A Tumor-Targeting Near-Infrared Heptamethine Cyanine Photosensitizer with Twisted Molecular Structure for Enhanced Imaging-Guided Cancer Phototherapy.

In recent years, cancer phototherapy has been extensively studied as noninvasive cancer treatment. To present efficient recognition toward cancer cells, most photosensitizers (PSs) are required to couple with tumor-targeted ligands. Interestingly, the heptamethine cyanine IR780 displays an intrinsic tumor-targeted feature even without modification. However, the photothermal efficacy and photostability of IR780 are not sufficient enough for clinical use. Herein, we involve a twisted structure of tetraphenylethene (TPE) between two molecules of IR780 to improve the photothermal conversion efficiency (PCE). The obtained molecule T780T shows strong near-infrared (NIR) fluorescence and improved PCE (38.5%) in the dispersed state. Also, the photothermal stability and ROS generation capability of T780T at the NIR range (808 nm) are both promoted. In the aqueous phase, the T780T was formulated into uniform nanoaggregates (∼200 nm) with extremely low fluorescence and PTT response, which would reduce in vivo imaging background and side effect of PTT response in normal tissues. After intravenous injection into tumor-bearing mice, the T780T nanoaggregates display high tumor accumulation and thus remarkably inhibit the tumor growth. Moreover, the enhanced photostability of the T780T allows for twice irradiation after one injection and leads to more significant tumor inhibition. In summary, our study presents a tumor-targeted small-molecule PS for efficient cancer therapy and brings a new design of heptamethine cyanine PS for potential clinical applications.

A multifunctional nano-delivery system enhances the chemo-co-phototherapy of tumor multidrug resistance via mitochondrial-targeting and inhibiting P-glycoprotein-mediated efflux.

Despite the excellent progress of chemotherapy and phototherapy in tumor treatment, their effectiveness on multidrug-resistant (MDR) tumors is still unsatisfactory. One of the main obstacles is drug efflux caused by P-glycoprotein in MDR cells. Herein, we developed a nano-delivery system that combines a P-glycoprotein inhibitor with chemotherapy and phototherapy to overcome MDR. Briefly, the system is prepared by the self-assembly of a ROS-triggered doxorubicin prodrug (PTD) and mitochondrial-targeted D-α-tocopherol polyethyleneglycol succinate (TPP-TPGS), in which a photoactive drug, IR780, is encapsulated (PTD/TT/IR780). PTD/TT/IR780 can target the release of TPP-TPGS, doxorubicin and IR780 at the mitochondrial site of MDR cells through ROS trigger. D-α-Tocopherol polyethyleneglycol succinate (TPGS) is a P-glycoprotein inhibitor, which will reduce the efflux of doxorubicin and IR780 from MDR cells. Under irradiation of an 808 nm near-infrared laser, IR780 generates heat and ROS, causing mitochondrial damage and prompting MDR cell apoptosis. At the same time, ROS can reduce the ATP content, which inhibits the P-glycoprotein function. In addition, an increase in the ROS generates positive feedback, allowing more nanoparticles to be cleaved and further promoting payload release in MDR cells, thereby enhancing the synergistic efficacy of chemotherapy and phototherapy. The in vitro cellular assay showed that PTD/TT/IR780 significantly inhibited MDR cell proliferation at a very low drug concentration (IC50 = 0.27 µg mL-1 doxorubicin-equivalent concentration). In vivo animal experiments based on BALB/c nude mice bearing MCF-7/ADR tumors confirmed a superior antitumor efficacy and an excellent biosafety profile. These findings demonstrate that this multifunctional nanoplatform provides a new approach for the treatment of MDR tumors.

Survey of X-ray induced Cherenkov excited fluorophores with potential for human use.

X-ray induced molecular luminescence (XML) is a phenomenon that can be utilized for clinical, deep-tissue functional imaging of tailored molecular probes. In this study, a survey of common or clinically approved fluorophores was carried out for their megavoltage X-ray induced excitation and emission characteristics. We find that direct scintillation effects and Cherenkov generation are two possible ways to cause these molecules' excitation. To distinguish the contributions of each excitation mechanism, we exploited the dependency of Cherenkov radiation yield on X-ray energy. The probes were irradiated by constant dose of 6 MV and 18 MV X-ray radiation, and their relative emission intensities and spectra were quantified for each X-ray energy pair. From the ratios of XML, yield for 6 MV and 18 MV irradiation we found that the Cherenkov radiation dominated as an excitation mechanism, except for aluminum phthalocyanine, which exhibited substantial scintillation. The highest emission yields were detected from fluorescein, proflavin and aluminum phthalocyanine, in that order. XML yield was found to be affected by the emission quantum yield, overlap of the fluorescence excitation and Cherenkov emission spectra, scintillation yield. Considering all these factors and XML emission spectrum respective to tissue optical window, aluminum phthalocyanine offers the best XML yield for deep tissue use, while fluorescein and proflavine are most useful for subcutaneous or superficial use.

Near-Infrared Photothermal/Photodynamic-in-One Agents Integrated with a Guanidinium-Based Covalent Organic Framework for Intelligent Targeted Imaging-Guided Precision Chemo/PTT/PDT Sterilization.

Phototherapy holds great promise in the treatment of bacterial infections, especially the multidrug resistant bacterial infections. However, most therapeutic agents are based on the integration of individual photothermal agents and photosensitizers, always in the activated state, and generally lack bacterial specificity, resulting in uncertain pharmacokinetics and serious nonspecific damage to normal tissues. Herein, we report a pH-responsive nanoplatform with synergistic chemo-phototherapy function for smart fluorescence imaging-guided precision sterilization. pH reversible activated symmetric cyanine was designed and prepared as a bacterial-specific imaging unit and PTT/PDT-in-one agent. Meanwhile, a guanidinium-based covalent organic framework (COF) was employed as a nanocarrier and chemotherapy agent to build the intelligent nanoplatform via electrostatic self-assembly. The self-assembly of the PTT/PDT-in-one agent and the COF greatly improves the stability and blood circulation of the PTT/PDT-in-one agent and provides charge-reversed intelligent targeting ability. The developed smart nanoplatform not only enables bacterial-targeted imaging but also possesses chemo/PTT/PDT synergetic high-efficiency bactericidal effects with little side effects, showing great potential in practical applications.

68Ga-Labeled Magnetic-NIR Persistent Luminescent Hybrid Mesoporous Nanoparticles for Multimodal Imaging-Guided Chemotherapy and Photodynamic Therapy.

Featured with a zero-autofluorescence background, superior signal-to-noise ratio, high sensitivity, and deep penetration ability, near-infrared persistent luminescence nanoparticle (NIR-PLNP)-based multimodal nanoprobes show great potential for full-scale noninvasive cancer diagnosis. However, direct synthesis of NIR-PLNP-based multimodal nanoprobes with high drug loading capacity to meet growing cancer theranostic demands remains a challenge. In this work, multifunctional hybrid mesoporous nanoparticles (HMNPs) that integrate NIR-PLNPs (Ga2O3:Cr3+, Nd3+), magnetic nanoparticles (Gd2O3), and radionuclides (68Ga) are designed and constructed via a large-pore (mesoporous silica nanoparticle) MSN-templated strategy. The ingenious composition design endows HMNPs with rechargeable NIR-PL, superior longitudinal relaxivity, and excellent radioactivity, making these versatile nanoparticles available for long-term in vivo NIR-PL imaging, magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging. More importantly, the application of large-pore MSN templates maintains the mesoporous structure of HMNPs, promising excellent drug loading capacity of these nanoparticles. As a proof-of-concept, HMNPs loaded with a high dose of DOX (chemotherapy agent) and Si-Pc (photosensitizer) are rationally designed for chemotherapy and NIR-PL-sensitized photodynamic therapy (PDT), respectively. Studies with mice tumor models demonstrate that the DOX/Si-Pc-loaded HMNPs possess excellent cancer cell killing ability and an outstanding tumor suppression effect without systemic toxicity. This work shows the great potential of HMNPs as an "all-in-one" nanotheranostic tool for multimodal NIR-PL/MR/PET imaging-guided chemotherapy and NIR-PL-sensitized photodynamic cancer therapy and provides an innovative paradigm for the development of NIR-PLNP-based nanoplatforms in cancer theranostic.

Novel pH-Triggered Doxorubicin-Releasing Nanoparticles Self-Assembled by Functionalized ß-Cyclodextrin and Amphiphilic Phthalocyanine for Anticancer Therapy.

Cyclodextrins (CDs), as pharmaceutical excipients with excellent biocompatibility, non-immunogenicity, and low toxicity in vivo, are widely used to carry drugs by forming inclusion complexes for improving the solubility and stability of drugs. However, the limited space of CDs' lipophilic central cavity affects the loading of many drugs, especially with larger molecules. In this study, ß-CDs were modified by acetonization to improve the affinity for the chemotherapy drug doxorubicin (DOX), and doxorubicin-adsorbing acetalated ß-CDs (Ac-CD:DOX) self-assembled to nanoparticles, followed by coating with the amphiphilic zinc phthalocyanine photosensitizer ZnPc-(PEG)5 for antitumor therapy. The final product ZnPc-(PEG)5:Ac-CD:DOX was demonstrated to have excellent stability and pH-sensitive drug release characteristics. The cell viability and apoptosis assay showed synergistic cytotoxic effects of chemotherapy and phototherapy. The mechanism of cytotoxicity was analyzed in terms of intracellular reactive oxygen species, mitochondrial membrane potential, and subcellular localization. More importantly, in vivo experiments indicated that ZnPc-(PEG)5:Ac-CD:DOX possessed significant tumor targeting, prominent antitumor activity, and less side effects. Our strategy expands the application of CDs as drug carriers and provides new insights into the development of CD chemistry.

A photothermal-hypoxia sequentially activatable phase-change nanoagent for mitochondria-targeting tumor synergistic therapy.

To enhance the specificity and efficiency of anti-tumor therapies, we have designed a multifunctional nanoparticle platform for photochemotherapy using fluorescence (FL) and photoacoustic (PA) imaging guidance. Nanoparticles (NPs) composed of a eutectic mixture of natural fatty acids that undergo a solid-liquid phase transition at 39 °C were used to encapsulate materials for the rapid and uniform release of the hypoxia-activated prodrug tirapazamine (TPZ) and the photosensitizer IR780, which targets the mitochondria of tumor cells and can be used to induce hypoxic cell death via photodynamic therapy and photothermal therapy. In vitro, the NPs containing TPZ and IR7890 exhibited appreciable cell uptake and triggered drug release when irradiated with a NIR laser. In vivo, photochemotherapy of the NPs achieved the best anti-tumor efficacy under PA and FL imaging guidance and monitoring. By combining IR780 mitochondria-targeting phototherapy with TPZ, we observed improved anti-tumor effectiveness and this has the potential to reduce the side effects of traditional chemotherapy. Herein, we demonstrate a new intracellular photochemotherapy nanosystem that co-encapsulates photosensitizers and hypoxia-activated drugs to enhance the overall anti-tumor effect precisely and efficiently.

Width-Consistent Mesoporous Silica Nanorods with a Precisely Controlled Aspect Ratio for Lysosome Dysfunctional Synergistic Chemotherapy/Photothermal Therapy/Starvation Therapy/Oxidative Therapy.

Although differently shaped mesoporous silica is widely studied, the formation of width-consistent mesoporous silica nanorods (MSNRs) with a precisely controlled aspect ratio (AR: length/width) is challenging and has not been reported. Herein, width-consistent (100 nm) MSNRs with ARs of 2, 3, 4, 6, 8, and 10 were obtained by increasing the concentrations while maintaining the molar ratio of cetyltrimethylammonium bromide (CTAB) and tetraethyl orthosilicate (TEOS). The results demonstrated that the as-prepared MSNR with an AR of 6 (AR6) possesses high cellular-uptake efficiency and drug-loading capacity. Thus, AR6-based cancer-cell-targeting nanosystems were designed. These nanosystems encapsulated doxorubicin (DOX) into the porous channel of AR6, adsorbed glucose oxidase (GOx), and then formed a polydopamine (PDA) layer for Siramesine (Siram, a lysosome dysfunctional drug) adsorption and folic acid modification. In this design, the PDA shell could prevent the leakage of loading components and keep the activity of GOx during delivery while achieving an on-demand drug release in the targeted location and photothermal therapy under near-infrared irradiation. The increase in temperature was highly beneficial for elevating the catalytic efficiency of GOx, accelerating the consumption of intracellular glucose, and generating a relatively high level of cytotoxic H2O2, all of which enhanced starvation and oxidative therapies. Siram was employed to inhibit lysosomal metabolism and accompany GOx to reach a dual-enhanced starvation therapy effect. In addition, DOX entered the nucleus and altered DNA for chemotherapy. The results showed that the nanosystems have superior therapeutic efficacy against cancer cells and not much toxicity to normal cells. Therefore, this study provides a novel strategy for lysosome dysfunctional synergistic chemotherapy/photothermal therapy/starvation therapy/oxidative therapy based on MSNR.

Multifunctional siRNA-Laden Hybrid Nanoplatform for Noninvasive PA/IR Dual-Modal Imaging-Guided Enhanced Photogenetherapy.

Small interfering RNA (siRNA)-induced gene therapy has been recognized as a promising avenue for effective cancer treatment, while easy enzymatic degradation, poor transfection efficiency, nonspecific biodistribution, and uncontrolled release hinder its extensive clinical applications. Zeolitic imidazolate frameworks-8 (ZIF-8) have emerged as promising drug carriers without an in-depth exploration in programmable siRNA delivery. Herein, we report a multifunctional PDAs-ZIF-8 (PZ) nanoplatform for delivering siRNA with combined photothermal therapy (PTT) and gene therapy (GT) via the noninvasive guidance of photoacoustic (PA)/near-infrared (IR) dual-modal imaging. The ingenious PZ nanocarriers mediated the tumor-specific accumulation of therapeutic siRNA without undesired degradation and preleakage. The pH-responsive ZIF-8 decomposed in an acidic tumor microenvironment that was accompanied by the release of siRNA payloads for cleaving target mRNA in gene silencing therapy. Meanwhile, the polydopamine nanoparticles (PDAs) could simultaneously serve as a powerful noninvasive PA/IR imaging contrast agent and versatile photothermal agent for diagnosis-guided photogenetherapy. The systematic in vitro and in vivo experimental explorations demonstrated that our PDAs-siRNA-ZIF-8 (PSZ) could greatly enhance the therapeutic efficiency as compared with the corresponding PTT or GT monotherapy. This work holds great potential to advance the development of more intelligent diagnosis and therapeutic strategies, thus supplying promising smart nanomedicines in the near future.

A sequential targeting nanoplatform for anaplastic thyroid carcinoma theranostics.

Effective accumulation of nanoparticles (NPs) in tumor regions is one of the major motivations in nanotechnology research and that the establishment of an efficient targeting nanoplatform for the treatment of malignant tumors is urgently needed for theranostic applications. In this study, we engineered multifunctional sequential targeting NPs for achieving synergistic antiangiogenic photothermal therapy (PTT) and multimodal imaging-guided diagnosis for anaplastic thyroid carcinoma (ATC) theranostics. Antibody bevacizumab with an affinity towards vascular endothelial growth factor (VEGF) on the tumor cell surface was conjugated onto the surface of polymer NPs for VEGF targeting and antiangiogenic therapy. Encapsulated IR825 was employed as a photothermal agent (PTA) with a mitochondrial targeting capability, which further cascades NPs into mitochondria to enhance hyperthermic efficiency in the ablation of tumor cells. Importantly, the combination of bevacizumab and IR825 in a single nanosystem achieved desirable accumulations of NPs and that sequential targeted PTT combined with antiangiogenesis significantly promoted the therapeutic efficiency in eradicating tumors by near-infrared (NIR) laser irradiation. Furthermore, these NPs are extraordinary contrast agents for photoacoustic, ultrasound and fluorescence imaging applications, providing multimodal imaging capabilities for therapeutic monitoring and a precise diagnosis. Therefore, this multifunctional nanoplatform provides a promising theranostic strategy for extremely malignant ATC. STATEMENT OF SIGNIFICANCE: Anaplastic thyroid carcinoma (ATC), with extremely aggressive behavior, lacks a satisfactory therapeutic method and a comprehensive early diagnostic strategy. Herein, we successfully synthesized a sequential targeting nanoplatform (IR825@Bev-PLGA-PFP NPs) with theranostic function, which specifically binds to VEGF on the tumor cell surface and further cascades into mitochondria to achieve effective accumulation of NPs in the tumor regions. As a result, it solves the urgent demand for ATC detection and therapy. By breaking the limitation of traditional target, such as low efficacy and frequent recurrence as the results of low accumulation, sequential targeting combined with synergistic antiangiogenic PTT completely eradicates tumors without any residual tissue and side effect. Therefore, this strategy paves a solid way for further investigation in the theranostic progressing of ATC.

An anti-inflammatory nanoagent for tumor-targeted photothermal therapy.

We developed an anti-inflammatory nanoagent by combining polydopamine nanospheres with aspirin and cancer cell membrane coating, which can effectively kill cancer cells and simultaneously eliminate photothermal therapy-induced inflammation.

Glucose oxidase and polydopamine functionalized iron oxide nanoparticles: combination of the photothermal effect and reactive oxygen species generation for dual-modality selective cancer therapy.

Cancer cells possess some inherent characteristics, such as glucose-dependence and intolerance to heat and exogenous reactive oxygen species (ROS). In this study, a strategy has been developed to target these vulnerable weaknesses of cancer cells using glucose oxidase (GOx) and polydopamine (PDA) functionalized iron oxide nanoparticles (Fe3O4@PDA/GOx NPs). PDA is first deposited on the surfaces of iron oxide NPs through self-polymerization, and then GOx is covalently linked with PDA upon mixing the enzyme and Fe3O4@PDA under alkaline conditions. In this system, the PDA layer along with iron oxide NPs serves as a photothermal transfer material converting near infrared (NIR) radiation into heat. The covalently linked GOx can competitively consume glucose and spontaneously generate ROS H2O2 that can be further converted by the iron oxide NPs into more toxic ˙OH, inducing apoptosis of cancer cells. The selective toxicity of Fe3O4@PDA/GOx NPs on cancer cells is demonstrated both in vitro and in vivo. In particular, a single injection rather than multiple doses results in significant suppression of tumors, and does not induce apparent histological lesions in the 4T1 tumor-bearing Balb/c mice. The versatility of the functionalization strategy reported in this study will contribute to developing efficient therapies for selective cancer treatment.

IR-780-loaded polymeric micelles enhance the efficacy of photothermal therapy in treating breast cancer lymphatic metastasis in mice.

Cancer metastasis is responsible for over 90% of breast cancer-related deaths, and inhibiting lymph node metastasis is an option to treat metastatic disease. Herein, we report the use of IR-780-loaded polymeric micelles (IPMs) for effective photothermal therapy (PTT) of breast cancer lymphatic metastasis. The IPMs were nanometer-sized micelles with a mean diameter of 25.6 nm and had good stability in simulated physiological solutions. Under 808-nm laser irradiation, IPMs exhibited high heat-generating capability in both in vitro and in vivo experiments. After intravenous injection, IPMs specifically accumulated in the tumor and metastatic lymph nodes and penetrated into these tissues. Moreover, a single IPMs treatment plus laser irradiation significantly inhibited primary tumor growth and suppressed lymphatic metastasis by 88.2%. Therefore, IPMs are an encouraging platform for PTT applications in treatment of metastatic breast cancer.

Botany: floral fluorescence effect.

The way flowers appear to insects is crucial for pollination. Here we describe an internal light-filtering effect in the flowers of Mirabilis jalapa, in which the visible fluorescence emitted by one pigment, a yellow betaxanthin, is absorbed by another, a violet betacyanin, to create a contrasting fluorescent pattern on the flower's petals. This finding opens up new possibilities for pollinator perception as fluorescence has not previously been considered as a potential signal in flowers.

[The combined use of photodynamic therapy with ionizing radiation on breast carcinoma cells in vitro]. / Kombinierte Anwendung der photodynamischen Therapie mit ionisierenden Strahlen bei Mammakarzinomzellen in vitro.

PURPOSE: The photodynamic therapy is a technique by which the tumor cells are selectively sensitized to destruction by light of an appropriate wavelength. The aim of this work is to analyze the biological effectiveness of photochemical reactions induced by laser light in tumor cells exposed to photosensitizers. MATERIAL AND METHODS: The toxicity of the 2 photosensitizers zinc phthalocyanine (ZnPC) and meso-tetrahydroxyphenylchlorine (m-THPC) as well as the biological effect of the combination of sensitizers with laser light were tested in vitro by means of a colony forming assay. In addition, the influence on the photodynamic reaction of a previous exposure of the tumor cells to ionizing radiation has been tested. RESULTS: For both sensitizers doses of 5 micrograms per milliliter of culture medium showed low toxicity, i.e. the survival of the treated cells exceeded 90%. For laser treatments the dose permitting 90% survival was determined to be around 10 J/cm2. With these doses, the combined application of photosensitizers and laser light proved to be very effective and resulted in a nearly complete reduction of survival. As expected, irradiation of the cells with doses of 1 and 2 Gy of X-rays reduced the survival to 66 and 47%, respectively, compared to untreated controls. Cells surviving such treatment showed no changes either in the response to treatments with photosensitizers or to combined applications of photosensitizers and laser light. CONCLUSION: The effects of photodynamic treatment by ionizing radiation seem to be additive and independent of each other. So, our preliminary results are quite encouraging and point out the need of further detailed studies in view of the intended clinical application of this new kind of a local treatment.