Endoscopic near-infrared photoimmunotherapy in an orthotopic head and neck cancer model.

Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to "see and treat" HNC. This method could also be applied to other types of cancer approachable with endoscopy.

Diagnostic imaging in near-infrared photoimmunotherapy using a commercially available camera for indocyanine green.

Near-infrared photoimmunotherapy (NIR-PIT) is a new type of cancer treatment, which was recently approved in Japan for patients with inoperable head and neck cancer. NIR-PIT utilizes antibody-IRDye700DX (IR700) conjugates and NIR light at a wavelength of 690 nm. NIR light exposure leads to physicochemical changes in the antibody-IR700 conjugate cell receptor complex, inducing rapid necrotic cell death. Just as fluorescence guided surgery is useful for surgeons to resect tumors completely, real-time information of tumor locations would help clinicians irradiate NIR light more precisely. IR700 is a fluorescence dye that emits at 702 nm; however, there is no clinically available device optimized for detecting this fluorescence. On the other hand, many indocyanine green (ICG) fluorescence imaging devices have been approved for clinical use. Therefore, we investigated whether LIGHTVISION, one of the clinically available ICG cameras, could be employed for tumor detection. We hypothesized that irradiation with even low-power 690-nm laser light, attenuated by 99% with a neutral-density filter, could be detected with LIGHTVISION without fluorescence decay or therapeutic effect because of the long emission tail of IR700 beyond 800 nm (within the detection range of LIGHTVISION). We demonstrated that the LIGHTVISION camera, originally designed for ICG detection, can detect the tail of IR700 fluorescence in real time, thus enabling the visualization of target tumors.

Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials.

Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

Effect of m-trifluoromethyl-diphenyl diselenide on acute and subchronic animal models of inflammatory pain: Behavioral, biochemical and molecular insights.

m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] is an organoselenium molecule that displays multiple pharmacological actions, including the antinociceptive effect. The current study investigated the (m-CF3-PhSe)2 restorative properties in models of acute and chronic inflammatory pain induced by complete Freund's adjuvant (CFA). Male adult Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h (acute) or 14 days (subchronic) later they were treated with a single or repeated (m-CF3-PhSe)2 schedule via intragastric route, respectively. The mechanical and thermal hypernociceptive behaviors were assessed by von Frey hair and hot plate tests. Samples of injected paw were collected to evaluate the tissue edema and myeloperoxidase (MPO) activity while cerebral contralateral cortex samples were used to determine the inflammatory proteins content (subchronic protocol). The acute (m-CF3-PhSe)2 administration (1 and 10 mg/kg) reduced the hypernociceptive behavior and both paw thickness and MPO activity induced by CFA injection. In the subchronic protocol, the repeated administration with a low effective dosage of (m-CF3-PhSe)2 reduced the mechanical and thermal hypernociception as well as restored the edema and MPO activity in paw samples. In addition, the repeated treatment schedule mitigated the increase in TNF-α, IL-1ß and COX-2 content in cerebral contralateral cortex induced by CFA injection. Collectively, these data showed that (m-CF3-PhSe)2 presents anti-inflammatory properties, which could be mediated by an interplay between peripheral and central mechanisms of action, reinforcing the potential biological properties of the compound.

Positive association between serum silicon levels and bone mineral density in female rats following oral silicon supplementation with monomethylsilanetriol.

UNLABELLED: Observational (epidemiological) studies suggest the positive association between dietary silicon intake and bone mineral density may be mediated by circulating estradiol level. Here, we report the results of a silicon supplementation study in rats that strongly support these observations and suggest an interaction between silicon and estradiol. INTRODUCTION: Epidemiological studies report strong positive associations between dietary silicon (Si) intake and bone mineral density (BMD) in premenopausal women and indicate that the association may be mediated by estradiol. We have tested this possibility in a mixed-gender rodent intervention study. METHODS: Tissue samples were obtained from three groups of 20-week-old Sprague Dawley rats (five males and five females per group) that had been supplemented ad libitum for 90 days in their drinking water with (i) <0.1 mg Si/L (vehicle control), (ii) 115 mg Si/L (moderate dose) or (iii) 575 mg Si/L (high dose). All rats received conventional laboratory feed, whilst supplemental Si was in the form of monomethylsilanetriol, increasing dietary Si intakes by 18 and 99 %, for the moderate- and high-dose groups, respectively. RESULTS: Fasting serum and tissue Si concentrations were increased with Si supplementation (p < 0.05), regardless of gender. However, only for female rats was there (i) a trend for a dose-responsive increase in serum osteocalcin concentration with Si intervention and (ii) strong significant associations between serum Si concentrations and measures of bone quality (p < 0.01). Correlations were weaker or insignificant for tibia Si levels and absent for other serum or tibia elemental concentrations and bone quality measures. CONCLUSIONS: Our findings support the epidemiological observations that dietary Si positively impacts BMD in younger females, and this may be due to a Si-estradiol interaction. Moreover, these data suggest that the Si effect is mediated systemically, rather than through its incorporation into bone.

Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells.

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25% of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.