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Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer., (© 2024. The Author(s).)

Photothermal therapy (PTT) has emerged as a noninvasive and precise cancer treatment modality known for its high selectivity and lack of drug resistance. However, the clinical translation of many PTT agents is hindered by the limited biodegradability of inorganic nanoparticles and the instability of organic dyes. In this study, a peptide conjugate, IR820-Cys-Trp-Glu-Trp-Thr-Trp-Tyr ( IR820-C ), was designed to self-assemble into nanoparticles for both potent PTT and vascular disruption in melanoma treatment. When co-assembled with the poorly soluble vascular disrupting agent (VDA) combretastatin A4 (CA4), the resulting nanoparticles ( IR820-C@CA4 NPs ) accumulate efficiently in tumors, activate systemic antitumor immune responses, and effectively ablate melanoma with a single treatment and near-infrared irradiation, as confirmed by our in vivo experiments. Furthermore, by exploiting the resulting tumor hypoxia, we subsequently administered the hypoxia-activated prodrug tirapazamine (TPZ) to capitalize on the created microenvironment, thereby boosting therapeutic efficacy and antimetastatic potential. This study showcases the potential of short-peptide-based nanocarriers for the design and development of stable and efficient photothermal platforms. The multifaceted therapeutic strategy, which merges photothermal ablation with vascular disruption and hypoxia-activated chemotherapy, holds great promise for advancing the efficacy and scope of cancer treatment modalities.

Recently, nanomaterials have been well-studied in cancer therapy, but some of them often experience difficulties with degradation in vivo , which could cause severe damage to the human body. Among numerous biodegradable nanomaterials, antimonene nanosheets (AMNSs) are versatile, and possess photothermal and photodynamic properties and photoacoustic imaging (PAI) and drug loading ability. Herein, we employed a clearable multifunctional system. The small molecule photosensitizer IR820 and the gold nanoparticles (AuNPs) at small sizes of approximately 5 nm were loaded onto AMNSs coated with biodegradable chitosan (CS). This nanoplatform showed excellent photothermal and photodynamic properties, satisfactory degradability and photoacoustic imaging ability, good biocompatibility and effective NIR light triggered intracellular synergistic treatment. It also displayed good fluorescence imaging ability in the experiment of cell uptake. These suggested that this versatile nanoplatform was able to significantly enhance the therapeutic efficiency based on synergistic phototherapy, and could also be applied in fluorescence and photoacoustic dual imaging for integrating diagnosis and treatment.

Photothermal therapy (PTT) has attracted wide attention due to its noninvasiveness and its thermal ablation ability. As photothermal agents are crucial factor in PTT, those with the characteristics of biocompatibility, non-toxicity and high photothermal stability have attracted great interest. In this work, new indocyanine green (IR-820) was utilized as a photothermal agent and near-infrared (NIR) fluorescence imaging nanoprobe. To improve the biocompatibility, poly(styrene-co-maleic anhydride) (PSMA) was utilized to encapsulate the IR-820 molecules to form novel IR-820@PSMA nanoparticles (NPs). Then, the optical and thermal properties of IR-820@PSMA NPs were studied in detail. The IR-820@PSMA NPs showed excellent photothermal stability and biocompatibility. The cellular uptaking ability of the IR-820@PSMA NPs was further confirmed in HeLa cells by the NIR fluorescent confocal microscopic imaging technique. The IR-820@PSMA NPs assisted PTT of living HeLa cells was conducted under 793 nm laser excitation, and a high PTT efficiency of 73.3% was obtained., (© 2021 Wiley-VCH GmbH.)

Background: As one of the leading threats for health among women worldwide, breast cancer has high morbidity and mortality. Surgical resection is the major clinical intervention for primary breast tumor, nevertheless high local recurrence risk and breast tissue defect remain two main clinical dilemmas, seriously affecting survival and quality of life of patients., Experimental: We developed a thermoresponsive and injectable hybrid hydrogel platform (IR820/Mgel) by integration of co-loaded porous microspheres (MPs) and IR820 for preventing postoperative recurrence of breast cancer via photothermal therapy and promoting subsequent breast reconstruction., Results: Our results suggested that IR820/Mgel could quickly heated to more than 50.0 ℃ under NIR irradiation, enabling killing effect on 4T1 cells in vitro and prevention effect on post-surgical tumor recurrence in vivo. In addition, the hydrogel platform was promising for its minimal invasion and capability of filling irregularly shaped defects after surgery, and the encapsulated MPs could help to increase the strength of gel to realize a long-term in situ function in vivo, and promoted the attachment and anchorage property of normal breast cells and adipose stem cells., Conclusions: This photothermal hydrogel platform provides a practice paradigm for preventing locally recurrence of breast cancer and a potential option for reconstruction of breast defects., (© 2021. The Author(s).)

The oxidative phosphorylation inhibitor atovaquone (ATO) and the photosensitizer new indocyanine green (IR820) were self-assembled into carrier-free nanodrugs (IR820/ATO NPs) to achieve superior photothermal therapy (PTT), offering an attractive mitochondrial metabolism-regulatable approach for breast cancer treatment, where adenosine triphosphate (ATP) was downregulated along with downregulating the expression of heat shock proteins (HSPs) to amplify the sensitivity of PTT.

Recently, shortwave-infrared (SWIR) fluorescence imaging for the optical diagnostics of diseases has attracted much attention as a new noninvasive imaging modality. For this application, the development of SWIR molecular imaging probes with high biocompatibility is crucial. Although many types of biocompatible SWIR fluorescent probes based on organic dyes have been reported, there are no SWIR-emitting molecular imaging probes that can be used for the detection of specific biomolecules in vivo. To apply SWIR-emitting molecular imaging probes to biomedical fields, we developed a biocompatible SWIR fluorescent dye based on π-conjugation extended indocyanine green (ICG), where ICG is the only approved near-infrared dye by the US Food and Drug Administration (FDA) for use in the clinic. Using the π-conjugation extended ICG, we prepared SWIR molecular imaging probes that can be used for in vivo tumor imaging. Herein, we demonstrate noninvasive SWIR fluorescence imaging of human epidermal growth factor receptor 2 (HER2)-positive and epidermal growth factor receptor (EGFR)-positive breast tumors using π-conjugation extended ICG and monoclonal antibody conjugates. The presented π-conjugation extended ICG analog probes will be a breakthrough to apply SWIR fluorescence imaging in biomedical fields.

Background: Fluorescence-guided surgery (FGS) is under investigation as a means to improve the extent of resection for primary central nervous system (CNS) tumors. Tozuleristide, known also as "Tumor Paint," is an investigational tumor-targeting agent covalently conjugated to a derivative of the fluorescent dye indocyanine green., Objective: To report the finding of avid intraoperative fluorescence of tozuleristide on cerebral vascular malformations., Methods: Our institution is participating in a phase 2/3 study of intraoperative near-infrared fluorescence detection of pediatric primary CNS tumors in patients receiving intravenous tozuleristide and imaged with the Canvas system. Our site enrolled 2 patients with intracranial lesions, suspected preoperatively of possibly being gliomas that proved to be cavernous vascular malformations after resection., Results: Each lesion had a dark blue mulberry appearance and each fluoresced avidly with tozuleristide. Each was completely resected, and the patients recovered without deficit. Pathological assessment showed cavernous angioma for both cases. Tozuleristide fluorescence is postulated to result from binding to matrix metalloproteinase-2 and annexin A2, and literature review demonstrates expression of both these ligands on multiple cerebrovascular lesions, including cavernous malformations., Conclusion: This finding deserves further investigation to determine if tozuleristide "Tumor Paint" may have a wider role in the identification of non-neoplastic intracranial pathologies., (© Congress of Neurological Surgeons 2021.)

Conventional biomaterial-mediated osteosarcoma therapy mainly focuses on its antitumor effect yet often fails to overcome the problem of post-treatment bone tissue defect repair. Simultaneously, minimally invasive drug delivery methods are becoming spotlights for normal tissue preservation. Herein, an injectable curcumin-microsphere/IR820 coloaded hybrid methylcellulose hydrogel (Cur-MP/IR820 gel) platform was designed for osteosarcoma therapy and bone regeneration. In vitro, the K7M2wt osteosarcoma cells were eradicated by hyperthermia and curcumin. Later, the sustained release of curcumin promoted alkaline phosphatase expression and calcium deposition of bone mesenchymal stem cells. In vivo, this hybrid hydrogel could reach tumor site via injection and turned into hydrogel due to heat sensitivity. Under the irradiation of an 808 nm laser, localized hyperthermia (∼51 °C) generated in 5 min to ablate the tumor. Meanwhile, the thermal-accelerated curcumin release and thermal-increased cell membrane permeability led to tumor cell apoptosis. Tumors in photothermal- co -chemotherapy group were successfully restrained from day 2 after treatment. After that, bone reconstruction was promoted because of sustained released curcumin. The chemo- co -thermal efficacy and osteogenic capacity of Cur-MP/IR820 hydrogel suggest a promising approach to the treatment of osteosarcoma and provide provoking inspiration for treating bone tumors and repairing bone tissue.

Cyanine fluorescent dyes are attractive diagnostic or therapeutic agents due to their excellent optical properties. However, in free form, their use in biological applications is limited due to the short circulation time, instability, and toxicity. Therefore, their encapsulation into nano-carriers might help overcome the above-mentioned issues. In addition to indocyanine green (ICG), which is clinically approved and therefore the most widely used fluorescent dye, we tested the structurally similar and cheaper alternative called IR-820. Both dyes were encapsulated into liposomes. However, due to the synthetic origin of liposomes, they can induce an immunogenic response. To address this challenge, we proposed to use erythrocyte membrane vesicles (EMVs) as "new era" nano-carriers for cyanine dyes. The optical properties of both dyes were investigated in different biological relevant media. Then, the temperature stability and photo-stability of dyes in free form and encapsulated into liposomes and EMVs were evaluated. Nano-carriers efficiently protected dyes from thermal degradation, as well as from photo-induced degradation. Finally, a hemotoxicity study revealed that EMVs seem less hemotoxic dye carriers than clinically approved liposomes. Herein, we showed that EMVs exhibit great potential as nano-carriers for dyes with improved stability and hemocompatibility without losing excellent optical properties.

Combined photothermal therapy/chemotherapy by co-delivery of a photosensitizer (PS) and a chemotherapeutic drug has demonstrated great potential for cancer treatment. The intrinsic drawbacks of traditional drug delivery systems (DDSs), such as tedious synthetic procedures, side effects originated from the carrier materials, low loading efficiency, and uncontrolled drug release, however, have impaired their further advancement. On the other hand, enediyne antibiotics are highly cytotoxic toward cancer cells through the generation of lethal carbon radicals via thermal-induced cyclization, endowing them with great potential to achieve enhanced synergistic anticancer performance by incorporation with the photothermal effect of PS. To this end, a carrier-free and NIR/acid dual-responsive DDS was constructed for combined photothermal therapy/chemotherapy. The facile co-assembly of maleimide-based enediyne and PS IR820 was achieved in aqueous solution to give nanoparticles (EICN) with a hydrodynamic diameter of 90 nm and high stability. In vitro study confirmed the acid/NIR dual-responsive degradation and drug release, free radical generation and DNA-cleaving ability of EICN, which was accomplished by the corporation of enediyne and IR820 moieties. Further tests on HeLa cells verified the excellent synergistic anticancer performance of EICN including the improved cellular uptake, NIR-enhanced drug release, DNA damage and histone deacetylase inhibitor capacity. Overall, this carrier-free DDS with dual acid/NIR-responsivity would potentially provide new insights for the development of combined photothermal/chemotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses antibody-IRDye700DX (IR700) conjugates and was recently approved in Japan for patients with inoperable head and neck cancer. Exposure of the tumor with NIR light at a wavelength of 690 nm leads to physicochemical changes in the antibody-IR700 conjugate-cell receptor complex, resulting in increased hydrophobicity and damage to the integrity of the cell membrane. However, it is important that the tumor be completely exposed to light during NIR-PIT, and thus, a method to provide real-time information on tumor location would help clinicians direct light more accurately. IR700 is a fluorophore 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 in operating rooms. Therefore, we investigated whether LIGHTVISION, one of the clinically available ICG cameras, could be employed for NIR-PIT target tumor detection. Due to the limited benefits of adding IR700 molecules, the additional conjugation of IRDye800CW (IR800) or ICG-EG4-Sulfo-OSu (ICG-EG4), which has an overlapping spectrum with ICG, to trastuzumab-IR700 conjugates was performed. Conjugation of second NIR dyes did not interfere the efficacy of NIR-PIT. The dual conjugation of IR800 and IR700 to trastuzumab clearly visualized target tumors with LIGHTVISION by detecting emission light of IR800. We demonstrated that the conjugation of second NIR dyes enables us to provide a real-time feedback of tumor locations prior to NIR-PIT.

Objective: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy., Materials and Methods: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect., Results: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H 2 O 2 , which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly., Conclusion: The present study presents a novel nanoplatform for melanoma treatment., Competing Interests: The authors declare no conflict of interest., (© 2020 Hou et al.)

Purpose: The degradation of drugs within endolysosomes has been widely addressed as a cause of poor bioavailability. One of the strategies to allow molecules to escape from a destructive fate is to introduce a photosensitizing moiety into a drug carrier enabling the permeabilization of endosomes and endolysosomes upon irradiation. This paper presents an alternative delivery nanosystem composed of cost-effective soybean phosphatides mixed with IR-820, a near-infrared (NIR) sensitizer, to load various active compounds and trigger an endolysosomal escape with a low cytotoxic effect., Methods: IR-820-incorporated phosphatides-based nanoparticles were formulated using a thin-film hydration method to encapsulate different molecular probes and a drug model. The nanoparticles were characterized in vitro using dynamic light scattering, transmission electron microscopy, as well as ultraviolet-visible and fluorescence spectroscopy techniques. The NIR-corresponding generation of the photochemical products, the content release, and the cytotoxicity toward the HaCaT keratinocyte cell line were evaluated. The cellular internalization and endolysosomal escape were monitored using a cytochemical marker and fluorescent probes with a colocalization analysis., Results: The IR-820-combined nanoparticles revealed the NIR-triggered changes in the singlet oxygen presence, nanoparticle architecture, and release rate without being cytotoxic. Additionally, the nanoplatform appeared to enhance cellular uptake of the macromolecules. The localization of the cytochemical marker and the colocalization analysis on the fluorescence signals of the encapsulated fluorophore and the lysosome-labeling reporter implied the transient endolysosomal escape of the cargo within the HaCaT cells after NIR irradiation., Conclusion: The inclusion of IR-820 into a soybean-phosphatides base ingredient provides NIR responsiveness, particularly the endolysosomal escape of the payload, to the formulated nanoparticles, while preserving the beneficial properties as a drug carrier. This alternative delivery nanomedicine system has future potential to provide high bioavailability of cytosolic drugs utilizing time- and spatial-controllable NIR triggerability as well as the synergistic therapeutic effects with NIR-biomodulation., Competing Interests: Chaiyarerk Homsirikamol reports grants from National Research Council of Thailand (NRCT), during the conduct of the study. The authors report no other potential conflicts of interest in this work., (© 2020 Homsirikamol et al.)

Backgrounds: Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors., Methods: In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer., Results: The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs., Conclusions: Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.

Due to the lack of effective strategies on the treatment of castration resistant prostate cancer (CRPC), we established a multifunctional nanoplatform (GNS@IR820/DTX-CD133) for the synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemotherapy (CT) under the monitoring of multimodal near-infrared (NIR) fluorescence/photoacoustic (PA) imaging. Benefiting from the guided effect of CD133 antibody, GNS@IR820/DTX-CD133 can targetedly deliver the loaded drug to the tumor tissues, which can further contribute to the combined therapeutic effect. Our experimental results prove that the bio-distribution of GNS@IR820/DTX-CD133 can be monitored with NIR fluorescence and PA imaging. In addition, the application of GNS@IR820/DTX-CD133 for in vitro and in vivo therapy achieves the excellent antitumor effects of the synergistic PTT/PDT/CT strategies under the NIR-light irradiation. Therefore, as a multifunctional nanoplatform integrating the PTT/PDT/CT strategies with tumor multimodal imaging or drug tracing, GNS@IR820/DTX-CD133 has the great potential for clinical applications in the antitumor therapy of CRPC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used photothermal agent, IR820, and chemotherapeutic drug, doxorubicin hydrochloride (DOX), are both hydrophilic molecules that suffer from the drawbacks of a short circulation time, rapid elimination and off-target effects., Methods and Results: Herein, a novel nanodrug that combined HCC-targeted IR820 and DOX was developed based on excipient-free co-assembly. First, lactosylated IR820 (LA-IR820) was designed to target HCC. Then, the LA-IR820/DOX nanodrug (LA-IR820/DOX ND) was purely self-assembled without excipient assistance. The physicochemical properties and the chemo-photothermal antitumour activity of the excipient-free LA-IR820/DOX ND were evaluated. More importantly, the obtained LA-IR820/DOX ND exhibited 100% drug loading, remarkable HCC targeting and excellent antitumour efficacy., Conclusion: This excipient-free LA-IR820/DOX ND may be a promising candidate for the synchronous delivery and synergistic targeting of IR820 and DOX as a combined chemo-photothermal therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Jiang et al.)

Due to their high biocompatibility, high spatial resolution, chromatographic capability, and adjustable size and morphology, magnetic nanoparticles have become the most promising nanomaterials for clinical application in noninvasive imaging and drug delivery for the treatment of malignant tumors. Herein, a novel magnetic nanoparticle coated with calcium carbonate was prepared and loaded with near-infrared drugs to be used as a multifunctional theranostic nanoplatform for the diagnosis and treatment of malignant tumors. Then, these drug-loaded nanoparticles were used for combined photodynamic/photothermal therapy by intravenous administration that was simultaneously guided by fluorescence/MR imaging. Due to the targeted induction of the external magnetic field and tumor response degradation of the calcium carbonate layer, the nanoprobe demonstrated excellent tumor targeting and greatly improved drug aggregation at the tumor site. Finally, single wavelength-mediated photothermal/photodynamic therapy was applied to liver cancer model mice, ultimately achieving an exciting antitumor therapeutic effect. This study may promote further exploration of nanoplatforms based on magnetic nanoparticles for clinical application in the treatment of malignant tumors.

The synergistic combination of gene therapy and photothermal therapy (PTT) has been widely investigated as a promising strategy for cancer treatment. To deliver genes and photothermal agents simultaneously and accurately to a tumor site, a microneedle (MN) patch co-loaded with p53 DNA and IR820 was fabricated by a two-step casting method. Hyaluronic acid was chosen as a matrix and p53 DNA and IR820 were mainly loaded into the tips to enhance utilization and reduce waste. The MN patch could efficiently penetrate the stratum corneum, and dissolve rapidly to release p53 DNA and IR820 in the subcutaneous tumor site. Due to the efficient photothermal efficacy of IR820, the temperature of the tumor site where the MN patch was applied increased by 14.7 °C under near-infrared light irradiation. The MN patch showed excellent antitumor effects in vivo owing to the synergistic effect of gene therapy and PTT. Consequently, the p53 DNA/IR820 MN patch may be a promising synergistic strategy for subcutaneous tumor treatments.

Background and Objectives: To compare the long-term toxicity of infracyanine green (IFCG) to brilliant blue G (BBG) in inverted internal limiting membrane flap surgery (I-ILMFS) for large, full-thickness macular holes (FTMHs). Materials and Methods: Prospective randomized study including 39 eyes with ≥ 400 µm idiopathic FTMH who underwent I-ILMFS with either IFCG or BBG. Postoperative 6- and 12-month corrected distance visual acuity (CDVA), closure rate, and swept-source optical coherence tomography parameters, including ellipsoid zone (EZ) and external limiting membrane (ELM) mean defect length, central foveal thicknesses (CFT), parafoveal macular thickness (MT), ganglion cells and inner plexiform layer (GCL++) thickness, and peripapillary nerve fiber layer (pRNFL) thickness, were compared. Results: Nineteen eyes were included in the IFCG group and 20 eyes in the BBG group. In all cases a FTMH closure was found. CDVA improved at 6 and 12 months in both groups ( p < 0.0005); the increase at 12 months was greater in the BBG group (p = 0.036). EZ and ELM defects did not differ between groups at either follow-up time. CFT at 12 months was greater in the BBG group ( p = 0.041). A 12-months compared to 6-months MT decrease was present in both groups ( p < 0.01). The GCL++ superior inner sector was thicker in the BBG group at 12 months ( p = 0.036), as were the superior outer sector ( p = 0.039 and p = 0.027 at 6 and 12 months, respectively) and inferior outer sector ( p = 0.011 and p = 0.009 at 6 and 12 months, respectively). Conclusion: In our study BBG in I-ILMFS exhibits better long-term CDVA and retinal thickness than does IFCG, suggesting a lesser toxicity from BBG. These findings support the use of BBG over IFCG in I-ILMFS.

A novel core‑shell type thermo‑nanoparticle (CSTNP) co‑loaded with temozolomide (TMZ) and the fluorescein new indocyanine green dye IR820 (termed IT‑CSTNPs) was designed and combined with a near‑infrared (NIR) laser to realize its photothermal conversion. The IT‑CSTNPs were prepared using a two‑step synthesis method and comprised a thermosensitive shell and a biodegradable core. IR820 and TMZ were entrapped in the shell and the core, respectively. Dynamic light scattering results demonstrated that the average hydrodynamic size of the IT‑CSTNPs was 196.4±3.1 nm with a ζ potential of ‑24.9±1.3 mV. The encapsulation efficiencies of TMZ and IR820 were 6.1 and 16.6%, respectively. Temperature increase curves under NIR laser irradiation indicated that the IT‑CSTNPs exhibited the desired photothermal conversion efficiency. The in vitro drug release curves revealed a suitable release capability of IT‑CSTNP under physiological conditions, whereas NIR laser irradiation accelerated the drug release. Inverted fluorescence microscopy and flow cytometry results revealed that the uptake of IT‑CSTNPs by A375 melanoma cells occurred in a concentration‑dependent manner. Confocal laser scanning microscopy results indicated that IT‑CSTNPs entered tumour cells via endocytosis and were located in intercellular lysosomes. In summary, the present study explored the photothermal conversion capability, cellular uptake, and intracellular localization of IT‑CSTNPs.

Anticancer nanomedicine-based multimodal imaging and synergistic therapy hold great promise in cancer diagnosis and therapy owing to their abilities to improve therapeutic efficiency and reduce unnecessary side effects, producing promising clinical prospects. Herein, we integrated chemotherapeutic drug camptothecin (CPT) and near-infrared-absorbing new indocyanine green (IR820) into a single system by charge interaction and obtained a tumor-microenvironment-activatable PCPT SS /IR820 nanoreactor to perform thermal/fluorescence/photoacoustic-imaging-guided chemotherapy and photothermal therapy simultaneously. Specifically, the generated PCPT SS /IR820 showed an excellent therapeutic agent loading content and size stability, and the trials in vitro and in vivo suggested that the smart PCPT SS /IR820 could deeply permeate into tumor tissues due to its suitable micellar size. Upon near-infrared laser irradiation, the nanoreactor further produced a terrific synergism of chemo-photo treatment for cancer therapy. Therefore, the PCPT SS /IR820 polyprodrug-based nanoreactor holds outstanding promise for multimodal imaging and combined dual therapy.

One of the main challenges for immune checkpoint blockade antibodies lies in malignancies with limited T-cell responses or immunologically "cold" tumors. Inspired by the capability of fever-like heat in inducing an immune-favorable tumor microenvironment, mild photothermal therapy (PTT) is proposed to sensitize tumors to immune checkpoint inhibition and turn "cold" tumors "hot." Here we present a combined all-in-one and all-in-control strategy to realize a local symbiotic mild photothermal-assisted immunotherapy (SMPAI). We load both a near-infrared (NIR) photothermal agent IR820 and a programmed death-ligand 1 antibody (aPD-L1) into a lipid gel depot with a favorable property of thermally reversible gel-to-sol phase transition. Manually controlled NIR irradiation regulates the release of aPD-L1 and, more importantly, increases the recruitment of tumor-infiltrating lymphocytes and boosts T-cell activity against tumors. In vivo antitumor studies on 4T1 and B16F10 models demonstrate that SMPAI is an effective and promising strategy for treating "cold" tumors.

Tumor metastases account for about 90% of cancer-related death, among which lymphatic metastases play a pivotal role. Therefore, high-efficiency sentinel lymph node (SLN) identification is significant for lymph node (LN) metastasis diagnosis in clinic. Herein, a novel in vivo covalent albumin-binding near-infrared (NIR) fluorescent IR820-maleimide conjugate (IR-Mal) is firstly designed as a SLN dual-mode imaging agent. The IR-Mal conjugate exhibits bright blue appearance and its large Stokes shift (over 100 nm) increases the fluorescent imaging resolution effectively. The fluorescence intensity of covalent albumin-binding IR-Mal (BSA-IR-Mal) complex is considerably stronger than that of IR-Mal. In vivo, IR-Mal could rapidly covalently bind the tissue interstitial albumin following subcutaneous administration and BSA-IR-Mal complexes could specifically accumulate on LN, and detect both normal and metastatic SLN through naked-eye and fluorescence imaging with high resolution. Moreover, the light stability and enhanced fluorescence intensity of BSA-IR-Mal complex facilitates its diagnosis accuracy. These findings suggest that such in vivo irreversible albumin-binding fluorescence conjugates could serve as a new agent for dual-mode imaging and have a great potential to be applied in the SLNs imaging and diagnosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types., Objective: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma., Methods: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures., Results: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery., Conclusion: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Significant efforts are currently being funneled into the improvement of therapeutic outcomes in cancer by designing hybrid nanomaterials that synergistically combine chemotherapeutic abilities and near-infrared (NIR) light-activated photothermal (PTT) and photodynamic (PDT) activity. Herein, a nanotherapeutic platform is specifically designed to integrate combinational functionalities: chemotherapy, PTT, PDT and traceable optical properties. The system, based on chitosan-reduced graphene oxide (chit-rGO), incorporates and carries a large payload of IR820 dye with dual PTT and PDT activity and a chemotherapeutic drug, doxorubicin (DOX). The potential of the fabricated nanoplatforms to operate as an NIR activatable therapeutic agent is first assessed in aqueous solution by investigating its ability to generate singlet oxygen and heat under NIR irradiation with 785 nm laser irradiation. The in vitro anticancer activity of chit-rGO-IR820-DOX is evaluated against murine colon carcinoma cells (C26). The fabricated nanosystem exhibits synergistic anticancer activity against C26 cancer cells by combining IR820 induced PDT, simultaneous graphene and IR820 induced PTT and the chemotherapeutic effect of DOX. Notably, the therapeutic performance of chit-rGO-IR820-DOX can be controlled by the ratio between IR820 and DOX. Moreover, chit-rGO-IR820-DOX facilitates localization inside cancer cells correlated with the release of DOX via mapping by confocal Raman microscopy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The concept of integrating immunogenic cell death (ICD) with tailoring the immunosuppressive tumor microenvironment (TME) is promising for immunotherapy. Photothermal therapy (PTT) could efficiently induce ICD, while an indoleamine 2,3-dioxygenase (IDO) inhibitor could convert the "cold" TME. Therefore, combination of PTT and the IDO inhibitor is an attractive approach for immunotherapy. Unfortunately, combination of PTT and the IDO inhibitor for tumor therapy is rarely reported. Herein, organic photothermal agent IR820 and IDO inhibitor 1-methyl-tryptophan (1MT) were, for the first time, designed to be an all-rolled-into-one molecule nanoplatform via a molecular engineering strategy. The designed IR820-1MT molecule could self-assemble into nanoparticles with remarkably high dual-therapeutic agent loading (88.8 wt %). Importantly, poor water solubility of 1MT and inadequate targeting and short lifetime of IR820 were all well solved within as-prepared IR820-1MT nanoparticles. The laser-triggered IR820-1MT nanoparticles remarkably enhanced accumulation of cytotoxic T cells, helper T cells, and memory T cells and simultaneously suppressed a proportion of regulatory T cells, resulting in excellent immunotherapy against tumor metastasis and recurrence. Our molecular engineering strategy provides a promising alternative option for design of a robust immunotherapy weapon against tumor metastasis and recurrence.

Context.—: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens., Objectives.—: To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins., Design.—: Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin-stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements., Results.—: Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively., Conclusions.—: Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.

Rationale: Cerebrovascular diseases, together with malignancies, still pose a huge threat to human health nowadays. With the advantages of its high spatial resolution and large penetration depth, fluorescence bioimaging in the second near-infrared spectral region (NIR-II, 900-1700 nm) and its related imaging-guided therapy based on biocompatible fluorescence dyes have become a promising theranostics method. Methods: The biocompatibility of IR-820 we used in NIR-II fluorescence bioimaging was verified by long-term observation. The model of the mouse with a cranial window, the mouse model of middle cerebral artery occlusion (MCAO) and a subcutaneous xenograft mouse model of bladder tumor were established. NIR-II fluorescence cerebrovascular functional imaging was carried out by IR-820 assisted NIR-II fluorescence microscopy. Bladder tumor was treated by NIR-II fluorescence imaging-guided photothermal therapy. Results: We have found that IR-820 has considerable NIR-II fluorescence intensity, and shows increased brightness in serum than in water. Herein, we achieved real time and in vivo cerebrovascular functional imaging of mice with high spatial resolution and large penetration depth, based on IR-820 assisted NIR-II fluorescence microscopy. In addition, IR-820 was successfully employed for NIR-II fluorescence imaging and photothermal therapy of tumor in vivo , and the subcutaneous tumors were inhibited obviously or eradicated completely. Conclusion: Due to the considerable fluorescence intensity in NIR-II spectral region and the good photothermal effect, biocompatible and excretable IR-820 holds great potentials for functional angiography and cancer theranostics in clinical practice., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Triple-negative breast cancer (TNBC) accounts for 15-25% of breast cancer cases and lacks expression of the three most common receptors seen on other subtypes of breast cancer. This lack of expression makes TNBC unsusceptible to currently available targeted or hormonal therapies, so new treatment strategies are desperately needed. Photothermal therapy (PTT), which utilizes nanoparticles (NPs) embedded in tumors as exogenous energy absorbers to convert externally applied near-infrared (NIR) light into heat to ablate cancer cells, has shown promise as an alternative strategy. However, it typically uses gold-based NPs that will remain in the body for extended period of time with unknown long-term health effects. To enable PTT with biodegradable, polymeric NPs, we encapsulated the NIR-absorbing dye IR820 in poly(lactic-co-glycolic acid) (PLGA) NPs. We characterized the physicochemical properties of these IR820-loaded PLGA NPs and evaluated their performance as PTT agents using both in vitro and in vivo models of TNBC. The results demonstrate that these NPs are potent mediators of PTT that induce cell death primarily through apoptosis to effectively hinder the growth of TNBC tumors. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1702-1712, 2019., (© 2019 Wiley Periodicals, Inc.)

Phototherapy as a promising cancer diagnostic and therapeutic strategy has aroused extensive attention. However, single-wavelength near-infrared (NIR) light-triggered combinational treatment of photothermal therapy (PTT) and photodynamic therapy (PDT) is still a great challenge. Herein, a multifunctional micelle activated by a single-wavelength laser for simultaneous PTT and PDT as well as fluorescence imaging is developed. Briefly, new indocyanine green (IR820) is conjugated to d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via the linker 6-aminocaproic acid, and then, chlorin e6 (Ce6) is encapsulated into the micelles formed by TPGS-IR820 conjugates to fabricate TPGS-IR820/Ce6 micelles. As the well-designed TPGS-IR820 conjugate shares a similar peak absorption wavelength with Ce6, this micelle can be applied with a single NIR laser (660 nm). The stable micelles exhibit excellent photothermal conversion efficiency in vitro and in vivo as well as high singlet oxygen generation capacity in tumor cells. After efficient cellular internalization, the as-prepared micelles display outstanding anticancer activity upon single NIR laser irradiation in vitro and in vivo. Furthermore, TPGS-IR820/Ce6 micelles show negligible systemic toxicity. The highly safe and effective TPGS-IR820/Ce6 micelles can offer an innovative strategy to construct single NIR light-induced PTT and PDT combined phototherapy nanoplatforms via suitable modification of organic phototherapeutic agents., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Recently we have reported electronic pre-resonance stimulated Raman scattering (epr-SRS) microscopy as a powerful technique for super-multiplex imaging ( Wei, L. ; Nature 2017 , 544 , 465 - 470 ). However, under rigorous electronic resonance, background signal, which mainly originates from pump-probe process, overwhelms the desired vibrational signature of the chromophores. Here we demonstrate electronic resonant stimulated Raman scattering (er-SRS) microspectroscopy and imaging through suppression of electronic background and subsequent retrieval of vibrational peaks. We observed a change of the vibrational band shapes from normal Lorentzian, through dispersive shapes, to inverted Lorentzian as the electronic resonance was approached, in agreement with theoretical prediction. In addition, resonant Raman cross sections have been determined after power-dependence study as well as Raman excitation profile calculation. As large as 10 -23 cm 2 of resonance Raman cross section is estimated in er-SRS, which is about 100 times higher than previously reported in epr-SRS. These results of er-SRS microspectroscopy pave the way for the single-molecule Raman detection and ultrasensitive biological imaging.

The short lifetime and easy quick elimination of the near-infrared (NIR) dye new indocyanine green (IR820) in the body restrict its practical application as a photothermal agent in cancer therapy. Meanwhile, the drawback of poor water solubility of the chemotherapeutic drug paclitaxel (PTX) largely restricts its clinical applications. Herein, we, for the first time, combined IR820 and PTX in an "all-in-one" fluorescence imaging-guided chemo-photothermal therapy (PTT) platform by a rational design of a novel pH- and enzyme-sensitive IR820-PTX conjugate assembly. Specifically, the IR820-PTX conjugate nanoparticles exhibit an extremely high therapeutic agent content (IR820 and PTX, 95.7%). Besides the good stability in bloodstream, the IR820-PTX nanoparticles can target tumors for high accumulation via the enhanced permeation and retention effect. Particularly, our IR820-PTX nanoparticles simultaneously solve the obstacles of PTX poor solubility and the short lifetime of IR820 for cancer therapy. The simultaneous release of the free drug and dye can efficiently kill tumor cells by the combination of PTT and chemotherapy via NIR irradiation. Furthermore, the combined therapy can be imaging-guided by measuring the NIR fluorescence imaging resulting from the IR820 component. Therefore, our rationally designed pH- and enzyme-sensitive IR820-PTX conjugate nanoparticles provide an alternative "all-in-one" option for an efficient combinational dual-therapy and imaging.

Although demanding, the development of multifunctional theranostic nanoplatforms is attracting considerable worldwide interest. Herein, a theranostic nanoplatform with multifunctions based on polydopamine (PDA) nanoparticles (NPs) was developed, owning dual-imaging and dual-therapy functions for cancer theranostic applications. PDA NPs were generated using a facile polymerization method under alkaline conditions, followed by poly(ethylene glycol) (PEG) modification. Then, the obtained NPs were loaded with IR820 and Fe 3+ ions to produce the final PEGylated PDA/IR820/Fe 3+ (PPIF) NPs. The PPIF NPs thus generated displayed increasingly brighter photoacoustic and magnetic resonance signals with increasing NP concentration and were demonstrated to be cytocompatible and effectively taken up and internalized into HeLa cells. Under near-infrared light irradiation, PPIF NPs can produce heat and reactive oxygen species for photothermal/photodynamic combined cancer therapy. In this study, the versatility of PDA NPs was demonstrated to be promising as a multifunctional nanoplatform for potential cancer theranostic applications.

The development of nanoparticles-based drug delivery systems with a high therapeutic efficacy is necessary to treat multidrug-resistant (MDR) cancer cells. Herein, photothermal agents (IR820 dyes) and anticacner drugs (doxorubicin, DOX) were successively incorporated into amino-terminated porous silicon nanoparticles (NH 2 -PSiNPs) via electrostatic attractions, to prepare DOX/IR820/NH 2 -PSiNPs nanocomposites with a high loading amount of DOX (13.3%, w/w) and IR820 (18.6%, w/w), respectively. Meanwhile, DOX molecules were also directly loaded into NH 2 -PSiNPs to form DOX/NH 2 -PSiNPs nanocomposites (DOX, 18.7%, w/w). Compared with low release percentage (20.3%) of DOX molecules from DOX/NH 2 -PSiNPs in acidic environments under NIR laser irradiation, DOX/IR820/NH 2 -PSiNPs had dual pH/NIR light-triggered release and their release percentage could reach 88.1% under the same conditions. Furthermore, cellular interactions tests demonstrated that DOX/IR820/NH 2 -PSiNPs could delivery more DOX molecules into the nuclei of MDR cancer cells, with efficient intracellular release triggered by NIR light, in contrast to DOX/NH 2 -PSiNPs. Finally, DOX/IR820/NH 2 -PSiNPs exhibited an enhanced chemo-photothermal therapeutic efficacy (cell viability, 38.4%) of killing MDR cancer cells in vitro, compared with 85.4% of free DOX and 75.9% of DOX/NH 2 -PSiNPs. Therefore, based on PSiNPs-based nanocarriers conjugated with photothermal agents and anticancer drugs, NIR light-triggered drug delivery system with higher efficacy of combined chemo-photothermal therapy would have important potential on MDR cancer treatments in future., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To enhance synergistic therapeutic effects in breast cancer therapy. Here, we used hollow mesoporous silica nanoparticles as a biocompatible carrier to coload chemotherapy drugs Irinotecan and near-infrared IR-820 dye, which enhanced antitumor efficacy by combining chemotherapy and phototherapy., Methods: The successful synthesis of hollow mesoporous silica nanoparticles/Irinotecan/IR820 (HMII) nanocomplex was confirmed by Fourier  transform infrared spectroscopy and Fluorescence spectra. The photothermal conversion efficiency and antitumor efficiency in murine breast cancer cells (EMT-6) bearing mice were further evaluated., Results: The results demonstrated that HMII enhanced the delivery of Irinotecan and IR-820 into EMT-6 cells. HMII generated a high temperature upon a near-infrared laser irradiation (808 nm), and showed higher therapeutic efficacy in EMT-6-bearing mice compared with either HMII without laser or free drug with a laser., Conclusion: HMII is a desired drug codelivery system to efficiently inhibit the growth of breast cancer.

Nanoparticle-based drug delivery systems are designed to reach tumor sites based on their enhanced permeation and retention effects. However, a lack of interaction of these nanoparticles with cancer cells might lead to reduced uptake in the tumors, which might compromise the therapeutic efficacy of the system. Therefore, we developed bortezomib and IR-820-loaded hybrid-lipid mesoporous silica nanoparticles conjugated with the hydrophobic-binding peptide, cyclosporine A (CsA), and referred to them as CLMSN/BIR. Upon reaching the tumor site, CsA interacts hydrophobically with the cancer cell membranes to allow effective uptake of the nanoparticles. Nanoparticles ∼160 nm in size were prepared and the stability of IR-820 significantly improved. High cellular uptake of the nanoparticles was evident with pronounced apoptotic effects in PANC-1 and MIA PaCa-2 cells that were mediated by the chemotherapeutic effect of bortezomib and the photothermal and reactive oxygen species generation effects of IR-820. An in vivo biodistribution study indicated there was high accumulation in the tumor with an enhanced photothermal effect in PANC-1 xenograft mouse tumors. Furthermore, enhanced antitumor effects in PANC-1 xenograft tumors were observed with minimal toxicity induction in the organs of mice. Cumulatively, these results indicated the promising effects of CLMSN/BIR for effective chemo-phototherapy of pancreatic cancers.

The major challenge in current clinic contrast agents (CAs) and chemotherapy is the poor tumor selectivity and response. Based on the self-quench property of IR820 at high concentrations, and different contrast effect ability of Gd-DOTA between inner and outer of liposome, we developed "bomb-like" light-triggered CAs (LTCAs) for enhanced CT/MRI/FI multimodal imaging, which can improve the signal-to-noise ratio of tumor tissue specifically. IR820, Iohexol and Gd-chelates were firstly encapsulated into the thermal-sensitive nanocarrier with a high concentration. This will result in protection and fluorescence quenching. Then, the release of CAs was triggered by near-infrared (NIR) light laser irradiation, which will lead to fluorescence and MRI activation and enable imaging of inflammation. In vitro and in vivo experiments demonstrated that LTCAs with 808 nm laser irradiation have shorter T 1 relaxation time in MRI and stronger intensity in FI compared to those without irradiation. Additionally, due to the high photothermal conversion efficiency of IR820, the injection of LTCAs was demonstrated to completely inhibit C6 tumor growth in nude mice up to 17 days after NIR laser irradiation. The results indicate that the LTCAs can serve as a promising platform for NIR-activated multimodal imaging and photothermal therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Theranostics based on nanoparticles have developed rapidly in the past decade and have been widely used in the diagnosis and treatment of liver cancer, breast cancer, and other tumors. However, for skin cancers, there are limited studies. In the present study, we successfully synthesized a theranostic nanoparticle by grating IR820 onto the surface of chitosan-coated magnetic iron oxide, IR820-CS-Fe 3 O 4 , showing an excellent magnetic resonance imaging (MRI) capability and cytotoxic effects against melanoma under irradiation with a near-infrared (NIR) laser (808 nm) in vitro. Furthermore, good stability for up to 8 days and negligible cytotoxicity were observed. These characteristics are important for biomedical applications of nanoparticles. In conclusion, we provide a novel and potential theranostic platform for melanoma treatment and detection., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Fluorescent silica nanoparticles (NPs) have potential in biomedical applications as diagnostics and traceable drug delivery agents. In this study, we have synthesized fluorescent dye grafted silica NPs in two step process. First, a stable method to synthesize various sizes of silica NPs ranging from 20 to 52, 95, 210 and 410nm have been successfully demonstrated. Secondly, as-synthesized silica NPs are readily grafted with some fluorescent dyes like IR-820 and fluorescein isothiocyanate (FITC) dyes by simple impregnation method. IR-820 and FITC dyes are 'activated' by (3-mercaptopropyl)trimethoxysilane (MPTMS) and (3-aminopropyl)triethoxysilane (APTS) respectively prior to the grafting on silica NPs. UV-vis spectroscopy is used to test the stability of dye grafted silica NPs. The fluorescent dye grafted silica NPs are quite stable in aqueous solution. Also, a new type of dual dye-doped hybrid silica nanoparticles has been developed. The combination of microscopic and spectroscopic techniques shows that the synthesis parameters have significant effects on the particle shape and size and is tuneable from a few nanometers to a few hundred nanometers. The ability to create size controlled nanoparticles with associated (optical) functionality may have significant importance in bio-medical imaging., (Copyright © 2016 Elsevier Inc. All rights reserved.)

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

In this study, we synthesized a kind of hollow mesoporous carbon (HMC) as near-infrared (NIR) nanomaterial and made a comparison between HMC and IR-820 commercially available in terms of heat generation properties and thermal stability exposed under NIR laser irradiation. The NIR-induced photothermal tests indicated that HMC had excellent heat generating capacity and remained stable after exposed to NIR laser irradiation for several times. On the contrary, the IR-820 was thermal unstable and degraded completely after exposed to NIR laser irradiation for only one time. The anticancer drug DOX was chosen as a model drug to evaluate the loading capacity and release properties of carboxylated HMC (HMC-COOH). The drug loading efficiency of HMC-COOH could reach to 39.7%. In vitro release results indicated that the release rate of DOX was markedly increased under NIR laser irradiation both in pH5.0 and pH7.4 PBS. Cell viability experiments indicated that HMC-COOH/DOX has a synergistic therapeutic effect by combination of chemotherapy and photothermal therapy. This present research demonstrated that HMC could be employed as NIR-adsorbing agents as well as drug carriers to load lots of drug, realizing the synergistic treatment of chemotherapy and photothermal therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Patients suffering from cancer have benefited from combination therapy. Nanocarriers are the ideal candidates for combination therapy. In this study, we constructed docetaxel (DTX) loaded micellar nanomedicines co-loaded with near infrared (NIR) dye-IR820 for photothermal therapy (PTT)/photodynamic therapy (PDT)/chemotherapy of breast cancer. Lyp-1, a tumor homing peptide, was introduced into the nanosystems to construct the active targeting nanomedicine. In order to deliver IR820 to the tumor site and overcome its short lifetime in vivo, a PEI derivative-PCL-g-PEI was introduced. IR820 with negative charge was formed stable static interaction with the amine groups, meanwhile, the absorption of IR820 in the NIR region was weakened. It indicated that the nanosystem constructed in this study may provide an alternative candidate for mild PTT. By the evaluation of the photothermal conversion in vivo, we can confirm that IR820 has been successfully delivered and effectively accumulated in the tumor site. Furthermore, the tumor cells targeting and anticancer performances of this nanosystem have been studied in vitro and in vivo. The results demonstrated Lyp-1 modification has enhanced the tumor targeting delivery of DTX and IR820. By combining PTT and PDT, DTX nanomedicine efficiently inhibited the growth and metastasis of breast cancer in mice. This nanosystem is a promising candidate for combination therapy of breast cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report a novel system of organically modified silica nanoparticles (Ormosil) capable of near infrared fluorescence and chemotherapy with adjuvant hyperthermia for image guided cancer therapy. Ormosil nanoparticles were loaded with a chemotherapeutic, Doxorubicin (DOX) and cyanine dye, IR820. Ormosil particles had a mean diameter of 51.2±2.4 nanometers and surface charge of -40.5±0.8mV. DOX was loaded onto Ormosil particles via physical adsorption (FDSIR820) or covalent linkage (CDSIR820) to the silanol groups on the Ormosil surface. Both formulations retained DOX and IR820 over a period of 2 days in aqueous buffer, though CDSIR820 retained more DOX (93.2%) compared to FDSIR820 (77.0%) nanoparticles. Exposure to near infrared laser triggered DOX release from CDSIR820. Uptake of nanoparticles was determined by deconvolution microscopy in ovarian carcinoma cells (Skov-3). CDSIR820 localized in the cell lysosomes whereas cells incubated with FDSIR820 showed DOX fluorescence from the nucleus indicating leakage of DOX from the nanoparticle matrix. FDSIR820 nanoparticles showed severe toxicity in Skov-3 cells whereas CDSIR820 particles had the same cytotoxicity profile as bare (No DOX and IR820) Ormosil particles. Furthermore, exposure of CDSIR820 nanoparticles to Near Infrared laser at 808 nanometers resulted in generation of heat (to 43°C from 37°C) and resulted in enhanced cell killing compared to Free DOX treatment. Bio-distribution studies showed that CDSIR820 nanoparticles were primarily present in the organs of Reticuloendothelial (RES) system., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Two near-infrared dyes featuring good dispersion and light-harvesting property present a remarkable nonlinear photoacoustic response in vitro and in vivo comparing with conventional gold nanorods. This study benefits the fabrication of drug delivery platforms with accurate targeting and control effect under photoacoustic image guidance., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The term "chromovitrectomy" has been coined to define the use of vital dyes in vitreoretinal surgery. The basic concept for the application of vital dyes during vitreoretinal surgery is to assist in highlighting preretinal membranes and tissues which are very thin and semitransparent and thus difficult to detect. Various dyes are currently being used in routine clinical procedures, however, the ideal staining agent has not yet been found. The vital dyes indocyanine green, infracyanine green, and brilliant blue stain the internal limiting membrane, trypan blue and triamcinolone acetonide help to visualize the epiretinal and vitreous membranes. New dyes with a better safety profile than the synthetic ones are important for optimizing the outcome of modern ophthalmic surgery and natural dyes, such as lutein, offer a potentially safer and more efficient method of identifying intraocular structures such as vitreous and ILM. Any dye, which is intravitreally injected has the potential to become toxic.

Importance: Surgical cure of head and neck squamous cell carcinoma (HNSCC) remains hampered by inadequately resected tumors and poor recognition of lesions with malignant potential. BLZ-100 is a chlorotoxin-based, tumor-targeting agent that has not yet been studied in HNSCC., Objective: To evaluate BLZ-100 uptake in models of HNSCC and oral dysplasia., Design, Setting, and Participants: This was an observational study (including sensitivity and specificity analysis) of BLZ-100 uptake in an orthotopic xenograft mouse model of HNSCC and a carcinogen-induced dysplasia model of hamster cheek pouches., Interventions: Various HNSCC xenografts were established in the tongues of NOD-scid IL2Rgammanull (NSG) mice. BLZ-100 was intravenously injected and fluorescence uptake was measured. To induce dysplasia, the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) was applied to the cheek pouch of Golden Syrian hamsters for 9 to16 weeks. BLZ-100 was subcutaneously injected, and fluorescence uptake was measured., Main Outcomes and Measures: The signal-to-background ratio (SBR) of BLZ-100 was measured in tumor xenografts. To calculate the sensitivity and specificity of BLZ-100 uptake, a digital grid was placed over tissue sections and correlative histologic sections to discretely measure fluorescence intensity and presence of tumor; a receiver operating characteristic (ROC) curve was then plotted. In the hamster dysplasia model, cheeks were graded according to dysplasia severity. The SBR of BLZ-100 was compared among dysplasia grades., Results: In HNSCC xenografts, BLZ-100 demonstrated a mean (SD) SBR of 2.51 (0.47). The ROC curve demonstrated an area under the curve (AUC) of 0.89; an SBR of 2.50 corresponded to 92% sensitivity and 74% specificity. When this analysis was focused on the tumor and nontumor interface, the AUC increased to 0.97; an SBR of 2.50 corresponded to 95% sensitivity and 91% specificity. DMBA treatment of hamster cheek pouches generated lesions representing all grades of dysplasia. The SBR of high-grade dysplasia was significantly greater than that of mild-to-moderate dysplasia (2.31 [0.71] vs 1.51 [0.34], P = .006)., Conclusions and Relevance: BLZ-100 is a sensitive and specific marker of HNSCC and can distinguish high-risk from low-risk dysplasia. BLZ-100 has the potential to serve as an intraoperative guide for tumor margin excision and identification of premalignant lesions.

Near-infrared (NIR) dyes functionalized magnetic nanoparticles (MNPs) have been widely applied in magnetic resonance imaging (MRI), NIR fluorescence imaging, drug delivery, and magnetic hyperthermia. However, the stability of MNPs and NIR dyes in water is a key problem to be solved for long-term application. In this study, a kind of superstable iron oxide nanoparticles was synthesized by a facile way, which can be used as T1 and T2 weighted MRI contrast agent. IR820 was grafted onto the surface of nanoparticles by 6-amino hexanoic acid to form IR820-CSQ-Fe conjugates. Attached IR820 showed increased stability in water at least for three months and an enhanced ability of singlet oxygen production of almost double that of free dyes, which will improve its efficiency for photodynamic therapy. Meanwhile, the multispectral optoacoustic tomography (MSOT) and NIR imaging ability of IR820-CSQ-Fe will greatly increase the accuracy of disease detection. All of these features will broaden the application of this material as a multimodal theranostic platform.

Vibrational spectroscopy is a powerful analytical tool that assesses molecular properties based on spectroscopic signatures. In this study, the effect of gold nanoparticle morphology (spherical vs multi-branched) was assessed for the characterization of a Raman signal (ie, molecular fingerprint) that may be helpful for numerous medical applications. Multi-branched gold nanoparticles (MBAuNPs) were fabricated using a green chemistry method which employed the reduction of gold ion solute by 2-[4-(2-hydroxyethyl)-1-piperazyl] ethane sulfonic acid. Two types of reporter dyes, indocyanine (IR820 and IR792) and carbocyanine (DTTC [3,3'-diethylthiatricarbocyanine iodide] and DTDC [3,3'-diethylthiadicarbocyanine iodide]), were functionalized to the surface of the MBAuNPs and stabilized with denatured bovine serum albumin, thus forming the surface-enhanced Raman spectroscopy tag. Fluorescein isothiocyanate-conjugated anti-epidermal growth factor receptor to the surface-enhanced Raman spectroscopy tags and the properties of the resulting conjugates were assessed through determination of the Raman signal. Using the MBAuNP Raman probes synthesized in this manner, we demonstrated that MBAuNP provided significantly more surface-enhanced Raman scattering signal when compared with the associated spherical gold nanoparticle of similar size and concentration. MBAuNP enhancements were retained in the surface-enhanced Raman spectroscopy tags complexed to anti-epidermal growth factor receptor, providing evidence that this could be a useful biological probe for enhanced Raman molecular fingerprinting. Furthermore, while utilizing IR820 as a novel reporter dye linked with MBAuNP, superior Raman signal fingerprint results were obtained. Such results provide significant promise for the use of MBAuNP in the detection of numerous diseases for which biologically specific surface markers exist.

Tumor hypoxia is associated with the rapid proliferation and growth of malignant tumors, and the ability to detect tumor hypoxia is important for predicting tumor response to anti-cancer treatments. We have developed a class of dye-conjugates that are related to indocyanine green (ICG, ) to target tumor hypoxia, based on in vivo infrared fluorescence imaging using nitroimidazole moieties linked to indocyanine fluorescent dyes. We previously reported that linking 2-nitroimidazole to an indocyanine dicarboxylic acid dye derivative () using an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG, ), led to a dye-conjugate that gave promising results for targeting cancer hypoxia in vivo. Structural modification of the dye conjugate replaced the ethanolamine unit with a piperazineacetyl unit and led a second generation dye conjugate, piperzine-2-nitroimidazole-ICG (). This second generation dye-conjugate showed improved targeting of tumor hypoxia when compared with . Based on the hypothesis that molecules with more planar and rigid structures have a higher fluorescence yield, as they could release less absorbed energy through molecular vibration or collision, we have developed a new 2-nitroimidazole ICG conjugate, , with two carbon atoms less in the polyene linker. Dye-conjugate was prepared from our new dye (), and coupled to 2-nitroimidazole using a piperazine linker to produce this third-generation dye-conjugate. Spectral measurements showed that the absorption/emission wavelengths of 657/670 were shifted ∼100 nm from the second-generation hypoxia dye of 755/780 nm. Its fluorescence quantum yield was measured to be 0.467, which is about 5 times higher than that of (0.083). In vivo experiments were conducted with balb/c mice and showed more than twice the average in vivo fluorescence intensity in the tumor beyond two hours post retro-orbital injection as compared with . These initial results suggest that may significantly improve in vivo tumor hypoxia targeting.