NIR/MRI-Guided Oxygen-Independent Carrier-Free Anti-Tumor Nano-Theranostics.

Imaging-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer treatment are beneficial for precise localization of the malignant lesions and combination of multiple cell killing mechanisms in eradicating stubborn thermal-resistant cancer cells. However, overcoming the adverse impact of tumor hypoxia on PDT efficacy remains a challenge. Here, carrier-free nano-theranostic agents are developed (AIBME@IR780-APM NPs) for magnetic resonance imaging (MRI)-guided synergistic PTT/thermodynamic therapy (TDT). Two IR780 derivatives are synthesized as the subject of nanomedicine to confer the advantages for the nanomedicine, which are by feat of amphiphilic IR780-PEG to enhance the sterical stability and reduce the risk from reticuloendothelial system uptake, and IR780-ATU to chelate Mn2+ for T1 -weighted MRI. Dimethyl 2,2'-azobis(2-methylpropionate) (AIBME), acting as thermally decomposable radical initiators, are further introduced into nanosystems with the purpose of generating highly cytotoxic alkyl radicals upon PTT launched by IR780 under 808 nm laser irradiation. Therefore, the sequentially generated heat and alkyl radicals synergistically induce cell death via synergistic PTT/TDT, ignoring tumor hypoxia. Moreover, these carrier-free nano-theranostic agents present satisfactory biocompatibility, which could be employed as a powerful weapon to hit hypoxic tumors via MRI-guided oxygen-independent PTT and photonic TDT.

Oxygen Challenge Imaging Reveals Differences in Metabolic Activity Between Kurtosis Lesion and Diffusion/Kurtosis Lesion Mismatch in a Rodent Model of Acute Stroke.

OBJECTIVE: Accurate identification of potentially salvageable tissues is critical for improving acute stroke treatment. A previous study showed that the kurtosis lesion exhibited insignificant response after prompt reperfusion treatment, while the diffusion/kurtosis lesion mismatch could recover after reperfusion. We hypothesized that these 2 regions are in different metabolic states. MATERIALS AND METHODS: Transient oxygen challenge (OC) is a procedure that uses oxygen as a metabolic bio-tracer and has been performed to explore metabolic activity in tissues. We combined OC with multiparameter magnetic resonance imaging (including diffusion kurtosis imaging and T2* mapping sequences) to study metabolic activity in the ischemic brain of Sprague Dawley rats. RESULTS: Oxygen challenge image analysis revealed changes in T2* values, most significantly in the mean diffusivity (MD)/mean kurtosis (MK) lesion mismatch (22.3 ± 1.6%) and least significantly in the MK lesions (6.6 ± 0.6%). The MD images acquired within 138 ± 9 minutes after ischemia showed a larger ischemic lesion (45.5 ± 3.0% of the total area) than the MK images (33.2 ± 4.2% of the total area). The change rate of the MK value (53.0 ± 4.4%) was higher than that of the MD value (37.5 ± 3.2%). CONCLUSIONS: The present study shows that MK lesion and MD/MK lesion mismatch exhibited different metabolic activity states. The MK lesion presented metabolic-related values close to the ischemic core, while at least part of the MD/MK mismatch area was comparable with ischemic penumbra metabolic activity. These findings are important to support image-guided individualized stroke therapies.

Development of a New FR-Targeting Agent 99mTc-HYNFA with Improved Imaging Contrast and Comparison of Multimerization and/or PEGylation Strategies for Radio-Folate Modification.

This study aims to develop a new folate receptor (FR)-targeting agent for SPECT imaging with improved contrast and evaluate the modification strategies of multimerization and/or PEGylation in the development of new radio-folates. A series of novel folate derivatives have been synthesized and radiolabeled with 99mTc using tricine and TPPTS as coligands. To better investigate their pharmacokinetics, cell uptake, biodistribution, and microSPECT/CT imaging were evaluated. Four radioligands displayed high KB cell uptake after incubation for 2 and 4 h. Presaturated with excess folic acid (FA) resulted in a significant blocking effect in KB cells, indicating specificity of these radioligands toward FR. Biodistribution and microSPECT imaging studies in KB tumor-bearing mice showed that the folate conjugate 99mTc-HYNFA with poly(ethylene glycol) (PEG) and triazole linkage displayed the highest tumor uptake (16.30 ± 2.01 %ID/g at 2 h p.i. and 14.9 ± 0.62 %ID/g at 4 h p.i. in mice biodistribution) and best imaging contrast, indicating promising application prospect. More interestingly, the in vivo performance of this monomeric 99mTc-HYNFA was much better than that of FA multimers and non-PEGylated monomers, suggesting that multimerization may not be a feasible method for the design of radio-folates. PEG linkage rather than FA multimerization should be taken into consideration in the development of folate-based radiopharmaceuticals in the future.

A Novel Copolymer-Based Functional SPECT/MR Imaging Agent for Asialoglycoprotein Receptor Targeting.

The aim of this study is to develop a copolymer-based single-photon emission computed tomography/magnetic resonance (SPECT/MR) dual-modality imaging agent that can be labeled with both technetium-99m (99mTc) and gadolinium (Gd) and target asialoglycoprotein receptor (ASGPR) via galactose. Monomers of N-p-vinylbenzyl-6-(2-(4-dimethylamino)benzaldehydehydrazono) nicotinate (VNI) for labeling of 99mTc, 5,8-bis(carboxymethyl)-3-oxo-11-(2-oxo-2-((4-vinylbenzyl)amino)ethyl)-1-(4-vinylphenzyl)-2,5,8,11-tetraazatridecan-13-oic acid (V2DTPA) for labeling of Gd, and vinylbenzyl-O-ß-d-galactopyranosyl-d-gluconamide (VLA) for targeting ASGPR were synthesized, respectively. Then the copolymer P(VLA-co-VNI-co-V2DTPA) (pVLND2) was synthesized and characterized by gel permeation chromatography, dynamic light scattering, and high-performance liquid chromatography analysis. After labeling with 99mTc and Gd simultaneously, the radiochemical purity, toxicity, relaxivity (r1), and in vivo SPECT/MR imaging in mice were evaluated. Single-photon emission computed tomography/magnetic resonance imaging and biodistribution results showed that pVLND2 could target ASGPR well. The significantly improved signal to noise ratio was observed in mice liver during MR imaging. All the results suggest that this novel kind of copolymer has the potential to be further developed as a functional SPECT/MR imaging agent.

Synthesis and Evaluation of (99m)Tc-Labeled Dimeric Folic Acid for FR-Targeting.

The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D1-FA2) was radiolabeled with (99m)Tc using tricine and trisodium triphenylphosphine-3,3',3″-trisulfonate (TPPTS) as coligands ((99m)Tc-HYNIC-D1-FA2) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = -2.52 ± 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that (99m)Tc-HYNIC-D1-FA2 had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of (99m)Tc-HYNIC-D1-FA2 was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.

Hollow magnetic vortex nanorings loaded with quercetin encapsulated in polydopamine: A high-performance, intelligent nanotheranostic platform for enhanced tumor imaging and dual thermal treatment.

Nanoparticle-mediated thermotherapeutic research strives innovative, multifunctional, efficient, and safe treatments. Our study introduces a novel nanoplatform: the hollow magnetic vortex nanorings within a polydopamine layer (HMVNp), which exhibit dual functionality as magnetic and photothermal agents. Utilizing a "Dual-mode" approach, combining an alternating magnetic field (AMF) with near-infrared (NIR) laser irradiation, HMVNp demonstrated a significant enhancement in heating efficacy (58 ± 8 %, SAR = 1441 vs 1032 W/g) over traditional solid magnetite nanoparticles coated with polydopamine (SMNp). The unique geometry larger surface area to volume ratio facilitates efficient magnetic vortex dynamics and enhanced heat transfer. Addressing the challenge of heat resistant heat shock protein (Hsp) expression, encapsulated quercetin (Q) within HMVNp leverages tumor acidity and dual-mode thermal therapy to enhance release, showing a 28.8 ± 6.81 % increase in Q loading capacity compared to traditional SMNp. Moreover, HMVNp significantly improves contrast for both magnetic resonance imaging (MRI) and photoacoustic imaging (PAI), with an approximately 62 % transverse relaxation (R2 = 81.5 vs 31.6 mM-1s-1 [Fe]). In vivo studies showed that while single treatments slowed tumor growth, dual-mode therapy with quercetin significantly reduced tumors and effectively prevented metastases. Our study highlights the potential of HMVNp/Q as a versatile agent in thermotherapeutic interventions, offering improved diagnostic imaging capabilities.

A new 3D phase unwrapping method by region partitioning and local polynomial modeling in abdominal quantitative susceptibility mapping.

Background: Accurate phase unwrapping is a critical prerequisite for successful applications in phase-related MRI, including quantitative susceptibility mapping (QSM) and susceptibility weighted imaging. However, many existing 3D phase unwrapping algorithms face challenges in the presence of severe noise, rapidly changing phase, and open-end cutline. Methods: In this study, we introduce a novel 3D phase unwrapping approach utilizing region partitioning and a local polynomial model. Initially, the method leverages phase partitioning to create initial regions. Noisy voxels connecting areas within these regions are excluded and grouped into residual voxels. The connected regions within the region of interest are then reidentified and categorized into blocks and residual voxels based on voxel count thresholds. Subsequently, the method sequentially performs inter-block and residual voxel phase unwrapping using the local polynomial model. The proposed method was evaluated on simulation and in vivo abdominal QSM data, and was compared with the classical Region-growing, Laplacian_based, Graph-cut, and PRELUDE methods. Results: Simulation experiments, conducted under different signal-to-noise ratios and phase change levels, consistently demonstrate that the proposed method achieves accurate unwrapping results, with mean error ratios not exceeding 0.01%. In contrast, the error ratios of Region-growing (N/A, 84.47%), Laplacian_based (20.65%, N/A), Graph-cut (2.26%, 20.71%), and PRELUDE (4.28%, 10.33%) methods are all substantially higher than those of the proposed method. In vivo abdominal QSM experiments further confirm the effectiveness of the proposed method in unwrapping phase data and successfully reconstructing susceptibility maps, even in scenarios with significant noise, rapidly changing phase, and open-end cutline in a large field of view. Conclusion: The proposed method demonstrates robust and accurate phase unwrapping capabilities, positioning it as a promising option for abdominal QSM applications.

Nitrogen removal performance and microbial community changes in subsurface wastewater infiltration systems (SWISs) at low temperature with different bioaugmentation strategies.

Poor nitrogen removal efficiency (mainly nitrate, NO3--N) at low temperatures strongly limits application of subsurface wastewater infiltration systems (SWISs). Seven psychrophilic strains (heterotrophic nitrifying bacteria and aerobic denitrifying bacteria) were isolated and added to SWISs to investigate the effect of embedding and direct-dosing bioaugmentation strategies on sewage treatment performance at low temperature. Both bioaugmentation strategies improved ammonium (NH4+-N) removal efficiencies, and the embedding strategy also exhibited satisfactory NO3--N and total nitrogen (TN) removal efficiencies. Pyrosequencing results of the bacterial 16S rRNA gene indicated that the embedding strategy significantly decreased the indigenous soil microbial diversity (p < .05) and altered the bacterial community structure, significantly increasing the relative abundance of Clostridia, which have good nitrate-reducing activity.

Synthesis and preliminary evaluation of a 99m Tc-labeled folate-PAMAM dendrimer for FR imaging.

Folate receptor is an ideal target for tumor-specific diagnostic and therapeutic. The aim of this study was to synthesize 99m Tc-labeled folate-polyamidoamine dendrimer modified with 2-hydrazinonicotinic acid (99m Tc-HP3 FA) for FR imaging. The 99m Tc-HP3 FA conjugate was prepared using N-tris-(hydroxymethyl)-methylglycine and trisodium triphenylphosphine-3,3',3″-trisulfonate as coligands. Physicochemical properties, in vitro cell uptake study, and in vivo micro-single-photon emission computed tomography/CT imaging were performed. The radiolabeled 99m Tc-HP3 FA conjugate was prepared with high radiolabeling yield, good stability, and water solubility (logP = -1.70 ± 0.21). In cell uptake study, the radiolabeled conjugate showed high uptakes in the FR-abundant KB cells and could be blocked significantly by excess folic acid. The 7721 cells which served as control group substantially had no uptakes. The results of micro-single-photon emission computed tomography/CT imaging exhibited that high accumulation of activity was found in FR-overexpressed KB tumor, and the tumor-to-muscle ratio was approximately 25.78, while, using free FA as inhibitor, the uptakes of 99m Tc-HP3 FA in KB tumor and kidney were obviously inhibited. In summary, a new radiocompound was synthesized successfully with specific FR targeting ability. The feasibility of 99m Tc-HP3 FA for early diagnosis of FR-positive tumors with non-invasive single-photon emission computed tomography imaging was demonstrated and the possibility of imaging-guided drug delivery based on multifunctional polyamidoamine will be studied in the future.

Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia.

Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO2 NPs) toward hydrogen peroxide (H2O2) for the simultaneous production of O2 and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO2 NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO2 NPs to lessen tumor hypoxia and modulate chemoresistance. The HA-coated, mannan-conjugated MnO2 particle (Man-HA-MnO2) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO2 NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO2 NPs toward endogenous H2O2 highly enhanced T1- and T2-MRI performance for tumor imaging and detection.

Simultaneous SPECT imaging of multi-targets to assist in identifying hepatic lesions.

Molecular imaging technique is an attractive tool to detect liver disease at early stage. This study aims to develop a simultaneous dual-isotope single photon emission computed tomography (SPECT)/CT imaging method to assist diagnosis of hepatic tumor and liver fibrosis. Animal models of liver fibrosis and orthotopic human hepatocellular carcinoma (HCC) were established. The tracers of (131)I-NGA and (99m)Tc-3P-RGD2 were selected to target asialoglycoprotein receptor (ASGPR) on the hepatocytes and integrin αvß3 receptor in tumor or fibrotic liver, respectively. SPECT imaging and biodistribution study were carried out to verify the feasibility and superiority. As expected, (99m)Tc-3P-RGD2 had the ability to evaluate liver fibrosis and detect tumor lesions. (131)I-NGA showed that it was effective in assessing the anatomy and function of the liver. In synchronized dual-isotope SPECT/CT imaging, clear fusion images can be got within 30 minutes for diagnosing liver fibrosis and liver cancer. This new developed imaging approach enables the acquisition of different physiological information for diagnosing liver fibrosis, liver cancer and evaluating residual functional liver volume simultaneously. So synchronized dual-isotope SPECT/CT imaging with (99m)Tc-3P-RGD2 and (131)I-NGA is an effective approach to detect liver disease, especially liver fibrosis and liver cancer.

Superfluorinated PEI Derivative Coupled with (99m) Tc for ASGPR Targeted (19) F MRI/SPECT/PA Tri-Modality Imaging.

Fluorinated polyethylenimine derivative labeled with radionuclide (99m) Tc is developed as a (19) F MRI/SPECT/PA multifunctional imaging agent with good asialoglycoprotein receptors (ASGPR)-targeting ability. This multifunctional agent is safe and suitable for (19) F MRI/SPECT/PA imaging and has the potential to detect hepatic diseases and to assess liver function, which provide powerful support for the development of personalized and precision medicine.

Ultrahigh (19)F Loaded Cu1.75S Nanoprobes for Simultaneous (19)F Magnetic Resonance Imaging and Photothermal Therapy.

(19)F magnetic resonance imaging (MRI) is a powerful noninvasive, sensitive, and accurate molecular imaging technique for early diagnosis of diseases. The major challenge of (19)F MRI is signal attenuation caused by the reduced solubility of probes with increased number of fluorine atoms and the restriction of molecular mobility. Herein, we present a versatile one-pot strategy for the fabrication of a multifunctional nanoprobe with high (19)F loading (∼2.0 × 10(8 19)F atoms per Cu1.75S nanoparticle). Due to the high (19)F loading and good molecular mobility that results from the small particle size (20.8 ± 2.0 nm) and ultrathin polymer coating, this nanoprobe demonstrates ultrahigh (19)F MRI signal. In vivo tests show that this multifunctional nanoprobe is suitable for (19)F MRI and photothermal therapy. This versatile fabrication strategy has also been readily extended to other single-particle nanoprobes for ablation and sensitive multimodal imaging.

Comparisons between the 35 mm quadrature surface resonator at 300 K and the 40 mm high-temperature superconducting surface resonator at 77 K in a 3T MRI imager.

This study attempts to compare the signal-to-noise ratio (SNR) of the 40 mm High-Temperature Superconducting (HTS) surface resonator at 77 K and the 35 mm commercial quadrature (QD) surface resonator at 300 K in a 3 Tesla (T) MRI imager. To aquire images for the comparison, we implemented a phantom experiment using the 40 mm diameter Bi2Sr2Ca2Cu3Ox (Bi-2223) HTS surface resonator, the 35 mm commercial QD surface resonator and the 40 mm professionally-made copper surface resonator. The HTS surface resonator at 77 K provided a 1.43-fold SNR gain over the QD surface resonator at 300 K and provided a 3.84-fold SNR gain over the professionally-made copper surface resonator at 300 K on phantom images. The results agree with the predictions, and the difference between the predicted SNR gains and measured SNR gains is 1%. Although the geometry of the HTS surface resonator is different from the QD surface resonator, its SNR is still higher. The results demonstrate that a higher image quality can be obtained with the HTS surface resonator at 77 K. With the HTS surface resonator, the SNR can be improved, suggesting that the HTS surface resonator is a potentially helpful diagnostic tool for MRI imaging in various applications.

Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging.

INTRODUCTION: Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with (99m)Tc by formulated kit for SPECT imaging of hepatic function. METHODS: p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for (99m)Tc labeling. Radiotracer (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. RESULTS: (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (>99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49±10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1h and 4h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. CONCLUSION: (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of (99m)Tc-labeling provides great potential for the evaluation of hepatocyte function in clinical application.

Synthesis and preliminary evaluation of novel (99m)Tc-labeled folate derivative via click reaction for SPECT imaging.

The folate receptor is over expressed in a wide variety of human tumors. In this study, a novel (99m)Tc-labeled folate derivative ((99m)Tc-HYNIC-T-FA) was synthesized as a potential FR-targeting imaging probe and its efficiency was evaluated. This (99m)Tc-complex could be obtained through practical manner and showed improved in vivo characteristics compared with other radiofolates. Thus, this novel (99m)Tc-HYNIC-T-FA compound could serve as a potential imaging agent for folate receptor positive tumors.