A torus source and its application for non-primary radiation evaluation.

Objective. Non-primary radiation doses to normal tissues from proton therapy may be associated with an increased risk of secondary malignancies, particularly in long-term survivors. Thus, a systematic method to evaluate if the dose level of non-primary radiation meets the IEC standard requirements is needed.Approach. Different from the traditional photon radiation therapy system, proton therapy systems are composed of several subsystems in a thick bunker. These subsystems are all possible sources of non-primary radiation threatening the patient. As a case study, 7 sources in the P-Cure synchrotron-based proton therapy system are modeled in Monte Carlo (MC) code: tandem injector, injection, synchrotron ring, extraction, beam transport line, scanning nozzle and concrete reflection/scattering. To accurately evaluate the synchrotron beam loss and non-primary dose, a new model called the torus source model is developed. Its parametric equations define the position and direction of the off-orbit particle bombardment on the torus pipe shell in the Cartesian coordinate system. Non-primary doses are finally calculated by several FLUKA simulations.Main results. The ratios of summarized non-primary doses from different sources to the planned dose of 2 Gy are all much smaller than the IEC requirements in both the 15-50 cm and 50-200 cm regions. Thus, the P-Cure synchrotron-based proton therapy system is clean and patient-friendly, and there is no need an inner shielding concrete between the accelerator and patient.Significance. Non-primary radiation dose level is a very important indicator to evaluate the quality of a PT system. This manuscript provides a feasible MC procedure for synchrotron-based proton therapy with new beam loss model. Which could help people figure out precisely whether this level complies with the IEC standard before the system put into clinical treatment. What' more, the torus source model could be widely used for bending magnets in gantries and synchrotrons to evaluate non-primary doses or other radiation doses.

In-situ fabrication of novel Au nanoclusters-Cu2+@sodium alginate/hyaluronic acid nanohybrid gels for cuproptosis enhanced photothermal/photodynamic/chemodynamic therapy via tumor microenvironment regulation.

Multimodal combined therapy (MCT) is an emerging avenue to eliminate tumor cells by the synergistic effect of various therapeutic methods. However, the complex tumor microenvironment (TME) is becoming the key barrier to the therapeutic effect of MCT due to the excessive existence of H+ ions, H2O2, and glutathione (GSH), the lack of O2, and the relaxation of ferroptosis. To overcome these limitations, smart nanohybrid gels with excellent biocompatibility, stability and targeting function were prepared by using gold nanoclusters as cores and an in situ cross-linking composite gel of sodium alginate (SA)/hyaluronic acid (HA) as the shell. The obtained Au NCs-Cu2+@SA-HA core-shell nanohybrid gels possessed near-infrared light response synergistically benefitting photothermal imaging guided photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the H+-triggered release of Cu2+ ions from the nanohybrid gels not only induces cuproptosis to avoid the relaxation of ferroptosis, but also catalyzes H2O2 in the TME to generate O2 to simultaneously improve the hypoxic microenvironment and PDT effect. Furthermore, the released Cu2+ ions could consume the excessive GSH to form Cu+ ions effectively, which caused the formation of hydroxyl free radicals (·OH) to kill tumor cells, synergistically realizing GSH consumption-enhanced PDT and chemodynamic therapy (CDT). Hence, the novel design in our work provides another research avenue for cuproptosis-enhanced PTT/PDT/CDT via TME modulation.

Facile Synthesis of Fe3O4@Au/PPy-DOX Nanoplatform with Enhanced Glutathione Depletion and Controllable Drug Delivery for Enhanced Cancer Therapeutic Efficacy.

The complex physiological environment and inherent self-healing function of tumors make it difficult to eliminate malignant tumors by single therapy. In order to enhance the efficacy of antitumor therapy, it is significant and challenging to realize multi-mode combination therapy by utilizing/improving the adverse factors of the tumor microenvironment (TME). In this study, a novel Fe3O4@Au/PPy nanoplatform loaded with a chemotherapy drug (DOX) and responsive to TME, near-infrared (NIR) laser and magnetic field was designed for the combination enhancement of eliminating the tumor. The Fe2+ released at the low pH in TME can react with endogenous H2O2 to induce toxic hydroxyl radicals (·OH) for chemodynamic therapy (CDT). At the same time, the generated Fe3+ could deplete overexpressed glutathione (GSH) at the tumor site to prevent reactive oxygen species (ROS) from being restored while producing Fe2+ for CDT. The designed Fe3O4@Au/PPy nanoplatform had high photothermal (PT) conversion efficiency and photodynamic therapy (PDT) performance under NIR light excitation, which can promote CDT efficiency and produce more toxic ROS. To maximize the cancer-killing efficiency, the nanoplatform can be successfully loaded with the chemotherapeutic drug DOX, which can be efficiently released under NIR excitation and induction of slight acidity at the tumor site. In addition, the nanoplatform also possessed high saturation magnetization (20 emu/g), indicating a potential magnetic targeting function. In vivo and in vitro results identified that the Fe3O4@Au/PPy-DOX nanoplatform had good biocompatibility and magnetic-targeted synergetic CDT/PDT/PTT/chemotherapy antitumor effects, which were much better than those of the corresponding mono/bi/tri-therapies. This work provides a new approach for designing intelligent TME-mediated nanoplatforms for synergistically enhancing tumor therapy.

A multi-responsive Au NCs@PMLE/Ca2+ antitumor hydrogel formed in situ on the interior/surface of tumors for PT imaging-guided synergistic PTT/O2-enhanced PDT effects.

At present, although phototherapy and related imaging have proven to be promising cancer diagnosis and treatment strategies, the free diffusion of photosensitizers into normal tissues can cause side effects, and the efficiency of photodynamic therapy (PDT) can also be limited by the tumor hypoxic microenvironment. Herein, we designed and prepared a new cancer nanoplatform containing Au nanoclusters (NCs)@Premna microphylla leaf extract (PMLE) with both responsiveness to near-infrared (NIR) laser irradiation and tumor microenvironment (TME) by facile redox and coordination reactions. Then, the Au NCs@PMLE/Ca2+ hydrogel was constructed in situ inside and on the surface of tumors for locoregional antitumor activity under 808 nm laser irradiation. The Au NCs@PMLE nanoplatform showed distinguished performance in killing cancer cells and alleviating tumor hypoxia by enhancing the temperature of the tumor sites and producing reactive oxygen species (ROS) under NIR irradiation as well as catalyzing hydrogen peroxide (H2O2) decomposition in TME for oxygen (O2) generation via catalase in PMLE. The ultra-small size of about 3 nm of the Au NCs in this nanoplatform was obtained using the biological molecules present in PMLE as reductants and coordination agents simultaneously, which also demonstrated the outstanding capability of photothermal (PT) imaging and photothermal therapy (PTT) towards tumors. Furthermore, the Au NCs@PMLE/Ca2+ hydrogel formed in situ through natural PMLE and intrinsic Ca2+ in TME could not only improve the biocompatibility of the nanoplatform and stability of Au NCs but was also highly concentrated around the tumor thus enhancing the therapeutic efficiency and inhibiting its migration to normal tissues, decreasing the side effects. The results of the experiments confirmed that the Au NCs@PMLE/Ca2+ hydrogel possessed PT imaging-guided NIR laser/TME-responsive synergetic cancer PTT/O2-enhanced PDT and remarkable locoregional antitumor effect for cancer therapy. This work may open a new versatile route for multi-responsive localized cancer therapeutic nanoplatforms.

Self-assembled Au4Cu4/Au25 NCs@liposome tumor nanotheranostics with PT/fluorescence imaging-guided synergetic PTT/PDT.

Exploring and developing a new type of nanoplatform with diagnosis and treatment to effectively cure tumors and reduce side effects has become a hot spot for researchers and is of great significance. Herein, a cancer theranostic nanoplatform with dual-imaging, dual-phototherapy and laser-responsiveness to tumor microenvironment was successfully assembled by liposome (Lip) co-loaded with oil-soluble Au4Cu4 nanoclusters (NCs) and water-soluble Au25 NCs via a simple film hydration method and subsequent extraction process. The prepared Au4Cu4/Au25@Lip nanoplatform with core-shell structure and about 50 nm of uniform sphere shape presented highly biocompatible, stability and passive targeting due to the enhanced permeability and retention (EPR) effect. Furthermore, the Lip composed of lecithin and cholesterol has good affinity with the cell membrane, which can realize the effective accumulation of photosensitizers at the tumor site, so that improving phototherapy effect and reducing the damage to normal tissue. The loaded oil-soluble Au4Cu4 NCs were firstly and pleasantly surprised to find possessed not only ideal photodynamic effect, but also preferable catalysis towards endogenous hydrogen peroxide (H2O2) decomposition to produce oxygen (O2) for improving the tumor hypoxic environment besides the excellent photoluminescence ability while the water-soluble Au25 NCs own outstanding photothermogenesis effect and also photoluminescence performance. The in vitro and in vivo experiment results proved that in the Au4Cu4/Au25@Lip nanoplatform, the performances of both NCs were complementary, which presenting considerable photothermal/fluorescence imaging (PTI/FI)-guided synergistic photothermal therapy (PTT)/O2-enhanced photodynamic therapy (PDT) effect for the tumor under the irradiation of near infrared (NIR) laser. This work provides a useful inspiration and paves a new way for the assembly of NCs or namomaterials with different properties into an integrated anti-tumor theranostic nanoplatform.

An effective NIR laser/tumor-microenvironment co-responsive cancer theranostic nanoplatform with multi-modal imaging and therapies.

Cancer is still a major threat to human health at present. Developing new types of integrated nanoplatforms for the accurate diagnosis and effective treatment of cancer is very significant. Herein, an intelligent dual-stage core-shell cancer theranostic nanoplatform (Fe3+@Au1Ag24@PbP) with NIR laser/tumor-microenvironment (TME) co-responsiveness and multi-modal imaging-therapy was successfully prepared, which was composed of the precisely structured oil-soluble Au1Ag24 nanoclusters (NCs) and Fe3+ ions easily assembled within the oil and aqueous phases of the polyethylene glycol (PEG) block grafted polyketal (PK) copolymer (PK-b-PEG, PbP) vesicles, respectively. In this system, we were delighted to find that the prepared Au1Ag24 NCs possess multi-photoresponsive properties, endowing the nanoplatform with photoacoustic (PA)/photothermal (PT) imaging and synergetic photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer under near-infrared (NIR) laser irradiation. On the other hand, Fe3+ ions exhibit multi-TME response and regulation behaviors, including as catalysts for the decomposition of endogenous hydrogen peroxide (H2O2) in the solid tumor to produce O2 and as the oxidizing agent for the consumption of the intracellular GSH to avoid the reduction of the generated 1O2; therefore, the synchronously formed Fe2+ ions from the redox of Fe3+ with GSH could further react with H2O2 to produce hydroxyl radical (˙OH), which induced ferroptosis-based cancer treatment. The PbP shell possesses TME/pH sensitivity for controlled drug release and passive targeting, causing a large increase in Au1Ag24/Fe3+ accumulation within the weakly acidic tumor region and reducing the side effects on normal tissues. Both in vitro and in vivo experiments demonstrate that the Fe3+@Au1Ag24@PbP nanoplatform presented excellent PA/PT imaging-guided synergetic PTT/PDT/ferroptosis effects toward tumor cells and tumors. This integrating multi-responsive and multi-modal theranostic nanoplatform paves a new way for effective cancer therapy.

4-in-1 Fe3O4/g-C3N4@PPy-DOX nanocomposites: Magnetic targeting guided trimode combinatorial chemotherapy/PDT/PTT for cancer.

At present, cancer has become a major disease threatening human health worldwide. Therefore, developing targeting guided multimode synergetic therapy has become one of the hot spots in current antitumor research and is also a great challenge. Herein, a new Fe3O4/g-C3N4@PPy-DOX nanocomposite containing magnetic iron oxide (Fe3O4) nanoparticles (NPs), lamellar structure of graphite-like carbon nitride (g-C3N4) and polypyrrole (PPy) shell with the loaded anti-tumor drug doxorubicin hydrochloride (DOX) was designed and prepared. The monodisperse Fe3O4 nanoparticles (NPs) with the diameter of 20 nm endowed the nanocomposite with the magnetic targeting ability, reducing damage to normal tissues. It is very interesting that the Fe3O4 NPs also possessed photosensitizer function for photodynamic therapy (PDT). The g-C3N4 sheets as the photocatalysis towards the degradation of water for generating O2 could effectively improve the hypoxia of solid tumors and increase the efficiency of PDT. In addition, PPy has high light-to-heat conversion efficiency, so was chosen for the cancer photothermal therapy (PTT). Finally, an anticancer drug (DOX) was loaded on the nanocomposite because the presence of mesoporous structure. Thus, the prepared Fe3O4/g-C3N4@PPy-DOX nanocomposites exhibit synergetic chemotherapy/PTT/enhanced PDT antitumor effect. This study provides an inspiration for combining targeting and multimodality to improve the anticancer efficiency.