A Small-Molecule Based Organic Nanoparticle for Photothermal Therapy and Near-Infrared-IIb Imaging.

Near-infrared window IIb (NIR-IIb, 1500-1700 nm) fluorescence imaging demonstrates attractive properties including low scattering, low absorption, and deep tissue penetration, and photothermal therapy (PTT) is also a promising modality for cancer treatment. However, until now, there is no report on theranostic systems based on small organic molecules combining fluorescence imaging in the NIR-IIb and PTT, highlighting the challenge and strong need for development of such agents. Herein, we report a novel small molecule NIR-IIb dye IT-TQF with a D-A-D structure, which exhibited high fluorescence intensity in the NIR-IIb window. To further translate IT-TQF into an effective theranostic agent, IT-TQF was encapsulated into DSPE-PEG2000 to construct IT-TQF NPs. The physical and photochemical properties of the nanoprobe were investigated in vitro, and the in vivo NIR-IIb imaging and PTT performance were evaluated in normal, subcutaneous, orthotopic, and metastatic tumor mice models. IT-TQF NP-based NIR-IIb imaging demonstrated high spatial resolution and high tissue penetration depth, and small normal blood vessels (55.3 µm) were successfully imaged in the NIR-IIb window. Subcutaneous, orthotopic, and metastatic tumors were all clearly delineated. A high tumor signal-to-background ratio (SBR) of 9.42 was achieved for orthotopic osteosarcoma models, and the erosions of bone tissue caused by tumor cells were precisely visualized. Moreover, NIR-II image-guided surgery was successfully performed to completely remove the orthotopic tumor. Importantly, IT-TQF NPs displayed high PTT efficacy (photothermal conversion efficiency: 47%) for effective treatment of tumor mice. In conclusion, IT-TQF NPs are a novel and promising phototheranostic agent in the NIR-IIb window, and the nanoprobe has high potential for a broad range of biomedical applications.

Protein scaffolds: antibody alternatives for cancer diagnosis and therapy.

Although antibodies are well developed and widely used in cancer therapy and diagnostic fields, some defects remain, such as poor tissue penetration, long in vivo metabolic retention, potential cytotoxicity, patent limitation, and high production cost. These issues have led scientists to explore and develop novel antibody alternatives. Protein scaffolds are small monomeric proteins with stable tertiary structures and mutable residues, which emerged in the 1990s. By combining robust gene engineering and phage display techniques, libraries with sufficient diversity could be established for target binding scaffold selection. Given the properties of small size, high affinity, and excellent specificity and stability, protein scaffolds have been applied in basic research, and preclinical and clinical fields over the past two decades. To date, more than 20 types of protein scaffolds have been developed, with the most frequently used being affibody, adnectin, ANTICALIN®, DARPins, and knottin. In this review, we focus on the protein scaffold applications in cancer therapy and diagnosis in the last 5 years, and discuss the pros and cons, and strategies of optimization and design.

An active-passive strategy for enhanced synergistic photothermal-ferroptosis therapy in the NIR-I/II biowindows.

Ferroptosis therapy (FT) is an attractive strategy to selectively damage cancer cells through lipid peroxide (LPO) over-accumulation. However, this therapy suffers from poor therapeutic efficacy due to the limited Fenton reaction efficiency and the evolved intrinsic resistance mechanism in the tumor microenvironment (TME). The exploitation of novel ferroptosis inducers is of significance for improving the efficacy of FT. Here, we develop a plate-like Bi2Se3-Fe3O4/Au (BFA) theranostic nanoplatform, which can increase the Fenton reaction rate to enhance FT in an active-passive way. In detail, benefiting from the internal synergistic effect of Fe3O4 NPs and Au NPs and external NIR-mediated hyperthermia, the BFA NPs can boost hydroxyl radical (˙OH) generation to enhance intracellular oxidative stress and further induce ferroptosis by inactivating glutathione peroxidase 4 (GPX4). Furthermore, the BFA NPs show high photothermal conversion efficiency in both the NIR-I and NIR-II windows (66.2% at 808 nm and 58.2% at 1064 nm, respectively); therefore, as a photothermal agent (PTA), they can also ablate cancer cells directly by NIR-triggered photothermal therapy (PTT). Meanwhile, BFA NPs could be used as an efficient diagnostic agent for photoacoustic (PA)/magnetic resonance (MR)/X-ray imaging to guide the synergistic therapy of photothermal-ferroptosis. Therefore, BFA NP-mediated enhanced photothermal-ferroptosis therapy represents a promising strategy for the application of nanomaterials in tumor therapy.

Copper(II)-disulfiram loaded melanin-dots for cancer theranostics.

Copper(II) diethyldithiocarbamate complex (CuET), the metabolite of disulfiram complexed with copper, is the component responsible for cancer treatment efficacy of disulfiram. But the hydrophobic property of CuET limits its use in vivo, and an appropriate drug delivery system needs to be developed. Ultrasmall melanin nanoparticle (M-Dot) with excellent biosafety and biocompatibility properties has been synthesized in our previous studies. Herein we prepared CuET loaded with M-Dots through hydrophobic interaction, which could enhance the water solubility significantly. After the administration of M-Dots-CuET in mice tumor models, the nanoparticles showed good tumor accumulation as evidenced by the enhanced photoacoustic signal in tumor regions. M-Dots-CuET also displayed excellent tumor inhibition capability, and the tumor growth inhibition value (TGI) was 45.1%. When combined with photothermal therapy, the TGI reached up to 78.6%. In summary, M-Dots-CuET provide a new potential strategy for cancer theranostics.

Gadolinium-chelate functionalized bismuth nanotheranostic agent for in vivo MRI/CT/PAI imaging-guided photothermal cancer therapy.

Multifunctional nanomaterials with simple structure and good biosafety, integrating multimodal imaging and therapeutic functions, can facilitate the development of clinical cancer treatments. Here, a simple but powerful pure bismuth based nanoparticle (Gd-PEG-Bi NPs) was developed from pure Bi NPs and gadolinium-diethylenetriaminepentaacetic acid-bis-tetradecylamide, which not only shows high quality MRI/CT/PAI triple-modal imaging, but can also be a potent photothermal therapy agent under the guidance of the triple-modal imaging. The Gd-PEG-Bi NPs showed good stability and excellent biocompatibility. In vitro and in vivo study demonstrated that Gd-PEG-Bi NPs have ultrahigh X-ray attenuation coefficient, short T1 relaxation time in MRI, and strong PAI signal. Following the imaging diagnosis, the excellent light-to-heat conversion efficiency of Gd-PEG-Bi NPs was capable of suppressing the tumor growth effectively under near-infrared laser radiation in vivo. Such multifunctional nanoparticles were ideal candidates for cancer diagnosis and treatment.

Influence of Rhizoglomus irregulare on nutraceutical quality and regeneration of Lycium barbarum leaves under salt stress.

Whether arbuscular mycorrhizal fungi augment the nutraceutical quality of crops under salt stress is critical as a potential agronomic practice in salinized farmland. To evaluate the effect of Rhizoglomus irregulare on the nutraceutical quality of Lycium barbarum leaves under salt stress, we analyzed growth parameters and the rutin, polysaccharide, acidic polysaccharide, and amino acids contents of 2 harvests. Inoculation of R. irregulare significantly increased the regenerated bud number (partial eta squared (PES) = 0.577, P < 0.0001) and rutin concentration (PES = 0.544, P < 0.001) of L. barbarum leaves, with and without salt stress. The biomass of the 2nd harvest (PES = 0.355, P = 0.0091) and acidic polysaccharide (PES = 0.518, P = 0.001) of L. barbarum leaves were notably enhanced by R. irregulare under 200 mmol/L salt level. Rhizoglomus irregulare had insignificant effect on polysaccharide (PES = 0.092, P = 0.221) and amino acids levels (PES = 0.263, P = 0.130) in the leaves of L. barbarum. However, inoculation by R. irregulare decreased proline level (PES = 0.761, P = 0.001) in the leaves of L. barbarum when subjected to salt stress. Taken together, these results indicate that R. irregulare significantly improved the nutraceutical quality and facilitated the sustainable production of L. barbarum leaves exposed to salt stress.

18F-FAZA PET imaging response tracks the reoxygenation of tumors in mice upon treatment with the mitochondrial complex I inhibitor BAY 87-2243.

PURPOSE: We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity. EXPERIMENTAL DESIGN: Four PET tracers [(18)F-FDG, (18)F-Fpp(RGD)2, (18)F-FLT, and (18)F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle. At each point, RNA from treated and vehicle H460 tumor xenografts (n = 3 each) was isolated and analyzed for target genes. RESULTS: Significant changes in uptake of (18)F-FAZA, (18)F-FLT, and (18)F-Fpp(RGD)2 (P < 0.01) occurred with BAY 87-2243 treatment with (18)F-FAZA being the most prominent. (18)F-FDG uptake was unaffected. (18)F-FAZA tumor uptake declined by 55% to 70% (1.21% ± 0.10%ID/g to 0.35 ± 0.1%ID/g; n = 6, vehicle vs. treatment) in both H460 (P < 0.001) and PC3 (P < 0.05) xenografts 1 to 3 days after drug administration. (18)F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting (18)F-FAZA decrease reflected early changes in tumor metabolism. BAY 87-2243 reduced expression of hypoxia-regulated genes CA IX, ANGPTL4, and EGLN-3 by 99%, 93%, and 83%, respectively (P < 0.001 for all), which corresponds with reduced (18)F-FAZA uptake upon drug treatment. Heterogeneous expression of genes associated with glucose metabolism, vessel density, and proliferation was observed. CONCLUSIONS: Our studies suggest suitability of (18)F-FAZA-PET as an early pharmacodynamic monitor on the efficacy of anticancer agents that target the mitochondrial complex I and intratumor oxygen levels (e.g., BAY 87-2243).

Affibody modified and radiolabeled gold-iron oxide hetero-nanostructures for tumor PET, optical and MR imaging.

A highly monodispersed hetero-nanostructure with two different functional nanomaterials (gold (Au) and iron oxide (Fe(3)O(4,) IO)) within one structure was successfully developed as Affibody based trimodality nanoprobe (positron emission tomography, PET; optical imaging; and magnetic resonance imaging, MRI) for imaging of epidermal growth factor receptor (EGFR) positive tumors. Unlike other regular nanostructures with a single component, the Au-IO hetero-nanostructures (Au-IONPs) with unique chemical and physical properties have capability to combine several imaging modalities together to provide complementary information. The IO component within hetero-nanostructures serve as a T(2) reporter for MRI; and gold component serve as both optical and PET reporters. Moreover, such hetero-nanoprobes could provide a robust nano-platform for surface-specific modification with both targeting molecules (anti-EGFR Affibody protein) and PET imaging reporters (radiometal (64)Cu chelators) in highly efficient and reliable manner. In vitro and in vivo study showed that the resultant nanoprobe provided high specificity, sensitivity, and excellent tumor contrast for both PET and MRI imaging in the human EGFR-expressing cells and tumors. Our study data also highlighted the EGFR targeting efficiency of hetero-nanoparticles and the feasibility for their further theranostic applications.

[Clinical randomized controlled trial on splint external fixation combined with Chinese herbs in treating distal radius fractures of elderly patients].

OBJECTIVE: To explore the effects of Yishen Zhuanggu decoction ([Chinese characters: see text], YSZGD) on the fracture healing and function of wrist joint in osteoporotic distal radius fractures (ODRF) of elderly patients. METHODS: Ninety patients of ODRF were treated with splint external fixation and YSZGD, including 28 males and 62 females, with an average age of 63 years (ranged, 61 to 91 years). According to AO classification, all the patients were classified as type A or B1. Among the patients, 80 patients had a type of Colles fracture,7 patients were with a type of Smith fracture,and 3 patients had a type of Barton fracture. They were randomly divided into three groups included TCM, Western medicine and control group (30 cases each group) after the fractures were fixed manually by splint. Patients in TCM group took YSZGD orally, one potion and two time each day; the patients in Western medicine group treated with Calcitonin (50 units, intramuscular, 2 times each week), Caltrate D (1 tablets, taken orally, one time each day) and Alfacalcidol Soft Capsules (0.5 units, taken orally, one time each day); and the patients in control group took no medicine. X-ray examination on the fractured wrist was taken at the 4, 6, 8, 12th weeks after treating to observe, the fracture healings, the evaluation of wrist function and comparision of curative effects were taken at the 2nd month. RESULTS: The fracture healing time in TCM group was 7.12 +/- 2.32 weeks and that in the Western medicine group was 9.25 +/- 3.05 weeks, showing significant differences between them (PC < 0.05), and that in the control group was 11.57 +/- 1.93 weeks which was longer thant in that in the two medicine groups (P < 0.05); According to Dienst wrist rating system, the excellent and good rates of three groups were 93.3%, 86.7% and 60% respectively which showing significant differences between medicine groups and control group (P < 0.05), and the curative effects of medicine groups were more excellent than that of control group through Ridit analysis. CONCLUSION: YSZGD can promote the fracture healing evidently and shorten the healing time, whose curative effect surpassed Western medicine and promoted the restoration of wrist function.