Near-Infrared-II-Activatable Self-Assembled Manganese Porphyrin-Gold Heterostructures for Photoacoustic Imaging-Guided Sonodynamic-Augmented Photothermal/Photodynamic Therapy.

Porphyrins and their derivatives are widely used as photosensitizers and sonosensitizers in tumor treatment. Nevertheless, their poor water solubility and low chemical stability reduce their singlet oxygen (1O2) yield and, consequently, their photodynamic therapy (PDT) and sonodynamic therapy (SDT) efficiency. Although strategies for porphyrin molecule assembly have been developed to augment 1O2 generation, there is scope for further improving PDT and SDT efficiencies. Herein, we synthesized ordered manganese porphyrin (SM) nanoparticles with well-defined self-assembled metalloporphyrin networks that enabled efficient energy transfer for enhanced photocatalytic and sonocatalytic activity in 1O2 production. Subsequently, Au nanoparticles were grown in situ on the SM surface by anchoring the terminal alkynyl of porphyrin to form plasmonic SMA heterostructures, which showed the excellent near-infrared-II (NIR-II) region absorption and photothermal properties, and facilitated electron-hole pair separation and transfer. With the modification of hyaluronic acid (HA), SMAH heterostructure nanocomposites exhibited good water solubility and were actively targeted to cancer cells. Under NIR-II light and ultrasound (US) irradiation, the SMAH generates hyperthermia, and a large amount of 1O2, inducing cancer cell damage. Both in vitro and in vivo studies confirmed that the SMAH nanocomposites effectively suppressed tumor growth by decreasing GSH levels in SDT-augmented PDT/PTT. Moreover, by utilizing the strong absorption in the NIR-II window, SMAH nanocomposites can achieve NIR-II photoacoustic imaging-guided combined cancer treatment. This work provides a paradigm for enhancing the 1O2 yield of metalloporphyrins to improve the synergistic therapeutic effect of SDT/PDT/PTT.

Copper-Nitrogen-Coordinated Carbon Dots: Transformable Phototheranostics from Precise PTT/PDT to Post-Treatment Imaging-Guided PDT for Residual Tumor Cells.

Phototheranostics has attracted considerable attention in the fields of cancer diagnosis and treatment. However, the complete eradication of solid tumors using traditional phototheranostics is difficult because of the limited depth and range of laser irradiation. New phototheranostics enabling precise phototherapy and post-treatment imaging-guided programmed therapy for residual tumors is urgently required. Accordingly, this study developed a novel transformable phototheranostics by assembling hyaluronic acid (HA) with copper-nitrogen-coordinated carbon dots (CDs). In this transformable nanoplatform, named copper-nitrogen-CDs@HA, the HA component enables the specific targeting of cluster determinant (CD) 44-overexpressing tumor cells. In the tumor cells, redox glutathione converts Cu(II) (cupric ions) into Cu(I) (cuprous ions), which confers the novel transformable functionality to phototheranostics. Both in vitro and in vivo results reveal that the near-infrared-light-photoactivated CuII-N-CDs@HA could target CD44-overexpressing tumor cells for precise synergistic photothermal therapy and photodynamic therapy. This study is the first to observe that CuII-N-CDs@HA could escape from lysosomes and be transformed in situ into CuI-N-CDs@HA in tumor cells, with the d9 electronic configuration of Cu(II) changing to the d10 electronic configuration of Cu(I), which turns on their fluorescence and turns off their photothermal properties. This transformable phototheranostics could be used for post-treatment imaging-guided photodynamic therapy on residual tumor cells. Thus, the rationally designed copper-nitrogen-coordinated CDs offer a simple in situ transformation strategy for using multiple-stimulus-responsive precise phototheranostics in post-treatment monitoring of residual tumor cells and imaging-guided programmed therapy.

A NIR-II light-modulated injectable self-healing hydrogel for synergistic photothermal/chemodynamic/chemo-therapy of melanoma and wound healing promotion.

The development of an injectable multifunctional hydrogel with tumor therapy, antibacterial treatment and wound healing properties is essential for simultaneously eradicating melanoma and promoting wound healing of tumor-initiated skin defects. Herein, iron ion-doped polyaniline (PANI(Fe)) tethered with guar gum (GG) chains is employed for the first time as a building unit for constructing a superior hydrogel (GG@PANI(Fe)-borax) crosslinked by borate/didiol bonds. Due to the dynamic and reversible properties of boronate ester bonds, the GG@PANI(Fe)-borax hydrogels had convenient injectability, rapid self-healing ability, and reversible gel-sol transformations under thermal- or pH-stimuli. More importantly, they took advantage of the second near-infrared (NIR-II) responsive photothermal conversion capability, accompanied by the photothermal-enhanced high cytotoxic ˙OH generation in the H2O2-enriched tumor microenvironment induced by iron-doped PANI. The as-prepared hydrogels exhibited excellent photothermal effects and controllable NIR-triggered drug release, leading to distinctly synergistic photothermal/chemodynamic/chemo-therapy effects of melanoma both in vitro (98.2%) and in vivo (98.8%). In addition, the obtained hydrogels also exhibited good anti-bacterial activity (>97.1%) against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria because they were based on PANI(Fe) and borax, which exhibit antibacterial activity. Furthermore, these GG@PANI(Fe)-incorporated scaffolds could improve fibroblast cell proliferation and angiogenesis for accelerating wound repair in tumor-bearing and infected wound mice. Taken together, GG@PANI(Fe)-borax hydrogels may be used simultaneously for eradication of skin-tumor cells, inhibiting infection and accelerating wound healing. This work offers an effective and facile strategy to fabricate an "all-in-one" multifunctional hydrogel platform for synergetic multimodal integrated therapy of tumors.

Black SnO2-x based nanotheranostic for imaging-guided photodynamic/photothermal synergistic therapy in the second near-infrared window.

The shallow penetration depth of photothermal agents in the first near-infrared (NIR-I) window significantly limits their therapeutic efficiency. Multifunctional nanotheranostic agents in the second near-infrared (NIR-II) window have drawn extensive attention for their combined treatment of tumors. Here, for the first time, we created oxygen-deficient black SnO2-x with strong NIR (700-1200 nm) light absorption with NaBH4 reduction from white SnO2. Hyaluronic acid (HA) could selectively target cancer cells overexpressed CD44 protein. After modification with HA, the obtained nanotheranostic SnO2-x@SiO2-HA showed high dispersity in aqueous solution and good biocompatibility. SnO2-x@SiO2-HA was confirmed to simultaneously generate enough hyperthermia and reactive oxygen species with single NIR-II (1064 nm) light irradiation. Because HA is highly affined to CD44 protein, SnO2-x@SiO2-HA has specific uptake by overexpressed CD44 cells and can be accurately transferred to the tumor site. Furthermore, tumor growth was significantly inhibited following synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) with targeted specificity under the guidance of photoacoustic (PA) imaging using 1064 nm laser irradiation in vivo. Moreover, SnO2-x@SiO2-HA accelerated wound healing. This work prominently extends the therapeutic utilization of semiconductor nanomaterials by changing their nanostructures and demonstrates for the first time that SnO2-x based therapeutic agents can accelerate wound healing. STATEMENT OF SIGNIFICANCE: The phototherapeutic efficacy of nanotheranostics by NIR-I lightirradiation was restricted owing to the limitation of tissue penetration and maximum permissible exposure. To overcome these limitations, we hereby fabricated a NIR-IIlight-mediated multifunctional nanotheranostic based on SnO2-x. The introduction of oxygen vacancy strategy was employed to construct full spectrum responsive oxygen-deficient SnO2-x, endowing outstanding photothermal conversion, and remarkable production activity of reactive oxygen species under NIR-II light activation. Tumor growth was significantly inhibited following synergistic PDT/PTT with targeted specificity under the guidance of photoacoustic imaging using 1064 nm laser irradiation in vivo. Our strategy not only expands the biomedical application of SnO2, but also providea method to develop other inorganic metal oxide-based nanosystems for NIR-II light-activated phototheranostic of cancers.

Structural characterization of modified whey protein isolates using cold plasma treatment and its applications in emulsion oleogels.

Cold plasma as a green and expeditious tool was used to modify whey protein isolate (WPI) in order to improve its emulsion capability. The emulsion-based oleogels with antibacterial functions were then constructed using the modified WPI. The modified WPI treated with cold plasma under 10 s at 50 W power significantly lowered the oil-water interface tension. Meanwhile, the fluorescence intensity and the α-helix content of WPI reduced with the cold plasma treatment. It is noted that SEM results showed that the treated WPI had more regular dendritic structures. Such modified WPI was applied to construct oleogels loaded with thyme essential oil and coconut oil, which showed a porous uniform network structure and excellent antimicrobial activities against E.coli. As a proof of concept, this study demonstrated cold plasma could be as a new facile tool to modify food-sourced proteins and expected to enlarge their applications in oleogel productions.

A full-spectrum responsive B-TiO2@SiO2-HA nanotheranostic system for NIR-II photoacoustic imaging-guided cancer phototherapy.

The second near-infrared (NIR-II) window (1000-1350 nm) usually offers further improved light penetration, a higher maximum permissible exposure (MPE), and a lower background signal. Development of NIR-II optical diagnosis and phototherapy technologies is of great significance for precise, efficient tumor therapy. In this work, a new type of Ti-based targeting agent (B-TiO2@SiO2-HA) nanotheranostic system with strong NIR-II absorption was designed and fabricated for the first time. Oxygen vacancies were formed in B-TiO2 and its band gap was narrowed, resulting in nanotheranostic systems with full-spectrum responses to stimulation with light. The experimental results showed that B-TiO2@SiO2-HA not only can enable high NIR-II photothermal conversion and provide excellent reactive oxygen species (ROS) production capacity, but also can enable high-resolution photoacoustic imaging (PAI) under NIR-II laser irradiation. Moreover, HA modification gives the nanotheranostic systems the useful ability to target high-CD44-expression tumor cells and tissues. In vitro and in vivo experiments demonstrated that B-TiO2@SiO2-HA exhibited a targeted photothermal/photodynamic (PTT/PDT) effect that produced tumor-cell ablation and apoptosis under the guidance of real-time NIR-II PA imaging. B-TiO2@SiO2-HA exhibits precise nanotheranostic potential for PAI-guided tumor-targeting phototherapy.

Lysosome-Targeted Gold Nanotheranostics for In Situ SERS Monitoring pH and Multimodal Imaging-Guided Phototherapy.

The integration of surface-enhanced Raman spectrum (SERS) and fluorescence-photoacoustic multimodal imaging in near-infrared photothermal therapy is highly desirable for cancer theranostic. However, typically, gold nanotheranostics usually require an additional modification of fluorophores and complex design refinements. In this work, by integrating surface-modified cysteine-hydroxyl merocyanine (CyHMC) molecules onto AuNRs, a novel lysosome-targeted gold-based nanotheranostics AuNRs-CyHMC that combines the specificity of Raman spectrum, the speed of fluorescence imaging, and deep penetration of photoacoustic imaging was successfully fabricated. Interestingly, fluorescence and Raman signals in this AuNRs-CyHMC system do not interfere, but it has pH-sensitive Raman signals and self-fluorescence localization ability under different excitation wavelengths. Fluorescence co-localization experiments further confirmed the lysosome-targeting ability of AuNRs-CyHMC. Typically, the proposed nanotheranostics were capable of SERS monitoring pH changes in both phosphate-buffered saline and living cells. Meanwhile, in vitro and in vivo experiments revealed that AuNRs-CyHMC possessed excellent fluorescence-photoacoustic performance and could be used for multimodal imaging-guided photothermal therapy. Furthermore, our work implied that gold nanotheranostics can provide great potential for cancer diagnosis and treatment.

Full-spectrum responsive ZrO2-based phototheranostic agent for NIR-II photoacoustic imaging-guided cancer phototherapy.

Second near-infrared (NIR-II) window responsive phototheranostic agents have a precise spatiotemporal potential for the diagnosis and treatment of cancer. In this study, a full-spectrum responsive ZrO2-based phototheranostic agent was found to achieve NIR-II photoacoustic (PA) imaging-guided tumour-targeting phototherapy. Initially, the ZrO2-based phototheranostic agent was fabricated through NaBH4 reduction to form boron-doped oxygen-deficient zirconia (ZrO2-x-B), an amino-functionalised SiO2 shell and a further covalent connection with hyaluronic acid (HA), namely, ZrO2-x-B@SiO2-HA. In the ZrO2-x-B@SiO2-HA system, the oxygen vacancy and boron doping resulted in full-spectrum absorption, enabling a high NIR-II photothermal conversion, high-resolution PA imaging ability and a remarkable production of reactive oxygen species (ROS). The surface modification of HA provided ZrO2-x-B@SiO2-HA with water dispersibility and a targeting capability for CD44 overexpressed cancer cells. Furthermore, in vitro and in vivo experiments showed that NIR-II activated ZrO2-x-B@SiO2-HA had a targeted photothermal/photodynamic effect for cancer elimination under the real-time guidance of NIR-II PAs. Hence, ZrO2-x-B@SiO2-HA displays a precise NIR-II radiation-activated phototheranostic potential for PA imaging-guided cancer-targeting photothermal/photodynamic therapy.

Natural Polyphenol-Vanadium Oxide Nanozymes for Synergistic Chemodynamic/Photothermal Therapy.

The selection of suitable nanozymes with easy synthesis, tumor specificity, multifunction, and high therapeutics is meaningful for tumor therapy. Herein, a facile one-step assembly approach was employed to successfully prepare a novel kind of natural polyphenol tannic acid (TA) hybrid with mixed valence vanadium oxide nanosheets (TA@VOx NSs). In this system, VOx is assembled with TA through metal-phenolic coordination interaction to both introduce superior peroxidase-like activity and high near infrared (NIR) absorption owing to partial reduction of vanadium from V5+ to V4+ . The presence of mixed valence vanadium oxide in TA@VOx NSs is proved to be the key for the catalytic reaction of hydrogen peroxide (H2 O2 ) to . OH, and the corresponding catalytic mechanism of H2 O2 by TA@VOx NSs is proposed. Benefitting from such peroxidase-like activity of TA@VOx NSs, the overproduced H2 O2 of the tumor microenvironment allows the realization of tumor-specific chemodynamic therapy (CDT). As a valid supplement to CDT, the NIR absorption enables TA@VOx NSs to have NIR light-mediated conversion ability for photothermal therapy (PTT) of cancers. Furthermore, in vitro and in vivo experiments confirmed that TA@VOx NSs can effectively inhibit the growth of tumors by synergistic CDT/PTT. These results offer a promising way to develop novel vanadium oxide-based nanozymes for enhanced synergistic tumor-specific treatment.

An injectable thermosensitive photothermal-network hydrogel for near-infrared-triggered drug delivery and synergistic photothermal-chemotherapy.

Near-infrared (NIR)-responsive hydrogels have exhibited remarkable advantages in biomedical applications especially for in situ therapeutic delivery, because of their deep-tissue penetration capacity, minimal invasiveness, and high spatiotemporal selectivity. Nevertheless, conventional NIR-responsive nanocomposite hydrogels suffer from the disadvantages of limited photothermal effect and potential leakage of the physically mixed photothermal nanoagents. To overcome these limitations, we herein designed an injectable thermosensitive photothermal-network hydrogel (PNT-gel) through the host-guest self-assembly of a photothermal conjugated polymers and ɑ-cyclodextrin. The conjugated-polymer backbones can directly convert incident light into heat, endowing the PNT-gel with high photothermal conversion efficiency (η = 52.6%) and enhanced photothermal stability. Meanwhile, the mild host-guest assembly enable the shear-thinning injectability, photothermally-driven and reversible gel-sol conversion of the hydrogel. Consequently, the remotely controlled on-demand release of doxorubicin (DOX) was achieved via photothermal-induced gel-sol transition. Because the backbone of the hydrogel absorbs NIR light and mediates the photothermal conversion itself, the PNT-gel demonstrated the advantage of a prolonged retention time and thus permitting repeatable NIR treatment after a one-time intratumoral injection of this hydrogel. Under repeated NIR laser irradiation (0.15 W cm-2), the synergistic photothermal-chemotherapy mediated by the PNT-gel almost completely eradicated 4T1 breast cancer. This work not only presents a multifunctional therapeutic platform integrated with inherent photothermal characteristic and reversible stimuli responsiveness for on-demand delivery and combinatorial photothermal-chemotherapy, but also provides a new strategy for the development of the next-generation of light-modulated intelligent hydrogels. STATEMENT OF SIGNIFICANCE: The conventional NIR-responsive nanocomposite hydrogels suffer from the disadvantages of limited photothermal effect and possible leakage of the physically mixed photothermal nano-components. To overcome these limitations, we hereby fabricated a NIR-responsive themosensitive photothermal-network hydrogel through the supramolecular assembly of conjugated polymer. The conjugated polymeric backbones of the hydrogel directly convert NIR light to heat, endowing the hydrogel with good photothermal effect and long-term photothermal stability. Meanwhile, the dynamic crosslinkages via supramolecular assembly enabled the shear-thinning injectability and reversible gel-sol transition of the hydrogel, facilitating the photothermal-induced drug release. Our strategy demonstrated the efficacy of using conjugated polymer as the backbone of hydrogel for the construction of a new injectable NIR-responsive hydrogel system with enhanced photothermal capabilities and improved therapy outcomes.

Near-Infrared Light Responsive Imaging-Guided Photothermal and Photodynamic Synergistic Therapy Nanoplatform Based on Carbon Nanohorns for Efficient Cancer Treatment.

Indocyanine green (ICG) is an effective light absorber for laser-mediated photodynamic therapy. However, applications of ICG are limited due to its rapid degradation and poor photostability in water. Herein, we report the development of a multifunctional nanoplatform by coating ICG on the surface of single-walled carbon nanohorns (SWNHs) through π-π stacking, obtaining SWNH-ICGs with high solubility and stability under physiological conditions. The SWNH-ICGs could be used as a single nanoplatform to simultaneously produce satisfactory hyperthermia and reactive oxygen species under near-infrared (NIR) laser irradiation. In addition, the SWNH-ICGs not only improved the photostability of ICG in different media, but also protected it from light degradation. The SWNH-ICGs exhibited highly efficient thermal/photoacoustic (PA) imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) effects, even under low-power laser irradiation (0.3 W cm-2 ) in vitro. Combined PTT and PDT effectively killed triple-negative breast cancer 4T1 cells, demonstrating a markedly improved and synergistic therapeutic effect compared to PTT or PDT alone. Furthermore, significant tumor growth inhibition as well as tumor cell death were observed following PTT/PDT at 808 nm laser irradiation, confirming the synergistic effects of SWNH-ICGs over free ICG in vivo. This facile and simple methodology for thermal/PA imaging-guided PTT/PDT suggests that SWNH-ICGs may serve as an effective nanoplatform for cancer therapy.

Ginseng Stem-and-Leaf Saponin (GSLS)-Enhanced Protective Immune Responses Induced by Toxoplasma gondii Heat Shocked Protein 70 (HSP70) Against Toxoplasmosis in Mice.

Toxoplasma gondii is an obligate intracellular protozoan parasite and is able to infect birds and mammals including humans. In order to find effective antigen-adjuvant combinations that can boost the immunogenicity and protection of antigen vaccines against toxoplasmosis, we examined the protective efficacy in mice immunized with recombinant protein HSP70 when co-administered with ginseng stem-and-leaf saponins (GSLS) isolated from Panax ginseng . All immunized mice produced significantly high levels of specific antibodies against rTgHSP70, and splenocytes from mice presented strong proliferative immune responses. Vaccinated mice displayed a significantly increased percentage of CD4+ and CD8+ T cells, indicating a strong immune response was triggered. The cellular and humoral immune responses were enhanced, which could be reflected of the increased mRNA levels of IFN-γ and IL-4, respectively. Immunization with rTgHSP70 and GSLS prolonged survival time of the treated mice compared to the controls, which died within 6 days after challenge with the virulent T. gondii RH strain. Our data demonstrate that by addition with GSLS, rTgHSP70 induced a strong immune response and provided partial protection against T. gondii ; therefore GSLS could be used as a promising vaccine adjuvant against acute toxoplasmosis.

Poly(N-phenylglycine)-Based Nanoparticles as Highly Effective and Targeted Near-Infrared Photothermal Therapy/Photodynamic Therapeutic Agents for Malignant Melanoma.

Malignant melanoma is a highly aggressive tumor resistant to chemotherapy. Therefore, the development of new highly effective therapeutic agents for the treatment of malignant melanoma is highly desirable. In this study, a new class of polymeric photothermal agents based on poly(N-phenylglycine) (PNPG) suitable for use in near-infrared (NIR) phototherapy of malignant melanoma is designed and developed. PNPG is obtained via polymerization of N-phenylglycine (NPG). Carboxylate functionality of NPG allows building multifunctional systems using covalent bonding. This approach avoids complicated issues typically associated with preparation of polymeric photothermal agents. Moreover, PNPG skeleton exhibits pH-responsive NIR absorption and an ability to generate reactive oxygen species, which makes its derivatives attractive photothermal therapy (PTT)/photodynamic therapy (PDT) dual-modal agents with pH-responsive features. PNPG is modified using hyaluronic acid (HA) and polyethylene glycol diamine (PEG-diamine) acting as the coupling agent. The resultant HA-modified PNPG (PNPG-PEG-HA) shows negligible cytotoxicity and effectively targets CD44-overexpressing cancer cells. Furthermore, the results of in vitro and in vivo experiments reveal that PNPG-PEG-HA selectively kills B16 cells and suppresses malignant melanoma tumor growth upon exposure to NIR light (808 nm), indicating that PNPG-PEG-HA can serve as a very promising nanoplatform for targeted dual-modality PTT/PDT of melanoma.