We developed a novel treatment strategy for metastatic cancer by synergizing photothermal therapy (PTT), chemotherapy, and immunotherapy through a nanosystem to trigger host antitumor immunity. The ...nanosystem was constructed by loading mitoxantrone (MTX), a chemotherapeutic agent, and SB-431542 (SB), a transforming growth factor beta (TGF-β) inhibitor, onto reduced graphene oxide (rGO). Intratumoral administration of rGO/MTX/SB, followed by non-invasive irradiation of a near-infrared laser, destroyed local primary tumors and inhibited distant metastases in 4T1 mouse mammary tumor model, which is poorly immunogenic and highly metastatic. After treatment, 70% of the tumor-bearing mice became long-term survivors and developed a tumor type-specific immunity to resist rechallenged tumor cells. We found that rGO-based PTT provided an immunogenic antigen source, forming in situ vaccination with rGO as an immune-adjuvant. The use of SB changed the tumor microenvironment and improved the therapeutic effect of MTX-generated chemotherapy and rGO-based PTT. The immunological functions of MTX, SB, and rGO acted synergistically to induce an effective tumor vaccination, as evidenced by the increased infiltration of tumor-specific cytotoxic CD8+ T lymphocytes and decreased infiltration of regulatory T cells (Tregs) in distal tumors. Collectively, we demonstrated that rGO/MTX/SB combined with laser irradiation provided a synergistic chemo-immuno-photothermal effect against tumors by in situ vaccination and inhibition of immunosuppressive microenvironment. This unique combination embodies a promising approach to treat metastatic cancers by inducing a systemic antitumor response through a local intervention.
As a result of their unique compositions and properties, nanomaterials have recently seen a tremendous increase in use for novel cancer therapies. By taking advantage of the optical absorption of ...near-infrared light, researchers have utilized nanostructures such as carbon nanotubes, gold nanorods, and graphene oxide sheets to enhance photothermal therapies and target the effect on the tumor tissue. However, new uses for nanomaterials in targeted cancer therapy are coming to light, and the efficacy of photothermal therapy has increased dramatically. In this work, we review some of the current applications of nanomaterials to enhance photothermal therapy, specifically as photothermal absorbers, drug delivery vehicles, photoimmunological agents, and theranostic tools.
Combined phototherapy and immunotherapy demonstrates strong potential in the treatment of metastatic cancers. An upconversion nanoparticle (UCNP) based antigen‐capturing nanoplatform is designed to ...synergize phototherapies and immunotherapy. In particular, this nanoplatform is constructed via self‐assembly of DSPE‐PEG‐maleimide and indocyanine green (ICG) onto UCNPs, followed by loading of the photosensitizer rose bengal (RB). ICG significantly enhances the RB‐based photodynamic therapy efficiency of UCNP/ICG/RB‐mal upon activation by a near‐infrared (NIR) laser, simultaneously achieving selective photothermal therapy. Most importantly, tumor‐derived protein antigens, arising from phototherapy‐treated tumor cells, can be captured and retained in situ, due to the functionality of maleimide, which further enhance the tumor antigen uptake and presentation by antigen‐presenting cells. The synergized photothermal, photodynamic, and immunological effects using light‐activated UCNP/ICG/RB‐mal induces a tumor‐specific immune response. In the experiments, intratumoral administration of UCNP/ICG/RB‐mal, followed by noninvasive irradiation with an NIR laser, destroys primary tumors and inhibits untreated distant tumors, using a poorly immunogenic, highly metastatic 4T1 mammary tumor model. With the simultaneous use of anti‐CTLA‐4, about 84% of the treated tumor‐bearing mice achieve long‐term survival and 34% of mice develop tumor‐specific immunity. Overall, this antigen‐capturing nanoplatform provides a promising approach for the treatment of metastatic cancers.
An NIR‐triggered antigen‐capturing nanoplatform is designed to synergize photodynamic, photothermal, and immunotherapy for cancer treatment. The enhanced photothermal/photodynamic effects using the nanoplatform release tumor‐derived protein antigens, which in turn are captured and retained in situ by the nanoplatform. The enhanced uptake and presentation of antigens by antigen‐presenting cells facilitate a tumor‐specific immune response to inhibit tumor metastasis.
Endocytosis mechanisms are one of the methods that cells use to interact with their environments. Endocytosis mechanisms vary from the clathrin-mediated endocytosis to the receptor independent ...macropinocytosis. Macropinocytosis is a niche of endocytosis that is quickly becoming more relevant in various fields of research since its discovery in the 1930s. Macropinocytosis has several distinguishing factors from other receptor-mediated forms of endocytosis, including: types of extracellular material for uptake, signaling cascade, and niche uses between cell types. Nanoparticles (NPs) are an important tool for various applications, including drug delivery and disease treatment. However, surface engineering of NPs could be tailored to target them inside the cells exploiting different endocytosis pathways, such as endocytosis versus macropinocytosis. Such surface engineering of NPs mainly, size, charge, shape and the core material will allow identification of new adapter molecules regulating different endocytosis process and provide further insight into how cells tweak these pathways to meet their physiological need. In this review, we focus on the description of macropinocytosis, a lesser studied endocytosis mechanism than the conventional receptor mediated endocytosis. Additionally, we will discuss nanoparticle endocytosis (including macropinocytosis), and how the physio-chemical properties of the NP (size, charge, and surface coating) affect their intracellular uptake and exploiting them as tools to identify new adapter molecules regulating these processes.
•Macropinocytosis relevance and signaling.•Nanoparticle design and factors affecting nanoparticle delivery.•Nanoparticle -driven discovery of novel proteins associated with macropinocytosis and endocytosis.
Indocyanine green (ICG) is a near-infrared (NIR) imaging agent and is also an ideal light absorber for laser-mediated photothermal therapy. This NIR dye could serve as a basis of a dual-functional ...probe with integrated optical imaging and photothermal therapy capabilities. However, applications of ICG remain limited by its concentration-dependent aggregation, poor aqueous stability, nonspecific binding to proteins and lack of target specificity. To overcome these limitations, a novel ICG-containing nanostructure is designed utilizing the noncovalent self-assembly chemistry between phospholipid-polyethylene glycol (PL-PEG) and ICG. The interactions between both amphiphilic ICG and PL-PEG were studied using absorption and fluorescence spectroscopy. The properties of ICG-PL-PEG nanoprobe, such as absorption and fluorescence spectra, stability, morphology and size distribution, were also investigated. Two representative targeting molecules, namely, a small molecule, folic acid (FA), and a large protein, integrin αvβ3 monoclonal antibody (mAb), were conjugated to the surface of ICG-PL-PEG nanoprobe, displaying the diversity of ligand conjugation. The target specificity was confirmed using three cell lines with different levels of available folate receptors (FRs) or integrin αvβ3 expression via laser scanning confocal microscope and flow cytometry. This targeting ICG-PL-PEG nanoprobe could be internalized into targeted cells via ligand−receptor mediated endocytosis pathway. Our in vitro experiments showed that internalized ICG-PL-PEG could be used for cell imaging and selective photothermal cell destruction. These results represent the first demonstration of the dual functionality of ICG-containing nanostructure for targeted optical imaging and photothermal therapy of cancerous cells. This novel ICG-PL-PEG nanostructure, when conjugated with other therapeutic and imaging agents, could become a multifunctional probe for cancer diagnosis and treatment.
Indocyanine green (ICG) is a conventional dye that can be used in clinical near-infrared (NIR) imaging, and it is also an effective light absorber for laser-mediated photothermal therapy. However, ...applications of ICG were limited due to its fast degradation in aqueous media and quick clearance from the body. Herein, an ICG-containing nanostructure, ICG-PL-PEG, was developed for photothermal therapy, which was self-assembled by ICG and phospholipid-polyethylene glycol (PL-PEG). Our in vitro and in vivo experiments demonstrated that ICG-PL-PEG suspension was more efficient in producing a NIR-dependent temperature increase than ICG alone, due to the increase of ICG monomers from the addition of PL-PEG to match the central wavelength of the 808 nm laser. When conjugated with integrin αvβ3 monoclonal antibody (mAb), ICG-PL-PEG could be selectively internalized and retained in target tumor cells. Irradiation of an 808 nm laser after intravenous administration of ICG-PL-PEG-mAb resulted in tumor suppression in mice, while ICG alone had only limited effect. This is the first time an ICG-containing nanostructure has been used through systemic administration to achieve an efficient in vivo photothermal effect for cancer treatment. Therefore, ICG-PL-PEG could be used as a fluorescent marker as well as a light-absorber for imaging-guided photothermal therapy. All the components of ICG-PL-PEG have been approved for human use. Therefore, this unique ICG-containing nanostructure has great potential in clinical applications.
The growth of austenite from as-quenched martensite during intercritical annealing was studied in a quaternary Fe–0.1C–3Mn–1.5Si alloy. Fine austenite grains either grew from interlath-retained ...austenite films or were newly nucleated at lath and martensite packet boundaries. Both types grew to a size comparable to the width of the martensite lath. It was found both metallographically and by dilatometry that the austenite grew to an amount in excess of the volume fraction at final equilibrium. Simulation by DICTRA, which assumed local equilibrium at the α/γ boundary, confirmed that the development of austenite is composed of three stages: initial negligible-partitioning growth controlled by rapid carbon diffusion in ferrite, which is gradually replaced by carbon diffusion in austenite; intermediate slow growth, controlled by diffusion of Mn and/or Si in ferrite; and a final stage controlled by diffusion of substitutional elements in austenite for final equilibration, which may result in the shrinkage of austenite. The formation of austenite in excess of the equilibrium amount is considered to occur due to very slow substitutional diffusion in the growing austenite compared to the boundary migration.
The development of therapeutic methods that can effectively delay tumor growth, inhibit tumor metastases, and protect the host from tumor recurrence still faces challenges. Nanoparticle-based ...combination therapy may provide an effective therapeutic strategy. Herein, we show that bovine serum albumin (BSA)-bioinspired gold nanorods (GNRs) were loaded with an immunoadjuvant for combined photothermal therapy (PTT) and immunotherapy for the treatment of melanoma. In this work, cetyltrimethylammonium bromide (CTAB)-coated GNRs were successively decorated with polyethylene glycol (PEG) and BSA, and loaded with an immunoadjuvant imiquimod (R837). The synthesized mPEG-GNRs@BSA/R837 nanocomplexes under near-infrared (NIR) irradiation could effectively kill tumors and trigger strong immune responses in treating metastatic melanoma in mice. Furthermore, the nanocomplex-based PTT prevented lung metastasis and induced a strong long-term antitumor immunity to protect the treated mice from tumor recurrence. The nanocomplex-based PTT in combination with immunotherapy may be potentially employed as an effective strategy for the treatment of melanoma and other metastatic cancers.
•Basement gneisses of the Ordos Basin have late Archean/Paleoproterozoic protoliths.•Zircon and monazite ages define different stages of Paleoproterozoic orogenesis.•Gneissic basement has undergone ...medium to low pressure (amphibolite to granulite facies) metamorphism.•The basement of the northern Ordos Basin is closely associated with the Khondalite Belt.
Although it remains deeply hidden and largely enigmatic, the basement of the Ordos Basin has played a pivotal role in the evolution of the western part of North China Craton. Diverse gneiss samples collected from boreholes advanced into the deep basement of the Ordos Basin are investigated by integrating petrography, phase equilibria modeling and geochronology. The results reveal the basement gneisses have different protoliths with ages extending from the late Archean to the Paleoproterozoic. Medium to low pressure metamorphism from amphibolite to granulite facies (4.7–7.3 kbar and 740–810 °C) is constrained for the basement gneisses, using phase equilibrium modeling in the MnNCKFMASHTO system. Evidence is provided of metamorphic monazite growing later than zircon in the same basement gneisses, and multi-stage Paleoproterozoic orogenesis is delineated using metamorphic zircon and monazite ages from the basement gneisses. The basement gneisses from most boreholes across the basin are comparable to those in adjoining Paleoproterozoic belts in terms of metamorphic and geochronological characteristics. The results of the study suggest, in combination with previous data, that a large area of the basement was involved in the Paleoproterozoic orogenis. The northern part of the Ordos Basin basement is closely associated with the Khondalite Belt.
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