Trapped in Endosome PEGylated Ultra-Small Iron Oxide Nanoparticles Enable Extraordinarily High MR Imaging Contrast for Hepatocellular Carcinomas.

The early diagnosis of hepatocellular carcinomas (HCCs) remains challenging in the clinic. Primovist-enhanced magnetic resonance imaging (MRI) aids HCC diagnosis but loses sensitivity for tumors <2 cm. Therefore, developing advanced MRI contrast agents is imperative for improving the diagnostic accuracy of HCCs in very-early-stage. To address this challenge, PEGylated ultra-small iron oxide nanoparticles (PUSIONPs) are synthesized and employed as liver-specific T1 MRI contrast agents. Intravenous delivery produces simultaneous hyperintense HCC and hypointense hepatic parenchyma signals on T1 imaging, creating an extraordinarily high tumor-to-liver contrast. Systematic studies uncover PUSIONP distribution in hepatic parenchyma, HCC lesions at the organ, tissue, cellular, and subcellular levels, revealing endosomal confinement of PUSIONP without aggregation. By mimicking such situations, the dependency of relaxometric properties on local PUSIONP concentration is investigated, emphasizing the key role of different endosomal concentrations in liver and tumor cells for high tumor-to-liver contrast and clear tumor boundaries. These findings offer exceptional imaging capabilities for early HCC diagnosis, potentially benefiting real HCC patients.

Using Adaptive Imaging Parameters to Improve PEGylated Ultrasmall Iron Oxide Nanoparticles-Enhanced Magnetic Resonance Angiography.

The PEGylated ultrasmall iron oxide nanoparticles (PUSIONPs) exhibit longer blood residence time and better biodegradability than conventional gadolinium-based contrast agents (GBCAs), enabling prolonged acquisitions in contrast-enhanced magnetic resonance angiography (CE-MRA) applications. The image quality of CE-MRA is dependent on the contrast agent concentration and the parameters of the pulse sequences. Here, a closed-form mathematical model is demonstrated and validated to automatically optimize the concentration, echo time (TE), repetition time (TR) and flip angle (FA). The pharmacokinetic studies are performed to estimate the dynamic intravascular concentrations within 12 h postinjection, and the adaptive concentration-dependent sequence parameters are determined to achieve optimal signal enhancement during a prolonged measurement window. The presented model is tested on phantom and in vivo rat images acquired from a 3T scanner. Imaging results demonstrate excellent agreement between experimental measurements and theoretical predictions, and the adaptive sequence parameters obtain better signal enhancement than the fixed ones. The low-dose PUSIONPs (0.03 mmol kg-1 and 0.05 mmol kg-1) give a comparable signal intensity to the high-dose one (0.10 mmol kg-1) within 2 h postinjection. The presented mathematical model provides guidance for the optimization of the concentration and sequence parameters in PUSIONPs-enhanced MRA, and has great potential for further clinical translation.

Biomimetic Upconversion Nanoplatform Synergizes Photodynamic Therapy and Enhanced Radiotherapy against Tumor Metastasis.

The easy recurrence and high metastasis of fatal tumors require the development of a combination therapy, which is able to overcome the drawbacks of monomodal strategies such as surgery, photodynamic therapy (PDT), and radiotherapy (RT). Taking the complementary advantages of PDT and RT, we present herein the integration of lanthanide-doped upconversion nanoparticles (UCNPs) with chlorin e6 (Ce6)-imbedded RBC membrane vesicles as a near-infrared-induced PDT agent for achieving synchronous depth PDT and RT with reduced radiation exposure. In such a nanoagent, gadolinium-doped UCNPs with strong X-ray attenuation ability act not only as a light transductor to activate the loaded photosensitizer Ce6 to allow PDT but also as a radiosensitizer to enhance RT. PDT with enhanced low-dose RT can achieve synergistic inhibition of tumor growth by producing reactive oxygen species to destroy local tumor cells and inducing strong T-cell-dependent immunogenic cell death to arrest systemic cancer metastasis. This combination of PDT and RT might be a potential appealing strategy for tumor eradication.

Vision for Ratiometric Nanoprobes: In Vivo Noninvasive Visualization and Readout of Physiological Hallmarks.

Lesion areas are distinguished from normal tissues surrounding them by distinct physiological characteristics. These features serve as biological hallmarks with which targeted biomedical imaging of the lesion sites can be achieved. Although tremendous efforts have been devoted to providing smart imaging probes with the capability of visualizing the physiological hallmarks at the molecular level, the majority of them are merely able to derive anatomical information from the tissues of interest, and thus are not suitable for taking part in in vivo quantification of the biomarkers. Recent advances in chemical construction of advanced ratiometric nanoprobes (RNPs) have enabled a horizon for quantitatively monitoring the biological abnormalities in vivo. In contrast to the conventional probes whose dependency of output on single-signal profiles restricts them from taking part in quantitative practices, RNPs are designed to provide information in two channels, affording a self-calibration opportunity to exclude the analyte-independent factors from the outputs and address the issue. Most of the conventional RNPs have encountered several challenges regarding the reliability and sufficiency of the obtained data for high-performance imaging. In this Review, we have summarized the recent progresses in developing highly advanced RNPs with the capabilities of deriving maximized information from the lesion areas of interest as well as adapting themselves to the complex biological systems in order to minimize microenvironmental-induced falsified signals. To provide a better outlook on the current advanced RNPs, nanoprobes based on optical, photoacoustic, and magnetic resonance imaging modalities for visualizing a wide range of analytes such as pH, reactive species, and different derivations of amino acids have been included. Furthermore, the physicochemical properties of the RNPs, the major constituents of the nanosystems and the analyte recognition mechanisms have been introduced. Moreover, the alterations in the values of the ratiometric signal in response to the analyte of interest as well as the time at which the highest value is achieved, have been included for most of RNPs discussed in this Review. Finally, the challenges as well as future perspectives in the field are discussed.

Functionalized Ultrasmall Iron Oxide Nanoparticles for T1-Weighted Magnetic Resonance Imaging of Tumor Hypoxia.

Hypoxia is a common biological condition in many malignant solid tumors that plays an imperative role in regulating tumor growth and impacting the treatment's therapeutic effect. Therefore, the hypoxia assessment is of great significance in predicting tumor development and evaluating its prognosis. Among the plenty of existing tumor diagnosis techniques, magnetic resonance imaging (MRI) offers certain distinctive features, such as being free of ionizing radiation and providing images with a high spatial resolution. In this study, we develop a fluorescent traceable and hypoxia-sensitive T1-weighted MRI probe (Fe3O4-Met-Cy5.5) via conjugating notable hypoxia-sensitive metronidazole moiety and Cy5.5 dye with ultrasmall iron oxide (Fe3O4) nanoparticles. The results of in vitro and in vivo experiments show that Fe3O4-Met-Cy5.5 has excellent performance in relaxivity, biocompatibility, and hypoxia specificity. More importantly, the obvious signal enhancement in hypoxic areas indicates that the probe has great feasibility for sensing tumor hypoxia via T1-weighted MRI. These promising results may unlock the potential of Fe3O4 nanoparticles as T1-weighted contrast agents for the development of clinical hypoxia probes.

Self-illuminating NIR-II bioluminescence imaging probe based on silver sulfide quantum dots.

Bioluminescence (BL) imaging has emerged to tackle the potential challenges of fluorescence (FL) imaging including the autofluorescence background, inhomogeneous illumination over a wide imaging field, and the light-induced overheating effect. Taking advantage of the bioluminescence resonance energy transfer (BRET) mechanism between a conventional luciferin compound and a suitable acceptor, the visible light of the former can be extended to photons with longer wavelengths emitting from the latter. Although BRET-based self-illuminating imaging probes have already been prepared, employing potentially cytotoxic elements as the acceptor with the emission wavelengths which hardly reach the first near-infrared (NIR-I) window, has limited their applications as safe and high performance in vivo imaging agents. Herein, we report a biocompatible, self-illuminating, and second near-infrared (NIR-II) emissive probe to address the cytotoxicity concerns as well as improve the penetration depth and spatiotemporal resolution of BL imaging. To this end, NanoLuc luciferase enzyme molecules were immobilized on the surface of silver sulfide quantum dots to oxidize its luciferin substrate and initiate a single-step BRET mechanism, resulting in NIR-II photons from the quantum dots. The resulting dual modality (BL/FL) probes were successfully applied to in vivo tumor imaging in mice, demonstrating that NIR-II BL signals could be easily detected from the tumor sites, giving rise to ∼2 times higher signal-to-noise ratios compared to those obtained under FL mode. The results indicated that nontoxic NIR-II emitting nanocrystals deserve more attention to be tailored to fill the growing demands of preparing appropriate agents for high quality BL imaging.

Effects of PEG Chain Length on Relaxometric Properties of Iron Oxide Nanoparticles-Based MRI Contrast Agent.

Iron oxide nanoparticles (IONPs) as magnetic resonance imaging (MRI) contrast agents have received considerable interest due to their superior magnetic properties. To increase the biocompatibility and blood circulation time, polyethylene glycol (PEG) is usually chosen to decorate IONPs. Although the surface effect induced by the PEGylation has an impact on the relaxometric properties of IONPs and can subsequently affect the imaging results, the occurrence of particle aggregation has troubled researchers to deeply explore this correlation. To shed light on this relationship, three diphosphonate PEGs with molecular weights of 1000, 2000, and 5000 Da were used to replace the hydrophobic oleate ligands of 3.6 nm and 10.9 nm IONPs. Then, the contrast enhancement properties of the resultant "aggregation-free" nanoparticles were carefully evaluated. Moreover, related theories were adopted to predict certain properties of IONPs and to compare with the experimental data, as well as obtain profound knowledge about the impacts of the PEG chain length on transverse relaxivity (r2) and longitudinal relaxivity (r1). It was found that r2 and the saturated magnetization of the IONPs, independent of particle size, was closely related to the chain length of PEG. The results unveiled the correlation between the chain length of the coated PEG and the relaxometric properties of IONPs, providing valuable information which might hold great promise in designing optimized, high-performance IONPs for MRI-related applications.

Rational Constructed Ultra-Small Iron Oxide Nanoprobes Manifesting High Performance for T1-Weighted Magnetic Resonance Imaging of Glioblastoma.

Precise diagnosis and monitoring of cancer depend on the development of advanced technologies for in vivo imaging. Owing to the merits of outstanding spatial resolution and excellent soft-tissue contrast, the application of magnetic resonance imaging (MRI) in biomedicine is of great importance. Herein, Angiopep-2 (ANG), which can simultaneously help to cross the blood-brain barrier and target the glioblastoma cells, was rationally combined with the 3.3 nm-sized ultra-small iron oxide (Fe3O4) to construct high-performance MRI nanoprobes (Fe3O4-ANG NPs) for glioblastoma diagnosis. The in vitro experiments show that the resultant Fe3O4-ANG NPs not only exhibit favorable relaxation properties and colloidal stability, but also have low toxicity and high specificity to glioblastoma cells, which provide critical prerequisites for the in vivo tumor imaging. Furthermore, in vivo imaging results show that the Fe3O4-ANG NPs exhibit good targeting ability toward subcutaneous and orthotopic glioblastoma model, manifesting an obvious contrast enhancement effect on the T1-weighted MR image, which demonstrates promising potential in clinical application.

pH-dependent swelling and antibiotic release from citric acid crosslinked poly(vinyl alcohol) (PVA)/nano silver hydrogels.

In this work, a pH-sensitive and antibacterial drug delivery system based on poly(vinyl alcohol) (PVA)/citric acid (CA)/Ag nanoparticles (NPs) was designed using a completely green, facile and one-step route. Interestingly, the crosslinking of PVA with CA, and in-situ formation of Ag NPs within the polymeric matrix were simultaneously and simply carried out using an annealing process without need for any toxic chemicals. The developed hydrogels were characterized by FTIR, UV-vis spectra, SEM and TEM techniques. It was found that CA not only acted as a crosslinker of PVA via esterification reaction, but also it endowed pH-responsiveness and antibacterial activity to the PVA matrix due to presence of free carboxylic acid groups on CA. Hydrogels demonstrated a pH-dependent swelling as well as drug release behavior, as the swelling ratio and the drug release at pH 7.4 were found higher than pH 1.2. Furthermore, the release of ciprofloxacin was more sustained when Ag NPs were incorporated into hydrogels. In addition, the incorporation of CA, Ag NPs and ciprofloxacin into the PVA matrix provided an effective antibacterial activity against E. coli and S. aureus microorganisms. The developed hydrogels can be considered as a promising material in the prolonged antibiotic therapy such as intestinal infection treatment.