Bright Asymmetric Shielding Strategy-Based NIR-II Probes for Angiography and Localized Photothermal Therapy.

Fluorescent probes with fluorescence emission in the NIR-II window have been widely studied due to increased imaging depth. However, the currently reported NIR-II fluorescent probes present some disadvantages, such as complicated synthesis routes and low fluorescence quantum yields (QYs). The shielding strategy has been used in the development of NIR-II probes to improve their QYs. So far, this strategy has only been used for the symmetric NIR-II probes, especially those based on the benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole) (BBTD) skeleton. This work reports the synthesis of a series of asymmetric NIR-II probes based on shielding strategies accompanied by simple synthetic routes, high synthetic yields (above 90%), high QYs, and large Stoke shifts. Furthermore, the use of d-α-tocopheryl polyethylene glycol succinate (TPGS) as a surfactant for an NIR-II fluorescence probe (NT-4) improved its water solubility. In vivo studies showed that TPGS-NT-4 NPs with a high QY (3.46%) achieve high-resolution angiography and efficient local photothermal therapy, while displaying good biocompatibility. Hence, we combined angiography and local photothermal therapy to improve the tumor uptake of nanophotothermal agents while reducing their damage to normal tissues.

Unexpected detection of a submillimeter early hepatocellular carcinoma focus by intraoperative near-infrared fluorescence imaging-a case report.

Background: Prognosis of hepatocellular carcinoma (HCC) is closely related to residual tumor cells and tissues after tumor resection. Thus, close monitoring to ensure complete removal of residual tumor is fundamental. In this regard, intraoperative near-infrared fluorescence (NIRF) imaging has been of great assistance to surgeons for precision cancer surgeries. However, up to now, the identification of tiny lesions has not been reported. Herein, we report our findings on the case of an ultra-small HCC focus of about 430 µm that was successfully detected using NIRF during real-time monitored liver cancer surgery. The patient had a background of hepatitis B cirrhosis, which is the most phenomenon in China. Surgeons usually unable to distinguish sclerotic nodules from small tumor tissue with the naked eyes. Case Description: A 55-year-old man with chronic hepatitis B infection was preoperatively diagnosed with a space-occupying liver lesion. A fluorescence signal was detected on the surface of the liver through the NIRF imaging system which had not been found by preoperative computed tomography (CT) and ultrasound examination. We subsequently tested the residual liver surface and observed a high signal point, less than 1 mm in the right anterior lobe of the liver. Histopathological examination revealed that the tiny fluorescent spot belong to an early HCC focus. Conclusions: Based on these results, we think indocyanine green (ICG)-NIRF imaging may be used as a routine intraoperative detection method for liver cancer surgery in order to remove any residual tumor cells and tissue, hence minimizing further risk of remnant tumor regrowth.

A study on setting standards for near-infrared fluorescence-image guided surgery (NIRFGS) time lapse monitoring based on preoperative liver function assessment.

Background: This study aimed to explore the relationship between the fluorescence intensity of indocyanine green (ICG) in near-infrared fluorescence guided surgery (NIRFGS) and preoperative liver function indicators. Methods: A total of 12 4T1 tumor-bearing mice were used for model establishment. Intraperitoneal injection (i.p.) of 20% carbon tetrachloride (CCl4) corn oil solution (50 µL) was given to mice in the liver injury model group, 24 hours after injection, the model was established, while the control group received 0% CCl4 corn oil solution (50 µL) (n=6 for each group). Additionally, doses of 8 mg/kg and 1 mg/kg of free ICG were injected intravenously (i.v.) (n=3 in each group). Fluorescence was imaged in vivo using an NIR fluorescence imaging system at different time points (1, 2, 4, 8, 12, 24, 48, and 72 h) after injection. Results: The absolute fluorescence intensity of mice in the liver injury model group was stronger than that in the control group. Mice in the liver injury model group had the same clearance rate of ICG from the tumor as normal mice. However, the background clearance rate was slower than that of normal mice, which prolonged the optimal tumor to background ratio (TBR) time. Correlation analysis was also used to determine which preoperative liver function parameters were most correlated with hepatic ICG clearance. Conclusions: Liver injury does not significantly affect the maximum TBR, but prolongs the optimal TBR time, and at the same time, a wider and more stable surgical window will appear. This study showed that a prolonged surgical start time is feasible according to preoperative liver function testing using NIR fluorescence imaging technology.

Advantages of using indocyanine green in liver transplantation: a narrative review.

Objective: To assess the role of indocyanine green in liver transplantation and to lay the foundation for its application in clinical practice. Background: Liver transplantation offers the best prognosis for patients with end-stage liver disease. However, this invasive procedure involves multiple well-known challenges, including complications due to graft rejection and dysfunction, surgical risks, and critical postoperative management. Intraoperative methods to assess graft function rely on conventional methods, such as blood chemistries and Doppler ultrasound. However, these methods are limited in their abilities to assess liver conditions, predict functional outcomes of the graft, and prevent surgical complications. Thus, identifying a more effective and comprehensive detection method is necessary. Methods: The information used to write this narrative review was collected from the references' opinions and conclusions. Conclusions: Indocyanine green can effectively monitor blood flow during surgery, evaluate donor graft function, and monitor the recipients functional status during and after surgery. It may also help surgeons to predict the prognosis of patients throughout the liver transplantation process, from assessing patients for liver transplantation status to postoperative management. Therefore indocyanine green should be routinely used in liver transplantation to help re-organize the transplant waiting list and improve the surgical outcomes of liver transplantation patients.

A pilot study of near-infrared fluorescence guided surgery for primary tumor localization and lymph node mapping in colorectal cancer.

BACKGROUND: This pilot study aimed to evaluate the feasibility of near-infrared fluorescence imaging for primary tumor localization, lymph node mapping, and metastatic lymph node detection in colorectal cancer (CRC) using indocyanine green (ICG). METHODS: A total of 11 patients with CRC were prospectively enrolled. ICG (25 mg dissolved in 30 mL sterile water) was intravenously injected preoperatively, and the fluorescence intensity of the primary tumor, lymph nodes, and normal tissues, as well as the signal-to-background ratio (SBR) and contrast-to-noise ratio (CNR) were measured at 0.5, 1, 2, 4, and 24 h after ICG injection. RESULTS: The primary tumor could be located intraoperatively, and the tumor boundary was clear at 2-4 h. There was good contrast in the fluorescence intensity between tumor and normal tissues (SBR =2.11±0.36, CNR =8.74±0.35). The lymph node detection rate was 95% (38/40), and the SBR threshold of lymph nodes was 1.13. CONCLUSIONS: This pilot study showed that primary tumor localization and lymph node mapping in CRC is feasible using near-infrared fluorescence imaging technology, though metastatic lymph nodes cannot be discriminated from benign ones. In addition, cancer nodules missed by both white light mode and palpation by the surgeon were unexpectedly found, resulting in a change in the surgical prognosis in 9.1% (1/11) of patients.

Folate Receptor-Targeting and Reactive Oxygen Species-Responsive Liposomal Formulation of Methotrexate for Treatment of Rheumatoid Arthritis.

Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.

Mitoxantrone- and Folate-TPGS2k Conjugate Hybrid Micellar Aggregates To Circumvent Toxicity and Enhance Efficiency for Breast Cancer Therapy.

Mitoxantrone (MTO) is a potent drug used to treat breast cancer; however, efforts to expand its clinical applicability have been restricted because of its high risk for cardiotoxicity. In this study, we successfully conjugated MTO or folic acid (FA) to a synthesized D-α-tocopheryl polyethylene glycol 2000 succinate (TPGS2k), herein, shortened to MCT and FCT, respectively. The two produced conjugates could self-assemble to form MCT micelles or MCT/FCT mixed micelles (FMCT) aiming to lower systemic toxicity, enhance entrapment efficiency, and provide a platform for targeted delivery. Moreover, these micellar materials showed a significantly low CMC and could be used to load MTO. The diameters of MTO-loaded micelles (MTO-MCT and MTO-FMCT) were less than 100 nm with a negative zeta potential. We further characterized the pH-responsive drug release of MTO-MCT and MTO-FMCT and then assessed their cellular uptake and antitumor efficacy in human breast cancer cell lines (MCF-7) via confocal microscopy, flow cytometry, and cytotoxicity studies. All the results revealed that both MTO-MCT and MTO-FMCT increased drug loading and entrapment efficiency and possessed sufficient pH-sensitive release. Additionally, MTO-FMCT displayed an improved uptake through folate-mediated endocytosis, resulting in a higher cytotoxic effect on MCF-7 cells compared with that of MTO-MCT. Meanwhile, both MTO-MCT and MTO-FMCT exhibited a low toxicity on hCMEC/D3 normal cells. More importantly, pharmacokinetic study demonstrated that, in comparison with free MTO injection, MTO-MCT and MTO-FMCT, respectively, achieved half-lives 11.5 and 13 times longer and a 9.7- and 5.8-fold increase in AUC. In vivo, both MTO-MCT and MTO-FMCT formulations significantly prolonged the survival time of MCF-7 tumor-bearing mice and had a better efficacy/toxicity ratio. Promisingly, MTO-FMCT micelles remarkably increased MTO accumulation in tumors in vivo, induced higher tumor cell apoptosis, and showed lower toxicity toward major organs. These results imply that MTO-FMCT may be used as a potential drug delivery system for breast cancer targeted therapy.

Effects of the Preparation Method on the Formation of True Nimodipine SBE-ß-CD/HP-ß-CD Inclusion Complexes and Their Dissolution Rates Enhancement.

The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b-cyclodextrin (SBE-ß-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-ß-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-ß-CD and ND/HP-ß-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an AL-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M(-1) for ND/SBE-ß-CD and ND/HP-ß-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-ß-CD and HP-ß-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-ß-CD and HP-ß-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products.