Multifunctional MnO2/Ag3SbS3 Nanotheranostic Agent for Single-Laser-Triggered Tumor Synergistic Therapy in the NIR-II Biowindow.

Regulating the level of reactive oxygen species (ROS) in a tumor is an efficient and innovative anticancer strategy. However, the therapeutic efficacy of ROS-based therapies, such as chemodynamic therapy (CDT) and photodynamic therapy (PDT), offers finite outcomes due to the oxygen dependence and limited concentration of hydrogen peroxide (H2O2) and overexpression of glutathione (GSH) within the tumor microenvironment (TME), so a single therapeutic strategy is insufficient to completely eliminate tumors. Therefore, we demonstrated an omnipotent nanoplatform MnO2/Ag3SbS3 (abbreviated as MA) with strong optical absorbance in the NIR-II biowindow and oxygen self-sufficient ROS-mediated ability, which not only relieves tumor hypoxia significantly but also enhances the photothermal therapy (PTT)/PDT/CDT efficacy. By 1064 nm laser irradiation, MnO2/Ag3SbS3 nanoparticles (NPs) reveal a favorable photothermal conversion efficiency of 23.15% and achieve a single-laser-triggered NIR-II PTT/PDT effect, resulting in effective tumor elimination. Once internalized into the tumor, MnO2/Ag3SbS3 NPs will be degraded to Mn2+ and Ag3SbS3. The released Ag3SbS3 NPs as a NIR-II phototherapy agent could be utilized for photoacoustic imaging-guided NIR-II PDT/PTT. Mn2+ could be used as a Fenton-like catalyst to continuously catalyze endogenous H2O2 for generating highly virulent hydroxyl radicals (•OH) for CDT and O2 for PDT, enhancing the efficiency of PDT and CDT, respectively. Meanwhile, Mn2+ realizes magnetic resonance imaging-guided accurate tumor therapy. Moreover, the MnO2/Ag3SbS3 NPs could deplete intracellular GSH in TME to promote oxidative stress of the tumor, further strengthening ROS-mediated antitumor treatment efficacy. Overall, this work presents a distinctive paradigm of TME-responsive PDT/CDT/PTT in the second near-infrared biowindow by depleting GSH and decomposing H2O2 for efficient and precise cancer treatment.

Hollow carbon-based nanosystem for photoacoustic imaging-guided hydrogenothermal therapy in the second near-infrared window.

Compared with the near-infrared-I spectral window (NIR-I, 650-950 nm), a newly developed imaging and treatment window with a 1000-1700 nm range (defined as the NIR-II bio-window) has attracted much attention owing to its higher spatiotemporal resolution, increased tissue penetration depth and therapeutic efficacy. Herein, we designed a nanotheranostic platform (HC-AB NPs) via loading ammonia borane (AB) into hollow carbon nanoparticles (HCs) for NIR-II photoacoustic (PA) imaging-guided NIR-II hydrogenothermal therapy. Importantly, by exploiting the characteristics of beta zeolite as a hard template and a template-carbonization-corrosion process, the prepared HCs have excellent NIR-II absorption performance and AB loading capacity. With the high biocompatibility of HC-AB NPs, an efficient synergistic anti-tumor strategy has been achieved via high intratumoural accumulation and acid-stimulated H2 release as well as PA-guided precise NIR-II photothermal therapy. The HC-AB NPs as a promising nanotheranostic platform opens a new avenue for high-efficacy NIR-II hydrogenothermal therapy.

Design of ZIF-based hybrid nanoparticles with hyaluronic acid-augmented ROS behavior for dual-modality PA/NIR-II FL imaging.

Photoacoustic (PA) imaging has emerged as a promising bio-imaging technique due to its non-invasive visualization of lesions at great penetration depths. Fluorescence (FL) imaging in the second near-infrared window (NIR-II, 1000-1700 nm) achieves a higher imaging resolution and lower background signals compared to NIR-I. However, the single imaging method possesses its own disadvantages. Thus, we have demonstrated ZIF-8-IR820-MnPc-HA nanoparticles (ZIMH NPs) that can achieve visualization and localization of tumors in mice models with the help of a dual-modality PA/NIR-II FL imaging performance. Meanwhile, these excellent nanoparticles also induce the efficient generation of singlet oxygen (1O2) upon 808 nm laser illumination, and display excellent photodynamic therapy efficacy in cells, further indicating their potential application for in vivo PDT. In ZIMH NPs, hyaluronic acid (HA) impressively acts as a "sponge", enhancing the generation of 1O2 and facilitating the cellular therapeutic effects. We believe that ZIF-8-IR820-MnPc-HA NPs present a brand-new strategy for the exploration of efficient PDT photosensitizers with dual-modality imaging performance for use in various biomedical applications.

Biodegradable Multifunctional Nanotheranostic Based on Ag2S-Doped Hollow BSA-SiO2 for Enhancing ROS-Feedback Synergistic Antitumor Therapy.

Stimuli-responsive silica nanoparticles are an attractive therapeutic agent for effective tumor ablation, but the responsiveness of silica nanoagents is limited by intrastimulation level and silica framework structure. Herein, a biodegradable hollow SiO2-based nanosystem (Ag2S-GOx@BHS NYs) is developed by a novel one-step dual-template (bovine serum albumin (BSA) and cetyltrimethylammonium bromide (CTAB)) synthetic strategy for image-guided therapy. The Ag2S-GOx@BHS NYs can be specifically activated in the tumor microenvironment via a self-feedback mechanism to achieve reactive oxygen species (ROS)-induced multistep therapy. In response to the inherent acidity and H2O2 at the tumor sites, Ag2S-GOx@BHS would accelerate the structural degradation while releasing glucose oxidase (GOx), which could efficiently deplete intratumoral glucose to copious amounts of gluconic acid and H2O2. More importantly, the sufficient H2O2 not only acts as a reactant to generate Ag+ from Ag2S for metal-ion therapy and improves the oxidative stress but also combines with gluconic acid results in the self-accelerating degradation process. Moreover, the released Ag2S nanoparticles can help the Ag2S-GOx@BHS NYs realize the second near-infrared window fluorescence (NIR-II FL) and photoacoustic (PA) imaging-guided precise photothermal therapy (PTT). Taken together, the development of a self-feedback nanosystem may open up a new dimension for a highly effective multistep tumor therapy.

NIR-II FL/PA dual-modal imaging long-term tracking of human umbilical cord-derived mesenchymal stem cells labeled with melanin nanoparticles and visible HUMSC-based liver regeneration for acute liver failure.

Acetaminophen (APAP) has been widely used for relieving pain and fever, whilst overdose would lead to the occurrence of acute liver failure (ALF). Currently, few effective treatments are available for ALF in clinic, especially for severe, advanced- or end-stage patients who need liver transplantation. Human umbilical cord-derived mesenchymal stem cells (hUMSCs), as one of the mesenchymal stem cells, not only contribute to relieving hepatotoxicity and promoting hepatocyte regeneration due to their self-renewing, multi-differentiation potential, anti-inflammatory, immunomodulatory and paracrine properties, but possess lower immunomodulatory effects, faster self-renewal properties and noncontroversial ethical concerns, which may play a better role in the treatment of ALF. In this work, hUMSCs were rapidly labeled with near-infrared II fluorescent dye-modified melanin nanoparticles (MNP-PEG-H2), which could realize long-term tracking of hUMSCs by NIR-II fluorescent (FL)/photoacoustic (PA) dual-modal imaging and could visualize hUMSC-based liver regeneration in ALF. The nanoparticles exhibited good dispersibility and biocompatibility, high labeling efficiency for hUMSCs and excellent NIR-II FL/PA imaging performance. Moreover, the MNP-PEG-H2 labeled hUMSCs could be continuously traced in vivo for up to 21 days. After intravenous delivery, the NIR-II FL and PA images revealed that labeled hUMSCs were able to engraft in the injured liver and repair damaged tissue in ALF mice. Therefore, the hUMSCs labeled with endogenous melanin nanoparticles solve the key tracing problem of MSC-based regenerative medicine and realize the visualization of the treatment process, which may provide an efficient, safe and potential choice for ALF.

A tumor-targeted theranostic nanomedicine with strong absorption in the NIR-II biowindow for image-guided multi-gradient therapy.

Developing new strategies to enhance drug accumulation in the tumor and therapeutic efficacy is of great importance in the field of tumor therapy. Herein, a peanut-like multifunctional nanomedicine (CuS-PGH NMs) made of CuS nanoparticles encapsulated in poly(l-lysine)(PLL)/glucose oxidase (GOx)-hyaluronic acid (HA) shells has been constructed via layer-by-layer (LbL) assembly, and shows good biocompatibility and effective multi-gradient therapy. Because of the enhanced permeability and retention (EPR) effect, the CuS-PGH NMs could significantly enhance the cellular uptake by tumors overexpressing CD44 receptors, which respond to hyaluronidase (HAase)-triggered surface charge conversion. Once internalized by the tumor, GOx was the first to be exposed and could effectively deplete endogenous glucose for starvation therapy, and the excess H2O2 was then converted into highly toxic hydroxyl radicals (˙OH) via a Cu+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Meanwhile, the as-obtained Cu+ ions accompanied the regenerated less-active Cu2+ ions. Interestingly, the high content of H2O2 could, in turn, accelerate Cu2+/Cu+ conversion to promote the Cu+-H2O2 reaction for enhanced chemodynamic therapy (CDT), thereby achieving efficient tumor growth suppression via synergistic starvation/CDT therapy. Subsequently, owing to the strong NIR-II absorption capability of CuS-PGH NMs, effective photothermal tumor ablation of the weakened tumor cells could be realized with the precise guidance of NIR-II PAI. This multi-gradient therapeutic strategy has been demonstrated to have excellent antitumor activity with minimal nonspecific damages, and offers a new avenue to precise tumor therapy.

Matrix metalloproteinase-initiated aggregation of melanin nanoparticles as highly efficient contrast agent for enhanced tumor accumulation and dual-modal imaging.

Ultrasmall melanin nanoparticles (MNPs) have great application potential in medical imaging, owing to its satisfactory biodegradation, intrinsic photoacoustic (PA) property and natural chelating ability with metal ions for magnetic resonance imaging (MRI). Because of its ultrasmall particle size, it was easily metabolized by the kidney, but had relatively limited tumor retention according to our previous study. To further improve the intensities of MRI and PA signals for precise diagnosis, it is vital to enhance its tumor accumulation and prolong the retention time. In this study, we developed a matrix metalloproteinase-2 (MMP-2) activatable nanoprobe (PEG-PepMMP2-MNP-Gd), which was composed of water-insoluble gadolinium-chelated melanin (MNP-Gd), MMP-2 cleaved peptide and enzymatic detachable polyethylene glycol (PEG). In the presence of MMP-2 activity, PEG-coating on the surface was peeled off and the "hidden" hydrophobic segment was then exposed, which initiated the aggregation and size increase of nanoprobes. We demonstrated that the hydrodynamic size of the MMP-2 activatable nanoprobe increased from 17.1 nm to 90.2 nm after in vitro incubation with MMP-2. Moreover, the in vivo T1-weighted MRI and PA signals in tumors were both dramatically enhanced and extended after the PEG-PepMMP2-MNP-Gd nanoparticles were intravenously injected into mice. This could be attributed to the changed size selectively activated by highly expressed MMP-2 in tumors, and allowing nanoparticles to possess higher tumor accumulation and longer retention. In short, MMP2-initiated size-changeable PEG-PepMMP2-MNP-Gd could meet the paradoxical demand for size-leading permeability and retention in solid tumors, suggesting its promising applications as a highly efficient MRI/PA contrast agent for precise tumor diagnosis.

Two-stage activated nano-truck enhanced specific aggregation and deep delivery for synergistic tumor ablation.

Although nanomedicines have shown high performance in tumor theranostics, their anticancer activity is still limited by the drug delivery capacity, especially lack of targeting capability, poor tumor accumulation, and insufficient tumor deep-penetration. To address this challenge, a high biocompatibility nano-truck (BMP NT) with a two-stage delivery mechanism is designed and developed to achieve the precision therapeutic efficacy of cancer. In view of the enhanced permeability retention (EPR) effect, the surface cleavable layer of BMP NTs can be selectively removed by the overexpressed MMP-2 in a tumor-microenvironment to expose the hydrophobic segments for an induced "braking effect" strategy, resulting in a significant increase in tumor accumulation. Once internalized into cancer cells with the overproduced glutathione (GSH) and H2O2, the BMP NTs undergo the second-stage "unloading process" to release Mn2+ ions and ultrasmall Bi2S3@BSA nanoparticles, and the obtained Mn2+ ions can act as a Fenton-like catalyst for continuously catalyzing the endogenous H2O2 into highly toxic hydroxyl radicals (˙OH) for CDT. The GSH depletion will in turn improve the Mn2+-H2O2 reaction, further enhancing CDT efficiency. Meanwhile, the ultrasmall Bi2S3@BSA endows BMP NTs with excellent photothermal conversion ability to generate local hyperthermia and accelerate the intratumoral Fenton process, thus leading to an effective tumor therapeutic outcome in the synergistic function of CDT/photothermal therapy (PTT). Moreover, the BMP NTs can be used for in situ self-generation magnetic resonance imaging (MRI) and photoacoustic (PA) imaging to guide precision cancer therapy.

A simple POM clusters for in vivo NIR-II photoacoustic imaging-guided NIR-II photothermal therapy.

Photoacoustic (PA) imaging in the second near-infrared (NIR-II) window exhibits enhanced deep-tissue imaging capability. Likely, cancer therapy in the NIR-II window could provide deeper penetration depth and higher exposure to laser over NIR-I. However, the traditional application of excitation light is still in the NIR-I window. In view of the excellent imaging and therapeutic capabilities of NIR-II window, we have demonstrated a simple polyoxometalate (POM) clusters (molecular formula: (Na)n(PMo12O40) or (NH4+)n(PMo12O40)), which integrates NIR-II photoacoustic imaging and NIR-II photothermal therapy into an "all-in-one" theranostic nanoplatform, and could be used for PA imaging-guided photothermal therapy in the NIR-II window. In vivo experiments demonstrate that the POM clusters with good water solubility and biocompatibility were effective to kill tumor without recurrence and metastasis under 1064 nm laser illumination.

A continuous stimuli-responsive system for NIR-II fluorescence/photoacoustic imaging guided photothermal/gas synergistic therapy.

Nanosystems responsive to a tumor microenvironment (TME) have recently attracted great attention due to their potential in precision cancer theranostics. However, theranostic nanosystems with a TME-activated consecutive cascade for the accurate diagnosis and treatment of cancer have rarely been exploited. Herein, an activatable theranostic nanosystem (Bi2S3-Ag2S-DATS@BSA-N3 NYs) is designed and constructed on the basis of a one-pot biomineralization method and surface functional modification to improve second near-infrared (NIR-II) fluorescence/photoacoustic (PA) imaging-guided photothermal therapy (PTT)/gas therapy (GT). Based on enhanced penetration and retention (EPR) effect-mediated tumor accumulation, the tumor-overexpressed glutathione (GSH) can accelerate hydrogen sulfide (H2S) generation from the nanoparticles by reacting with the encapsulated diallyl trisulfide (DATS). Meanwhile, the in situ released H2S can be used not only for gas therapy, but also to start the reduction of -N3(-) to -NH2(+), thereby enhancing the tumor-specific aggregation of NYs. As a result, the activatable nanosystems with excellent tumor accumulation and biodistribution could achieve an accurate NIR-II/PA dual-modality imaging for guiding the synergistic anticancer efficacy (PTT/GT). Thus, this work provides a promising TME-mediated continuously responsive strategy for efficient anticancer therapy.

IR820 functionalized melanin nanoplates for dual-modal imaging and photothermal tumor eradication.

Melanin as an endogenous biomolecule is widely applied in the biomedical field, focusing especially on diagnostic imaging and photothermal therapy in cancer treatment. However, its photothermal conversion efficiency, a benchmark in tumor photothermal therapy (PTT), often could not satisfy PTT requirements to some degree, and this greatly influenced its use in photothermal cancer therapy. As for fluorescence imaging, a small-molecule NIR dye as a fluorescence probe is easily and rapidly metabolized in vivo, resulting in low accumulation in a tumor. To overcome these problems, we attempt to use melanin as a carrier to conjugate a fluorochrome, a recombinant small NIR dye IR820 nanoplatform containing melanin (MNP-PEG-IR820 abbreviated to MPI). The addition of IR820 not only enhances the PTT ability of the nanoplatform, but also endows the material with excellent NIR fluorescence behavior. Most importantly, the integration of fluorescence dye and melanin improves the circulation and stability performance of IR820 while reducing its toxicity in vivo, owing to the protectivity of melanin. Thus, the diagnostic capability is enhanced. Meanwhile, the behavior of the nanoplatform in PAI/PTT is significantly improved. The in vitro investigations reveal that the MPI NPs afford a potent PTT effect and ideal resistance to photobleaching. After intravenous injection, the MPI NPs display effective PTT tumor eradication in a Hep-2 tumor bearing mouse model with excellent dual NIR-I fluorescence/photoacoustic imaging guided phototherapy. Hence, our work shows the potential of MPI NPs as nano-theranostics for biomedical application to laryngocarcinoma.

The effect of metal ions on endogenous melanin nanoparticles used as magnetic resonance imaging contrast agents.

Melanin nanoparticles are of great importance in biomedicine. They have excellent affinity for metallic cations, especially paramagnetic ions, which has sparked interest in their application in the development of magnetic resonance imaging (MRI) contrast agents. In this work, we prepared ultrasmall water-soluble melanin nanoparticles, and investigated the binding properties of melanin toward different metal cations (Gd3+, Mn2+, Fe3+ and Cu2+), and compared their physicochemical properties and the MRI contrast enhancement ability in various metal chelated forms (MNP-PEG-M) in vitro and in vivo. We show that the saturation binding numbers of Gd3+, Mn2+, Fe3+ and Cu2+ per MNP-PEG were 49, 59, 69 and 62, respectively. MNP-PEG-Gd, MNP-PEG-Mn, MNP-PEG-Fe and MNP-PEG-Cu exhibited the maximum r1 relaxivities at the loading mass ratios of Gd3+ : MNP = 1 : 1, Mn2+ : MNP = 0.5 : 1, Fe3+ : MNP = 0.1 : 1 and Cu2+ : MNP = 0.1 : 1, corresponding to 49, 57, 54 and 51 chelated metals per MNP-PEG, respectively. The maximal per metal ion r1 relaxivity values were 61.9, 48.7, 11.1 and 9.7 mM-1 s-1 for MNP-PEG-Gd, MNP-PEG-Mn, MNP-PEG-Fe and MNP-PEG-Cu at 1.5 T, respectively. MNP-PEG-Gd and MNP-PEG-Fe presented larger sizes (6.9 nm and 5.8 nm) than MNP-PEG-Mn and MNP-PEG-Cu (3.4 nm and 3.7 nm), all featuring excellent solubility, high stability and ultrasmall size. A significant in vivo MRI signal enhancement in tissues was observed for all MNP-PEG-M after intravenous injection in mice, and these nanoparticles were excreted through renal and hepatobiliary pathways. In agreement with their r1 relaxivity values, MNP-PEG-Gd and MNP-PEG-Mn showed a significantly greater in vivo tissue maximum enhancement than MNP-PEG-Fe and MNP-PEG-Cu. This study could yield valuable insight into the development of a new class of MRI contrast agents.

Photoacoustic-imaging-guided therapy of functionalized melanin nanoparticles: combination of photothermal ablation and gene therapy against laryngeal squamous cell carcinoma.

Multimodality therapy under imaging-guidance is significant to improve the accuracy of cancer treatment. In this study, a photoacoustic imaging (PAI)-guided anticancer strategy based on poly-l-lysine functionalized melanin nanoparticles (MNP-PLL) was developed to treat laryngeal squamous cell carcinoma (LSCC). As a promising alternative to traditional therapies for LSCC, MNP-PLL/miRNA nanoparticles were combined with photothermal ablation against primary tumors and miR-145-5p mediated gene therapy for depleting the metastatic potential of tumor cells. Furthermore, taking advantage of the photoacoustic properties of melanin, PAI guided therapy could optimize the time point of NIR irradiation to maximize the efficacy of photothermal therapy (PTT). The in vitro and in vivo results proved that the combined treatments displayed the most significant tumor suppression compared with monotherapy. By integrating thermo-gene therapies into a theranostic nanoplatform, the MNP-PLL/miR-145-5p nanoparticles significantly suppressed the LSCC progression, indicating their great potential use for cancer therapy.

A Dual-Modality MR/PA Imaging Contrast Agent Based on Ultrasmall Biopolymer Nanoparticles for Orthotopic Hepatocellular Carcinoma Imaging.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death and early stage diagnosis can greatly increase the survival rate of patient. However, the accurate detection of HCC remains an urgent challenge in medical diagnosis. The combination of magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) are conducive for accurate locating of cancerous tissue. Therefore, it is necessary to explore a more facile and biosafe dual-modal contrast agent for orthotopic HCC detection. METHODS: In this study, a promising contrast agent had been identified based on gadolinium chelated melanin nanoparticles and evaluated its usage as a dual-modal T1 MRI and PAI contrast agent for orthotopic HCC detection. RESULTS: The gadolinium-based melanin nanoparticles presented ultrasmall size, high chelation stability and negligible cytotoxicity estimated by CCK-8 assay. Moreover, the nanoparticle exhibited higher r1 relaxivity (45.762 mM-1 s-1) than clinically approved Gadodiamide (4.975 mM-1 s-1) at 1.5 T MR scanning. A linear regression analysis confirmed that the nanoparticles were ideal candidates for PAI in vitro. After the nanoparticles were injected into vein in mice with orthotopic HCC, a dramatic increase in signal of the liver was observed at 0.5 hr by MRI and PAI, while the tumor exerted remarkable signal enhancement at 7 hrs, showing excellent detection sensitivity. In addition, the nanoparticles exhibited excellent biocompatibility and they can be excreted through both hepatobiliary and renal pathways after diagnosis. CONCLUSION: These results indicate that the ultrasmall gadolinium chelated melanin nanoparticles is a promising candidate as a dual-modal MRI/PAI contrast agent for the detection of orthotopic HCC.

Enhanced endosomal escape by photothermal activation for improved small interfering RNA delivery and antitumor effect.

BACKGROUND: Effective endosomal escape is still a critical bottleneck for intracellular delivery of small interfering RNAs (siRNAs) to maximize their therapeutic efficacy. To overcome this obstacle, we have developed a photothermally triggered system by using the near-infrared (NIR) irradiation to achieve "on-demand" endosomal escape and subsequent siRNA release into cytoplasm. MATERIALS AND METHODS: Herein, the poly-L-lysine (PLL) was successfully conjugated with melanin to obtain melanin-poly-L-lysine (M-PLL) polymer as a siRNA vehicle. The melanin was an efficient photothermal sensitizer, and the positive pendant amino groups of PLL could condense siRNAs to form stable complexes by electrostatic interactions. RESULTS AND DISCUSSION: Inspired by its excellent photothermal conversion efficiency, the melanin was first involved in the siRNA delivery system. Confocal laser scanning microscopic observation revealed that after cellular uptake the photothermally induced endosomal escape could facilitate siRNAs to overcome endosomal barrier and be delivered into cytoplasm, which resulted in significant silence in the luciferase expression over the NIR- and melanin-free controls. Moreover, the anti-survivin siRNA-loaded M-PLL nanoparticles displayed great inhibitory effect on 4T1 tumor growth in vitro and in vivo. CONCLUSION: These findings suggest that the M-PLL-mediated siRNA delivery is a promising candidate for therapeutic siRNA delivery and shows improved effect for cancer therapy via enhanced endosomal escape.

Ultrasmall endogenous biopolymer nanoparticles for magnetic resonance/photoacoustic dual-modal imaging-guided photothermal therapy.

Multi-modal imaging-guided photothermal therapy (PTT) has aroused extensive attention in biomedical research recently because it can provide more comprehensive information for accurate diagnosis and treatment. In this research, the manganese ion chelated endogenous biopolymer melanin nanoparticles were successfully prepared for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging-guided PTT. The obtained nanoparticles with an ultrasmall size of about 3.2 nm exhibited negligible cytotoxicity, high relaxivity for MRI, an excellent photothermal effect and PA activity. Moreover, in vivo MRI and PAI results all demonstrated that the nanoparticles began to diffuse in the blood after intratumoral injection into tumor-bearing mice and could spread throughout the whole tumor region at 3 h, indicating the optimal treatment time. The subsequent photothermal therapy of cancer cells in vivo was carried out and the result showed that tumor growth could be effectively inhibited without inducing any observed side effects. Besides, melanin as an endogenous biopolymer has native biocompatibility and biodegradability, and it can be excreted through both renal and hepatobiliary pathways after treatment. Therefore, the melanin-Mn nanoparticles may assist in better indicating the optimal treatment time, monitoring the therapeutic process and enhancing the therapeutic effect and showed great clinical translation potential for cancer diagnosis and therapy.

Melanin-manganese nanoparticles with ultrahigh efficient clearance in vivo for tumor-targeting T1 magnetic resonance imaging contrast agent.

Endogenous biomaterials in organisms, with native biocompatibility and biodegradability, appear more advantageous in the development of nanoscale diagnostic and therapeutic systems for future clinical translation. Herein, a novel tumor-targeting Magnetic Resonance Imaging (MRI) contrast agent was developed based on Mn2+-chelating ultrasmall water-soluble melanin nanoparticles (MNP-PEG-Mn). The nanoparticles, with a size of about 5.6 nm, presented high chelation stability and showed negligible cytotoxicity as estimated by MTT assay. Moreover, the r1 longitudinal relaxivity (20.56 mM-1 s-1) of MNP-PEG-Mn was much higher than that of Gadodiamide (6.00 mM-1 s-1), which is a clinically approved MRI contrast agent. In vivo MRI experiments revealed excellent tumor-targeting specificity after tumor-bearing mice were intravenously injected with MNP-PEG-Mn. Additionally, MNP-PEG-Mn could be excreted via renal and hepatobiliary pathways with negligible toxicity to body tissues. These preliminary results indicated the clinically translatable potential of MNP-PEG-Mn as a T1 MRI contrast agent for tumor-targeted imaging.

Two new spirobiflavonoids from Abies chensiensis with moderate NO production inhibitory activity.

Phytochemical investigation of the aerial parts of Abies chensiensis afforded two new (compounds 2 and 3) and 27 known compounds, including the related compound larixinol ( 1). The structures of spirobiflavonoids 1- 3 were established using 1D and 2D NMR spectroscopic techniques. In addition, the structure of larixinol ( 1) was confirmed by X-ray crystallographic analysis. Compounds 1- 3 were evaluated for inhibitory activities against LPS-induced NO production in macrophages. Larixinol ( 1) showed moderate effects, with an IC(50) value of 60.0 microg/mL. In addition, it did not show any cytotoxicity on RAW 264.7 macrophages at 100 microg/mL.