Realization of NIR-II 3D whole-body contour and tumor blood vessels imaging in small animals using rotational stereo vision technique.

Significance: Optical imaging in the second near-infrared (NIR-II, 1000 to 1700 nm) region is capable of deep tumor vascular imaging due to low light scattering and low autofluorescence. Non-invasive real-time NIR-II fluorescence imaging is instrumental in monitoring tumor status. Aim: Our aim is to develop an NIR-II fluorescence rotational stereo imaging system for 360-deg three-dimensional (3D) imaging of whole-body blood vessels, tumor vessels, and 3D contour of mice. Approach: Our study combined an NIR-II camera with a 360-deg rotational stereovision technique for tumor vascular imaging and 3D surface contour for mice. Moreover, self-made NIR-II fluorescent polymer dots were applied in high-contrast NIR-II vascular imaging, along with a 3D blood vessel enhancement algorithm for acquiring high-resolution 3D blood vessel images. The system was validated with a custom-made 3D printing phantom and in vivo experiments of 4T1 tumor-bearing mice. Results: The results showed that the NIR-II 3D 360-deg tumor blood vessels and mice contour could be reconstructed with 0.15 mm spatial resolution, 0.3 mm depth resolution, and 5 mm imaging depth in an ex vivo experiment. Conclusions: The pioneering development of an NIR-II 3D 360-deg rotational stereo imaging system was first applied in small animal tumor blood vessel imaging and 3D surface contour imaging, demonstrating its capability of reconstructing tumor blood vessels and mice contour. Therefore, the 3D imaging system can be instrumental in monitoring tumor therapy effects.

Observation and identification of autofluorescent urine crystals may be linked to a sign of urolithiasis.

Urolithiasis is a common disease of the urinary system. Its recurrence rate is high and may increase medical expenses. Urine stones are composed of urine crystals and other impurities. We discovered the existence of autofluorescence in some of the urine crystals, especially in urolithiasis patients. The fluorescent molecule existed in urine crystals was verified and identified. We have applied micro-Raman and fluorescence microscopy to classify the urine crystals, used confocal laser scanning microscopy (CLSM) to examine the 3D images and spectra of autofluorescence in crystals, used Fourier-transform infrared spectroscopy (FTIR) and mass spectrometry (MS) to identify the type of fluorophore in the autofluorescent urine crystals in urine. Riboflavin was identified as one of the major fluorophores in these autofluorescent urine crystals. The prevalence rates of the autofluorescent crystals in urolithiasis patients and subjects without the history of urolithiasis were to gather statistics. We observed that 80% of urolithiasis patients had autofluorescent crystals. Contrastingly, such crystals existed in only 7% of subjects without the history of urolithiasis. The presence of autofluorescent urine crystals may be linked to a sign of urolithiasis.

Development of Stereo NIR-II Fluorescence Imaging System for 3D Tumor Vasculature in Small Animals.

Near-infrared-II (NIR-II, 1000-1700 nm) fluorescence imaging boasts high spatial resolution and deep tissue penetration due to low light scattering, reduced photon absorption, and low tissue autofluorescence. NIR-II biological imaging is applied mainly in the noninvasive visualization of blood vessels and tumors in deep tissue. In the study, a stereo NIR-II fluorescence imaging system was developed for acquiring three-dimension (3D) images on tumor vasculature in real-time, on top of the development of fluorescent semiconducting polymer dots (IR-TPE Pdots) with ultra-bright NIR-II fluorescence (1000-1400 nm) and high stability to perform long-term fluorescence imaging. The NIR-II imaging system only consists of one InGaAs camera and a moving stage to simulate left-eye view and right-eye view for the construction of 3D in-depth blood vessel images. The system was validated with blood vessel phantom of tumor-bearing mice and was applied successfully in obtaining 3D blood vessel images with 0.6 mm- and 5 mm-depth resolution and 0.15 mm spatial resolution. The NIR-II stereo vision provides precise 3D information on the tumor microenvironment and blood vessel path.

Effect of Cerenkov Radiation-Induced Photodynamic Therapy with 18F-FDG in an Intraperitoneal Xenograft Mouse Model of Ovarian Cancer.

Ovarian cancer (OC) metastases frequently occur through peritoneal dissemination, and they contribute to difficulties in treatment. While photodynamic therapy (PDT) has the potential to treat OC, its use is often limited by tissue penetration depth and tumor selectivity. Herein, we combined Cerenkov radiation (CR) emitted by 18F-FDG accumulated in tumors as an internal light source and several photosensitizer (PS) candidates with matched absorption bands, including Verteporfin (VP), Chlorin e6 (Ce6) and 5'-Aminolevulinic acid (5'-ALA), to evaluate the anti-tumor efficacy. The in vitro effect of CR-induced PDT (CR-PDT) was evaluated using a cell viability assay, and the efficiency of PS was assessed by measuring the singlet oxygen production. An intraperitoneal ES2 OC mouse model was used for in vivo evaluation of CR-PDT. Positron emission tomography (PET) imaging and bioluminescence-based imaging were performed to monitor the biologic uptake of 18F-FDG and the therapeutic effect. The in vitro studies demonstrated Ce6 and VP to be more effective PSs for CR-PDT. Moreover, VP was more efficient in the generation of singlet oxygen and continued for a long time when exposed to fluoro-18 (18F). Combining CR emitted by 18F-FDG and VP treatment not only significantly suppressed tumor growth, but also prolonged median survival times compared to either monotherapy.

Enhancing Förster Resonance Energy Transfer (FRET) Efficiency of Titania-Lanthanide Hybrid Upconversion Nanomaterials by Shortening the Donor-Acceptor Distance.

Several robust titania (TiO2) coated core/multishell trivalent lanthanide (Ln) upconversion nanoparticles (UCNPs) hybrid architecture designs have been reported for use in photodynamic therapy (PDT) against cancer, utilizing the near-infrared (NIR) excited energy down-shifting and up-conversion chain of Nd3+ (λ793-808 nm) → Yb3+ (λ980 nm) → Tm3+(λ475 nm) → TiO2 to produce reactive oxygen species (ROS) for deep tissue-penetrating oxidative cytotoxicity, e.g., NaLnF4:Yb,Tm (Ln = Y, Gd). Herein, we demonstrate that by doping the Tm3+ emitter ions in the outer shell and the Nd3+ sensitizer ions in the core, the newly designed NaYF4:Nd,Yb@Yb@Yb,Tm@TiO2 hybrid UCNPs exert more ROS production than the reference NaYF4:Yb,Tm@Yb@Nd,Yb@ TiO2 with the Tm3+ ions in the core and the Nd3+ ions in the outer shell, upon 793 nm laser irradiation, primarily due to the shortening of the Tm3+-TiO2 distance of the former with greater Förster resonance energy transfer (FRET) efficiency. After coating with polyallylamine hydrochloride (PAH)/polyethylene glycol folate (PEG-FA), the resulting NaYF4:Nd,Yb@Yb@Yb,Tm@TiO2-PAH-PEG-FA hybrid nanocomposites could be internalized in MDA-MB-231 cancer cells, which also show low dark cytotoxicity and effective photocytotoxicity upon 793 nm excitation. These nanocomposites could be further optimized and are potentially good candidates as nanotheranostics, as well as for other light-conversion applications.

Optimising FRET-efficiency of Nd3+-sensitised upconversion nanocomposites by shortening the emitter-photosensitizer distance.

Nd3+-Sensitised luminescent upconversion nanoparticles (UCNPs) have gained interest recently as theranostics due to their near-infrared (NIR) light excitation with a better tissue penetration depth. One example is the core/shell design NaYF4:Yb,Er@Nd,Yb. When harvesting the upconversion energy in such architectures, the long emitter-photosensitizer (i.e. Er3+-PS) distances lead to inefficient Förster resonance energy transfer (FRET). Herein, we report a new nanocomposite NaYF4:Nd,Yb@Yb@Yb,Er@Y with Nd3+ ions in the core and Er3+ ions in the shell to shorten the Er-PS distance to achieve better FRET. Furthermore, an outer non-emitting protective Y3+ shell and a conducting Yb3+ shell reduced surface quenching and Er3+-to-Nd3+ energy back transfer effects, respectively. The upconversion FRET and downshifting emission efficiencies were simultaneously optimised by adjusting the thickness of the Y3+ shell, and the FRET efficiency was at least 3.7 times that of the reference NaYF4:Yb,Er@Yb@Nd,Yb@Y in a photodynamic therapy (PDT) model.

Magnetic targeted near-infrared II PA/MR imaging guided photothermal therapy to trigger cancer immunotherapy.

Rationale: Photothermal therapy (PTT) alone is easy to cause cancer recurrence and fail to completely resist metastasis, yet recurrence and metastasis are two major difficulties in cancer treatment. Titanium disulfide (TiS2) nanosheet anchored iron oxide nanoparticles (IO NPs) with strong absorption in the second near-infrared (NIR-II) window and excellent magnetic properties is developed as therapeutic agent for NIR-II photoacoustic (PA) imaging and magnetic resonance (MR) imaging guided NIR-II PTT triggered immunotherapy. Methods: The TiS2 nanosheets were prepared through a modified colloidal chemistry approach, and TSIO nanoagents were prepared by using a one pot self-assembly technique. The magnetic targeting capability of TSIO nanoagents were monitored by NIR-II PA, MR and thermal imaging in vivo. The NIR-II PTT combined with immunotherapy effect was investigated in mouse breast cancer tumor-bearing mice. Results: The TSIO nanoplatform showed enhanced tumor accumulation when a magnetic field was applied and had the ability to real time monitor the treatment process via dual NIR-II PA and MR imaging. In addition, the magnetic targeted NIR-II PA/MR imaging guided PTT provides an effective way to reverse the immunosuppression inside a tumor and to cooperate with immunotherapy to improve therapeutic outcome of the primary, distal and metastatic tumors.

Nd3+ sensitized core-shell-shell nanocomposites loaded with IR806 dye for photothermal therapy and up-conversion luminescence imaging by a single wavelength NIR light irradiation.

To perform photothermal therapy (PTT) and luminescence imaging by a single wavelength NIR light irradiation, we have designed and prepared a novel nanocomposite incorporating the IR806 photothermal sensitizers (PTS) into the core-shell-shell NaYF4:Yb,Er@ NaYF4:Yb@NaYF4:Yb,Nd up-conversion nanoparticles (UCNPs). Irradiation with the 793 nm near-infrared (NIR) laser, the Nd3+ ions in the UCNPs were sensitized to up-convert energy via Yb3+ to the Er3+ ions to emit visible light at 540 nm and 654 nm, as well as to down-convert energy to the Yb3+ ions to emit NIR light at 980 nm. For luminescence imaging, the 793 nm NIR radiation is more suitable to use for deeper-tissue penetration and to reduce overheating problem due to water absorption as compared to 980 nm radiation. Additionally, the same 793 nm NIR radiation could also excite the IR806 dye for effective PTT. Surface modifications of the UCNPs with mesoporous silica (mSiO2) and polyallylamine (PAH) allow stable loading of IR806 dye and further derivatization with polyethylene glycol-folic acid (PEG-FA) for tumor targeting. Preliminary in vitro studies demonstrated that the final UCNP@mSiO2/IR806@PAH-PEG-FA nanocomposites (UCNC-FAs) could be uptaken by the MDA-MB-231 cancer cells and were "dark" viable, and when irradiated with the 793 nm laser, the MDA-MB-231 cell viability was effectively reduced. This indicated that the UCNC-FAs nanocomposites could be potentially useful for targeted photothermal therapy and up-conversion luminescence imaging by a single wavelength NIR light irradiation.

Dinuclear Lanthanide(III)-m-ODO2A-dimer Macrocyclic Complexes: Solution Speciation, DFT Calculations, Luminescence Properties, and Promoted Nitrophenyl-Phosphate Hydrolysis Rates.

Potentiometric speciation studies, mass spectrometry, and DFT calculations helped to predict the various structural possibilities of the dinuclear trivalent lanthanide ion (LnIII , Ln=La, Eu, Tb, Yb, Y) complexes of a novel macrocyclic ligand, m-ODO2A-dimer (H4 L), to correlate with their luminescence properties and the promoted BNPP and HPNP phosphodiester bond hydrolysis reaction rates. The stability constants of the dinuclear Ln2 (m-ODO2A-dimer) complexes and various hydrolytic species confirmed by mass spectrometry were determined. DFT calculations revealed that the Y2 LH-1 and the Y2 LH-2 species tended to form structures with the respective closed- and open-form conformations. Luminescence lifetime data for the heterodimetallic TbEuL system confirmed the fluorescence resonance energy transfer from the TbIII to EuIII ion. The internuclear distance RTbEu values were estimated to be in the range of 9.4-11.3 Š(pH 6.7-10.6), which were comparable to those of the DFT calculated open-form conformations. Multiple linear regression analysis of the kobs data was performed using the equation: kobs,corr. =kobs -kobs,OH =kLn2LHM->1 [Ln2 LH-1 ]+kLn2LH-2 [Ln2 LH-2 ] for the observed Ln2 L-promoted BNPP/HPNP hydrolysis reactions in solution pH from 7 to 10.5 (Ln=Eu, Yb). The results showed that the second-order rate constants for the Eu2 LH-2 and Yb2 LH-2 species were about 50-400 times more reactive than the structural analogous Zn2 (m-12 N3 O-dimer) system.

Lanthanide-Doped Core-Shell-Shell Nanocomposite for Dual Photodynamic Therapy and Luminescence Imaging by a Single X-ray Excitation Source.

Photodynamic therapy (PDT) could be highly selective and noninvasive, with low side effects as an adjuvant therapy for cancer treatment. Because excitation sources such as UV and visible lights for most of the photosensitizers do not penetrate deeply enough into biological tissues, PDT is useful only when the lesions are located within 10 mm below the skin. In addition, there is no prior example of theranostics capable of both PDT and imaging with a single deep-penetrating X-ray excitation source. Here we report a new theranostic scintillator nanoparticle (ScNP) composite in a core-shell-shell arrangement, that is, NaLuF4:Gd(35%),Eu(15%)@NaLuF4:Gd(40%)@NaLuF4:Gd(35%),Tb(15%), which is capable of being excited by a single X-ray radiation source to allow potentially deep tissue PDT and optical imaging with a low dark cytotoxicity and effective photocytotoxicity. With the X-ray excitation, the ScNPs can emit visible light at 543 nm (from Tb3+) to stimulate the loaded rose bengal (RB) photosensitizer and cause death of efficient MDA-MB-231 and MCF-7 cancer cells. The ScNPs can also emit light at 614 and 695 nm (from Eu3+) for luminescence imaging. The middle shell in the core-shell-shell ScNPs is unique to separate the Eu3+ in the core and the Tb3+ in the outer shell to prevent resonance quenching between them and to result in good PDT efficiency. Also, it was demonstrated that although the addition of a mesoporous SiO2 layer resulted in the transfer of 82.7% fluorescence resonance energy between Tb3+ and RB, the subsequent conversion of the energy from RB to generate 1O2 was hampered, although the loaded amount of the RB was almost twice that without the mSiO2 layer. A unique method to compare the wt % and mol % compositions calculated by using the morphological transmission electron microscope images and the inductively coupled plasma elemental analysis data of the core, core-shell, and core-shell-shell ScNPs is also introduced.