Activatable Photodynamic Therapy with Therapeutic Effect Prediction Based on a Self-correction Upconversion Nanoprobe.

Though emerging as a promising therapeutic approach for cancers, the crucial challenge for photodynamic therapy (PDT) is activatable phototoxicity for selective cancer cell destruction with low "off-target" damage and simultaneous therapeutic effect prediction. Here, we design an upconversion nanoprobe for intracellular cathepsin B (CaB)-responsive PDT with in situ self-corrected therapeutic effect prediction. The upconversion nanoprobe is composed of multishelled upconversion nanoparticles (UCNPs) NaYF4:Gd@NaYF4:Er,Yb@NaYF4:Nd,Yb, which covalently modified with an antenna molecule 800CW for UCNPs luminance enhancement under NIR irradiation, photosensitizer Rose Bengal (RB) for PDT, Cy3 for therapeutic effect prediction, and CaB substrate peptide labeled with a QSY7 quencher. The energy of UCNPs emission at 540 nm is transferred to Cy3/RB and eventually quenched by QSY7 via two continuous luminance resonance energy transfer processes from interior UCNPs to its surface-extended QSY7. The intracellular CaB specifically cleaves peptide to release QSY7, which correspondingly activates RB with reactive oxygen species (ROS) generation for PDT and recovers Cy3 luminance for CaB imaging. UCNPs emission at 540 nm remains unchanged during the peptide cleavage process, which is served as an internal standard for Cy3 luminance correction, and the fluorescence intensity ratio of Cy3 over UCNPs (FI583/FI540) is measured for self-corrected therapeutic effect prediction. The proposed self-corrected upconversion nanoprobe implies significant potential in precise tumor therapy.

Covalent bridging of surface functionalized Fe3O4 and YPO4:Eu nanostructures for simultaneous imaging and therapy.

Magnetic luminescent hybrid nanostructures (MLHN) have received a great deal of attention due to their potential biomedical applications such as thermal therapy, magnetic resonance imaging, drug delivery and intracellular imaging. We report the development of bifunctional Fe3O4 decorated YPO4:Eu hybrid nanostructures by covalent bridging of carboxyl PEGylated Fe3O4 and amine functionalized YPO4:Eu particles. The surface functionalization of individual nanoparticulates as well as their successful conjugation was evident from Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), zeta-potential and transmission electron microscopy (TEM) studies. X-ray diffraction (XRD) analysis reveals the formation of highly crystalline hybrid nanostructures. TEM micrographs clearly show the binding/anchoring of 10 nm Fe3O4 nanoparticles onto the surface of 100-150 nm rice grain shaped YPO4:Eu nanostructures. These MLHN show good colloidal stability, magnetic field responsivity and self-heating capacity under an external AC magnetic field. The induction heating studies confirmed localized heating of MLHN under an AC magnetic field with a high specific absorption rate. Photoluminescence spectroscopy and fluorescence microscopy results show optical imaging capability of MLHN. Furthermore, successful internalization of these MLHN in the cells and their cellular imaging ability are confirmed from confocal microscopy imaging. Specifically, the hybrid nanostructure provides an excellent platform to integrate luminescent and magnetic materials into one single entity that can be used as a potential tool for hyperthermia treatment of cancer and cellular imaging.

Water-soluble oxoglaucine-Y(III), Dy(III) complexes: in vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis.

Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.

Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

BACKGROUND & AIMS: The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. METHODS: Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status <2 were screened. Radioembolization was administered using a sequential lobar approach. On day 3 after the last radioembolization procedure, sorafenib 200 mg twice daily was initiated escalating to 400 mg twice daily 1 week later; a matching sorafenib dose schedule was initiated in the control arm. RESULTS: Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. CONCLUSIONS: Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone.

Localized hyperthermia with iron oxide-doped yttrium microparticles: steps toward image-guided thermoradiotherapy in liver cancer.

PURPOSE: To test whether iron oxide (IO)-containing yttrium aluminosilicate (YAS) microparticles (MPs) can generate localized therapeutic hyperthermia (≥ 43°C) when injected intratumorally in an animal model of liver cancer and whether MP distributions could be visualized with magnetic resonance (MR) imaging. MATERIALS AND METHODS: Twenty-one Sprague-Dawley rats implanted with N1-S1 liver tumors were assigned to alternating magnetic field (AMF) exposure following intratumoral injection with IO-YAS MPs (n = 7), sham surgery (n = 7), or baseline iron quantification (n = 7). Three fiberoptic probes allowed spatial and temporal monitoring of temperatures during 24 minutes of AMF exposure. T2-weighted turbo spin-echo MR imaging was performed within 1 hour after the procedure to detect signal voids caused by IO-YAS deposition. Hematoxylin and eosin-stained pathologic slides were also obtained, and the presence of IO-YAS was evaluated with inductively coupled plasma optical emission spectroscopy. RESULTS: Following AMF exposure, intratumoral temperatures after IO-YAS MP injection achieved therapeutic hyperthermia whereas those after sham surgery did not (46.6°C ± 1.3 vs 36.8°C ± 0.4; P < .0001). Within the treated group, the normal hepatic parenchyma (NHP) and rectal temperatures were 37.4°C ± 0.9 and 36.5°C ± 1.0 (P = .0809) at the conclusion of AMF exposure, respectively. A T2-weighted signal void at the tumor site was observed in all seven treated animals, and intratumoral IO-YAS was visualized on subsequent histopathologic examination in each case. The mean ratio of tumor:NHP Fe concentrations attributable to IO-YAS MPs was 108:1. CONCLUSIONS: AMF exposure of intratumoral IO-YAS MPs generates localized therapeutic hyperthermia in an animal model of liver cancer. MR detectability and potential for combination brachytherapy warrants further investigation for thermoradiotherapy in liver cancer.

Laser and light therapy for onychomycosis: a systematic review.

More than just a cosmetic concern, onychomycosis is a prevalent and extremely difficult condition to treat. In older and diabetic populations, severe onychomycosis may possibly serve as a nidus for infection, and other more serious complications may ensue. Many treatment modalities for the treatment of onychomycosis have been studied, including topical lacquers and ointments, oral antifungals, surgical and chemical nail avulsion, and lasers. Due to their minimally invasive nature and potential to restore clear nail growth with relatively few sessions, lasers have become a popular option in the treatment of onychomycosis for both physicians and patients. Laser or light systems that have been investigated for this indication include the carbon dioxide, neodymium-doped yttrium aluminum garnet, 870/930-nm combination, and femtosecond infrared 800-nm lasers, in addition to photodynamic and ultraviolet light therapy. This systematic review will discuss each of these modalities as well as their respective currently published, peer-reviewed literature.

Treatment of onychomycosis using a submillisecond 1064-nm neodymium:yttrium-aluminum-garnet laser.

BACKGROUND: Laser treatment has emerged as a novel treatment modality for onychomycosis. OBJECTIVE: We sought to determine thermal response and optical effects of a submillisecond neodymium:yttrium-aluminum-garnet (Nd:YAG) 1064-nm laser on common fungal nail pathogens, and the clinical efficacy and safety of the Nd:YAG 1064-nm laser on onychomycotic toenails. METHODS: A 4-part in vitro and in vivo study was conducted using a Nd:YAG 1064-nm laser. The first portion evaluated 3 different nail pathogens in suspension at 7 heat and time exposures. The second and third parts of the study irradiated pure fungal colonies. The final portion involved an in vivo treatment of toenails over 5 treatment sessions. RESULTS: A fungicidal effect for Trichophyton rubrum was seen at 50°C after 15 minutes, and for Epidermophyton floccosum at 50°C after 10 minutes. Limited growth of Scytalidium was seen at 55°C after 5 minutes. No inhibition was observed after laser treatment of fungal colonies or suspensions. In vivo treatment of toenails showed no improvement in Onychomycosis Severity Index score. LIMITATIONS: The Nd:YAG 1064-nm laser was the only laser tested. CONCLUSIONS: Laser treatment of onychomycosis was not related to thermal damage or direct laser effects. In vivo treatment did not result in onychomycosis cure.

Comparative evaluation of wrinkle treatments.

BACKGROUND: Skin wrinkles are one of the most cosmetically concerning signs of aging for women, and improvements in the visual effect of wrinkles become a matter of concern that has an impact on the quality of life. Although various wrinkle treatments are being tried in the area of aesthetics and noninvasive cosmetic surgery, no guideline on how to treat wrinkles exists to date. This study evaluated the clinical effects of four wrinkle treatment methods [fractional erbium yttrium-aluminum-garnet (YAG) laser treatment, intense pulsed light (IPL) therapy, CD-atRA external application, and nutritional therapy with intake of amino acid supplements]. These four methods were selected as promising candidates in a pilot case study to improve wrinkles by following the consensus guideline (Task Force Committee for Evaluation of Anti-Aging Function, J Jpn Cosmet Sci Soc 31:411-431, 2007) for the evaluation of anti-wrinkle effects issued by the Japan Cosmetic Industry Association. METHODS: The wrinkle area fraction and skin viscoelasticity were measured by objective evaluation. Furthermore, a satisfaction survey of the subjects was conducted on the basis of subjective evaluations using the visual analog scale (VAS) method and in accordance with the guideline for the evaluation of antiwrinkle effects. RESULTS: Fractional erbium YAG laser treatment showed statistically significant improvement in both of the objective evaluations (wrinkle area and skin elasticity). The IPL method showed statistically significant improvement in both of the objective evaluations (wrinkle area and skin elasticity), and it especially demonstrated a more significant difference in skin elasticity. The CD-tretinoin external application method showed statistically significant improvement in both of the objective evaluations (wrinkle area and skin elasticity), and it especially demonstrated a more significant difference in wrinkle area. Nutritional therapy showed statistically significant improvement in wrinkle area, whereas IPL, CD-tretinoin external application, and nutritional therapy demonstrated statistically significant improvement in the degree of wrinkle. As for the subjective assessment of VAS, all four treatments demonstrated equivalent satisfaction. CONCLUSION: All four minimally invasive procedures (fractional erbium YAG treatment, IPL therapy, CD-atRA external application, and intake of amino acid supplements) showed significant improvement of wrinkles. Comparative evaluation of wrinkles using the same criteria is important. The findings clearly showed that an evidence-based approach to wrinkle treatments supported by validation of their effectiveness is required. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A multifunctional biphasic suspension of mesoporous silica encapsulated with YVO4:Eu3+ and Fe3O4 nanoparticles: synergistic effect towards cancer therapy and imaging.

Polyol mediated synthesized luminescent YVO(4):Eu(3+) nanoparticles (NPs) have been encapsulated in mesoporous silica nanoparticles (MSNs) using the sol-gel process. X-ray diffraction and Fourier transform infrared spectroscopy along with transmission electron microscopy confirm the encapsulation of the YVO(4):Eu(3+) NPs in the SiO(2) matrix. N(2) adsorption/desorption analysis confirms the mesoporous nature of the MSNs and YVO(4):Eu(3+)-MSNs. No significant quenching of the YVO(4):Eu(3+) luminescence is observed for YVO(4):Eu(3+)-MSNs. This nanocomposite has been tested as a potential drug carrier. Efficient loading of doxorubicin hydrochloride (DOX), a typical anticancer drug, is observed which reaches up to 93% in 8 mg ml(-1) of YVO(4):Eu(3+)-MSNs. pH sensitive release of DOX is observed, with 54% release for pH 4.3 and 31% in a physiological environment (pH 7.4). Both MSNs and YVO(4):Eu(3+)-MSNs nanocomposites do not show accountable toxicity to two cell lines, i.e. HeLa and MCF-7. However, as desired, toxicity is observed when cells are incubated with DOX loaded YVO(4):Eu(3+)-MSNs. Laser scanning confocal microscopy images confirm the uptake of the nanocomposite in both cell lines. The morphology of the cells (MCF-7) changes after incubation with DOX loaded YVO(4):Eu(3+)-MSNs, indicating an interaction of DOX with the cells. More cytotoxicity to both cell lines with ∼90% killing is observed due to the synergistic effect of magnetic fluid hyperthermia and chemotherapy using a biphasic suspension of superparamagnetic iron oxide magnetic nanoparticles and DOX loaded YVO(4):Eu(3+)-MSNs. In addition, an AC magnetic field triggers an enhanced drug release.

In vitro guidance of dental pulp cells by Nd:YAG laser-irradiated endothelial cells.

OBJECTIVE: After endothelial cells were ablated by neodymium:yttrium-aluminum-garnet (Nd:YAG) laser irradiation, we investigated the response of pulp cells by examining the expression of transforming growth factor beta-1 (TGF-ß1). BACKGROUND DATA: The reaction of stimulated blood vessels is related to the initiation of dentinogenesis. After artificial injury of endothelial cells, pulp cells migrate to the site of the injured endothelial cells. MATERIALS AND METHODS: Rat aortic endothelial cells were cultured in the lower compartment of the experimental assembly, and a pulsed Nd:YAG laser was used to ablate these cells. Pulp cells were fluorescence labeled and cultured in the upper compartment. After 7-14 days of laser irradiation, total RNA was extracted from the cells in the lower chamber, and RT-PCR was performed to examine the expression of TGF-ß1 and osteocalcin mRNA. TGF-ß1 was also examined with immunohistochemistry. RESULTS: Seven days after laser irradiation, migrating pulp cells that expressed TGF-ß1 were observed in the lower compartment, and the expression of TGF-ß1 mRNA and osteocalcin mRNA was altered. Without laser irradiation, few migrating pulp cells were observed, and the expression of TGF-ß1 mRNA and osteocalcin mRNA was weak. These results suggested that TGF-ß1 mRNA expression is detected earlier in pulp cells rather than in endothelial cells following injury to endothelial cells. CONCLUSIONS: Using the Nd:YAG laser as an ablative stimulant, this study model was useful for investigating pulp-endothelial cell interactions in reparative dentinogenesis.

The diagnosis and management of desmoplastic small round cell tumor: a review.

PURPOSE OF REVIEW: Desmoplastic small round cell tumor (DSRCT) is a rare disease of children, adolescents and young adults, which begins in the abdominal cavity. Less than 200 cases are reported in the world literature. Because of the rarity of this disease, little is known about optimal treatment. Patients may present with dozens to hundreds of tumors studding the peritoneal cavity. Despite this presentation, it is not primarily considered metastatic but multifocal. It can metastasize to the liver or lung. Chemotherapy, radiotherapy, and surgical approaches have not been standardized. Neoadjuvant chemotherapy often yields a partial response; however, tumors may remain surgically un-resectable. An aggressive approach to treatment is required to maximize long-term remission. This review is designed to outline the evidence-based multidisciplinary approach to DSRCT. RECENT FINDINGS: Complete surgical resection, including 1-2 mm implants, is necessary to achieve long-term disease control. Hyperthermic intraperitoneal chemotherapy using cisplatin has recently been found to be a low morbidity treatment option for DSRCT patients. Yttrium microspheres have been used successfully to treat liver metastasis from DSRCT. SUMMARY: DSRCT is a rare tumor that requires a multidisciplinary approach which includes aggressive surgical extirpation to provide long-term disease control.

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement.

Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.

Permanent makeup removal using Q-switched Nd:YAG laser.

Red-brown tattoos are usually treated with a frequency-doubled Q-switched (QS) neodymium:yttrium-aluminum-garnet Nd:YAG laser (532 nm), because red and pink pigments show maximum absorption between 500 and 570 nm. Using a QS laser for red-brown tattoo removal has sometimes led to paradoxical darkening of the tattoo pigments, and this darkened grey-black colour may be difficult to remove. A woman with red-brown cosmetic tattoos on her eyebrows was treated using a QS Nd:YAG laser (1064 nm) initially with low fluence and subsequently with increasing fluences at 6-weekly intervals. After the first treatment, a slight darkening of the tattoo pigments was seen, but this faded and complete clearance was achieved after five treatments. There was no downtime during every treatment and there were no scars, pigmentary alterations or textural changes.