailed instance of interfacial engineering to improve IO-based T1 contrast and a new guidance for designing effective high-performance T1 contrast agent for early cancer diagnosis.

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.

Albumin-stabilized manganese-based nanocomposites with sensitive tumor microenvironment responsivity and their application for efficient SiRNA delivery in brain tumors.

Mn(iv)-Based nanoparticles (NPs) are effective in improving tumor oxygenation (hypoxia) and reducing endogenous hydrogen peroxide and acidity in the tumor region. However, the optimized reduction conditions of conventional Mn(iv)-based NPs are generally reported at pH ≤ 6.5, while the usual pH range of the tumor microenvironment (TME) is 6.5-7.0. The dissatisfactory imaging performance in the weakly acidic environment may limit their further application in tumor diagnosis. In this study, Mn(iii) was introduced in a nanoplatform, because it is reduced into Mn(ii) in weakly acidic environments. Arg-Gly-Asp (RGD) peptide-decorated bovine serum albumin (BSA) was employed as the stabilizer and scaffold to fabricate Mn(iii)- and Mn(iv)-integrated nanocomposites (RGD-BMnNPs) with suitable size, good stability, and excellent biocompatibility. The as-prepared NPs showed clear contrast enhancement at pH 6.5-6.9 in vitro as well as sensitive and rapid T1-weighted imaging performance within the tumor region in a glioblastoma (U87MG) orthotopic model, owing to the intrinsic disproportionation reaction of Mn(iii) in the weakly acidic environment. In addition, these NPs could be used for efficient siRNA delivery. They showed superior advantages in this process, including increased tumour uptake, improved tumor accumulation and enhanced therapeutic effects with the modulation of the TME. These novel albumin-stabilized manganese-based NPs combined with efficient drug delivery capacity hold great potential to serve as intelligent theranostic agents for further clinical translation.

Improving Longitudinal Transversal Relaxation Of Gadolinium Chelate Using Silica Coating Magnetite Nanoparticles.

INTRODUCTION AND OBJECTIVE: Precisely and sensitively diagnosing diseases especially early and accurate tumor diagnosis in clinical magnetic resonance (MR) scanner is a highly demanding but challenging task. Gadolinium (Gd) chelate is the most common T 1 magnetic resonance imaging (MRI) contrast agent at present. However, traditional Gd-chelates are suffering from low relaxivity, which hampers its application in clinical diagnosis. Currently, the development of nano-sized Gd based T 1 contrast agent, such as incorporating gadolinium chelate into nanocarriers, is an attractive and feasible strategy to enhance the T 1 contrast capacity of Gd chelate. The objective of this study is to improve the T 1 contrast ability of Gd-chelate by synthesizing nanoparticles (NPs) for accurate and early diagnosis in clinical diseases. METHODS: Reverse microemulsion method was used to coat iron oxide (IO) with tunable silica shell and form cores of NPs IO@SiO2 at step one, then Gd-chelate was loaded on the surface of silica-coated iron oxide NPs. Finally, Gd-based silica coating magnetite NPs IO@SiO2-DTPA-Gd was developed and tested the ability to detect tumor cells on the cellular and in vivo level. RESULTS: The r 1 value of IO@SiO2-DTPA-Gd NPs with the silica shell thickness of 12 nm was about 33.6 mM-1s-1, which was approximately 6 times higher than Gd-DTPA, and based on its high T 1 contrast ability, IO@SiO2-DTPA-Gd NPs could effectively detect tumor cells on the cellular and in vivo level. CONCLUSION: Our findings revealed the improvement of T 1 relaxation was not only because of the increase of molecular tumbling time caused by the IO@SiO2 nanocarrier but also the generated magnetic field caused by the IO core. This nanostructure with high T 1 contrast ability may open a new approach to construct high-performance T 1 contrast agent.

Engineering the Infrared Luminescence and Photothermal Properties of Double-Shelled Rare-Earth-Doped Nanoparticles for Biomedical Applications.

The nascent field of theranostics, which couples targeted therapy with diagnostics, has catalyzed efforts toward improved nanoprobe designs that facilitate both localized treatment and diagnostic imaging. Rare-earth-doped nanoparticles (RENPs) have emerged as a leading candidate for theranostics because of their versatile synthesis and modification chemistries, photostability, and relative safety. Furthermore, their bright, tunable fluorescence using near-infrared (NIR) excitation enables multispectral imaging with high signal-to-background ratios. In this work, we have synthesized double-shelled RENPs with tunable properties for optimal fluorescent imaging, photoacoustic imaging, and photothermal therapy. The properties of the double-shelled RENPs were tailored by controlling the density of rare-earth ions (i.e., activator or sensitizer) by using either a functional amorphous organic or a crystalline outermost shell. This study systematically analyzes the effects of the functional organic or inorganic outermost shell on the imaging and photothermal conversion properties of our RENPs. Despite the weaker infrared absorption enhancement, the functional organic outermost shell impregnated with a low density of rare-earth ions led to minimal reduction of fluorescence emissions. In contrast, the higher density of rare-earth ions in the inorganic shell led to higher infrared absorption and consequently significant reduction in emissions arising from the undesired optical attenuation. Inorganic shell thickness was therefore modified to reduce the deleterious attenuation, leading to brighter emissions that also enabled the in vitro SWIR detection of ∼2500 cells/cluster. Using the enhanced infrared properties that arise from this functional inorganic layer, which could be engineered to respond to either NIR or SWIR, we demonstrated that (1) bright SWIR emissions allowed detection of small cell clusters; (2) strong PA signals allowed clear visualization of particle distribution within tumors; and (3) strong photothermal effects resulted in localized elevated temperatures. Collectively, these results highlight the utility of these double-shelled RENPs as theranostic agents that are compatible with both photoacoustic or fluorescent imaging platforms.

Interfacial engineered gadolinium oxide nanoparticles for magnetic resonance imaging guided microenvironment-mediated synergetic chemodynamic/photothermal therapy.

Engineering interfacial structure of biomaterials have drawn much attention due to it can improve the diagnostic accuracy and therapy efficacy of nanomedicine, even introducing new moiety to construct theranostic agents. Nanosized magnetic resonance imaging contrast agent holds great promise for the clinical diagnosis of disease, especially tumor and brain disease. Thus, engineering its interfacial structure can form new theranostic platform to achieve effective disease diagnosis and therapy. In this study, we engineered the interfacial structure of typical MRI contrast agent, Gd2O3, to form a new theranostic agent with improved relaxivity for MRI guided synergetic chemodynamic/photothermal therapy. The synthesized Mn doped gadolinium oxide nanoplate exhibit improved T1 contrast ability due to large amount of efficient paramagnetic metal ions and synergistic enhancement caused by the exposed Mn and Gd cluster. Besides, the introduced Mn element endow this nanomedicine with the Fenton-like ability to generate OH from excess H2O2 in tumor site to achieve chemodynamic therapy (CDT). Furthermore, polydopamine engineered surface allow this nanomedicine with effective photothermal conversion ability to rise local temperature and accelerate the intratumoral Fenton process to achieve synergetic CDT/photothermal therapy (PTT). This work provides new guidance for designing magnetic resonance imaging guided synergetic CDT/PTT to achieve tumor detection and therapy.