Functional hydrogels for hepatocellular carcinoma: therapy, imaging, and in vitro model.

Hepatocellular carcinoma (HCC) is among the most common malignancies worldwide and is characterized by high rates of morbidity and mortality, posing a serious threat to human health. Interventional embolization therapy is the main treatment against middle- and late-stage liver cancer, but its efficacy is limited by the performance of embolism, hence the new embolic materials have provided hope to the inoperable patients. Especially, hydrogel materials with high embolization strength, appropriate viscosity, reliable security and multifunctionality are widely used as embolic materials, and can improve the efficacy of interventional therapy. In this review, we have described the status of research on hydrogels and challenges in the field of HCC therapy. First, various preparation methods of hydrogels through different cross-linking methods are introduced, then the functions of hydrogels related to HCC are summarized, including different HCC therapies, various imaging techniques, in vitro 3D models, and the shortcomings and prospects of the proposed applications are discussed in relation to HCC. We hope that this review is informative for readers interested in multifunctional hydrogels and will help researchers develop more novel embolic materials for interventional therapy of HCC.

Progress and Challenges in Tumor Ferroptosis Treatment Strategies: A Comprehensive Review of Metal Complexes and Nanomedicine.

Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted.

X-ray sensitive selenium-containing Ru complexes sensitize nasopharyngeal carcinoma cells for radio/chemotherapy.

Radiotherapy has been extensively applied to cancer therapy in clinical trials. However, radiation resistance and dose limitation generally hamper the efficacy of radiotherapy. There is an urgent need for radiosensitizers with high efficiency and safety to enhance the anti-tumor effect of radiotherapy. In this paper, a selenium-containing (Se) ruthenium (Ru) complex (RuSe) was designed as a radiosensitizer to synergistically augment the killing effect of radiotherapy on nasopharyngeal carcinoma cells. In this system, the heavy atomic effect of Ru enhances the photoelectron production triggered by X-rays, thus inducing a burst of reactive oxygen species (ROS). In addition, Se atoms with a strong polarization property were introduced into the ligand of the metal complex to enhance the tumor chemo/radiotherapy effect. Consequently, RuC with a weak atomic polarization effect, as a comparison for RuSe, was also rationally explored to elucidate the role of Se atoms on chemo/radiotherapy sensitization. Indeed, compared with RuC, RuSe at a sub-toxic dose was able to potentiate the lethality of radiotherapy after preconditioning with cancer cells, by inducing ROS over-production, decreasing the mitochondrial membrane potential, and arresting the cell cycle at the sub-G1 phase. Furthermore, upon radiation, RuSe was superior to RuC, by inducing apoptotic cell death by activating caspase-3, -8, and -9. In summary, this study not only demonstrates an effective and safe strategy for the application of RuSe complexes to the cancer-targeted chemo/radiotherapy of human cancers, but also sheds light on the potential mechanisms of such Se-containing drugs as efficient radiotherapy sensitizers.

Thermosensitive Tri-Block Polymer Nanoparticle-Hydrogel Composites as Payloads of Natamycin for Antifungal Therapy Against Fusarium Solani.

Purpose: Fusarium Solani is the principal pathogen associated with fungal keratitis. As a sensitive drug to F. Solani, natamycin (NAT) was limited by the poor penetration and low bioavailability in clinical application. The aim of this study was to develop a new type of tri-block polymer nanoparticle-gel complex (Gel@PLGA-PEI-PEG@NAT) for delivering NAT and evaluate its physicochemical properties, antifungal activity, safety, penetrability, adhesion, and efficacy in treating fungal keratitis. Methods: PLGA-PEI-PEG@NAT was prepared and characterized with a nano-particle size analyzer, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR). The minimum inhibitory concentration (MIC), cytotoxicity, penetrability of NAT (Natacyn® 5% ophthalmic suspension; Alcon) and PLGA-PEI-PEG@NAT with different concentrations were assessed. The eye surface retention time, ocular irritation, and curative effect of the NAT ophthalmic suspension and Gel@PLGA-PEI-PEG@NAT on a rabbit fungal keratitis model were evaluated. Results: PLGA-PEI-PEG@NAT had a particle size of 150 nm, a positive surface charge, and a sustained-release effect. The MIC for F. Solani was 2 µg/mL. A cytotoxicity test and ocular irritation test showed that PLGA-PEI-PEG@NAT and Gel@PLGA-PEI-PEG@NAT had good biocompatibility and no obvious irritation for rabbit corneas. Penetration experiments confirmed that PLGA-PEI-PEG@NAT can successfully enter corneal epithelial cells and through the cornea to enter the anterior chamber. Compared with NAT ophthalmic suspension, Gel@PLGA-PEI-PEG@NAT had stronger cornea permeation at the same concentration. The therapeutic effect and precorneal retention ability of the NAT ophthalmic suspension and Gel@PLGA-PEI-PEG@NAT on the fungal keratitis rabbit model were compared. Gel@PLGA-PEI-PEG@NAT achieved a better therapeutic effect at a lower drug concentration, and its eye surface retention time was significantly longer than that of the NAT ophthalmic suspension. Conclusion: Gel@PLGA-PEI-PEG@NAT was shown to be a safe and effective nanodrug delivery system for NAT. It has great potential to improve the cure rate of fungal keratitis, reduce the administration frequency during the treatment process, and improve patient compliance.

Anti-Inflammatory Nanotherapeutics by Targeting Matrix Metalloproteinases for Immunotherapy of Spinal Cord Injury.

Neuroinflammation is critically involved in the repair of spinal cord injury (SCI), and macrophages associated with inflammation propel the degeneration or recovery in the pathological process. Currently, efforts have been focused on obtaining efficient therapeutic anti-inflammatory drugs to treat SCI. However, these drugs are still unable to penetrate the blood spinal cord barrier and lack the ability to target lesion areas, resulting in unsatisfactory clinical efficacy. Herein, a polymer-based nanodrug delivery system is constructed to enhance the targeting ability. Because of increased expression of matrix metalloproteinases (MMPs) in injured site after SCI, MMP-responsive molecule, activated cell-penetrating peptides (ACPP), is introduced into the biocompatible polymer PLGA-PEI-mPEG (PPP) to endow the nanoparticles with the ability for diseased tissue-targeting. Meanwhile, etanercept (ET), a clinical anti-inflammation treatment medicine, is loaded on the polymer to regulate the polarization of macrophages, and promote locomotor recovery. The results show that PPP-ACPP nanoparticles possess satisfactory lesion targeting effects. Through inhibited consequential production of proinflammation cytokines and promoted anti-inflammation cytokines, ET@PPP-ACPP could decrease the percentage of M1 macrophages and increase M2 macrophages. As expected, ET@PPP-ACPP accumulates in lesion area and achieves effective treatment of SCI; this confirmed the potential of nano-drug loading systems in SCI immunotherapy.

Designing highly stable ferrous selenide-black phosphorus nanosheets heteronanostructure via P-Se bond for MRI-guided photothermal therapy.

BACKGROUND: The design of stable and biocompatible black phosphorus-based theranostic agents with high photothermal conversion efficiency and clear mechanism to realize MRI-guided precision photothermal therapy (PTT) is imminent. RESULTS: Herein, black phosphorus nanosheets (BPs) covalently with mono-dispersed and superparamagnetic ferrous selenide (FeSe2) to construct heteronanostructure nanoparticles modified with methoxy poly (Ethylene Glycol) (mPEG-NH2) to obtain good water solubility for MRI-guided photothermal tumor therapy is successfully designed. The mechanism reveals that the enhanced photothermal conversion achieved by BPs-FeSe2-PEG heteronanostructure is attributed to the effective separation of photoinduced carriers. Besides, through the formation of the P-Se bond, the oxidation degree of FeSe2 is weakened. The lone pair electrons on the surface of BPs are occupied, which reduces the exposure of lone pair electrons in air, leading to excellent stability of BPs-FeSe2-PEG. Furthermore, the BPs-FeSe2-PEG heteronanostructure could realize enhanced T2-weighted imaging due to the aggregation of FeSe2 on BPs and the formation of hydrogen bonds, thus providing accurate PTT guidance and generating hyperthermia to inhabit tumor growth under NIR laser with negligible toxicity in vivo. CONCLUSIONS: Collectively, this work offers an opportunity for fabricating BPs-based heteronanostructure nanomaterials that could simultaneously enhance photothermal conversion efficiency and photostability to realize MRI-guided cancer therapy.

Uptake, transport, and metabolism of selenium and its protective effects against toxic metals in plants: a review.

Selenium (Se) is an essential trace element of fundamental importance to humans, animals, and plants. However, the uptake, transport, and metabolic processes of Se and its underlying mechanisms in plants have not been well characterized. Here, we review our current understanding of the adsorption and assimilation of Se in plants. First, we discussed the conversion of Se from inorganic Se into organic forms, the mechanisms underlying the formation of seleno-amino acids, and the detoxification of Se. We then discussed the ways in which Se protects plants against toxic metal ions in the environment, such as by alleviating oxidative stress, regulating the activity of antioxidant enzymes, sequestering metal ions, and preventing metal ion uptake and accumulation. Generally, this review will aid future research examining the molecular mechanisms underlying the antagonistic relationships between Se and toxic metals in plants.

Edible CaCO3 nanoparticles stabilized Pickering emulsion as calcium-fortified formulation.

BACKGROUND: Nanoparticles assembled from food-grade calcium carbonate have attracted attention because of their biocompatibility, digestibility, particle and surface features (such as size, surface area, and partial wettability), and stimuli-responsiveness offered by their acid-labile nature. RESULTS: Herein, a type of edible oil-in-water Pickering emulsion was structured by calcium carbonate nanoparticles (CaCO3 NPs; mean particle size: 80 nm) and medium-chain triglyceride (MCT) for delivery of lipophilic drugs and simultaneous oral supplementation of calcium. The microstructure of the as-made CaCO3 NPs stabilized Pickering emulsion can be controlled by varying the particle concentration (c) and oil volume fraction (φ). The emulsification stabilizing capability of the CaCO3 NPs also favored the formation of high internal phase emulsion at a high φ of 0.7-0.8 with excellent emulsion stability at room temperature and at 4 °C, thus protecting the encapsulated lipophilic bioactive, vitamin D3 (VD3), against degradation. Interestingly, the structured CaCO3 NP-based Pickering emulsion displayed acid-trigged demulsification because of the disintegration of the CaCO3 NPs into Ca2+ in a simulated gastric environment, followed by efficient lipolysis of the lipid in simulated intestinal fluid. With the encapsulation and delivery of the emulsion, VD3 exhibited satisfying bioavailability after simulated gastrointestinal digestion. CONCLUSIONS: Taken together, the rationally designed CaCO3 NP emulsion system holds potential as a calcium-fortified formulation for food, pharmaceutical and biomedical applications.

Coordination-Driven Enhancement of Radiosensitization by Black Phosphorus via Regulating Tumor Metabolism.

Coordination-driven surface modification is an effective strategy to achieve nanosystem functionalization and improved physicochemical performance. Black phosphorus (BP)-based nanomaterials demonstrate great potential in cancer therapy, but their poor stability, low X-ray mass attenuation coefficient, and nonselectivity limit the application in radiotherapy. Herein, we used unsaturated iridium complex to coordinate with BP nanosheets to synthesize a two-dimensional layered nanosystem (RGD-Ir@BP) with higher biostability. Ir complex improves the photoelectric properties and photoinduced charge carrier dynamics of BP, hence Ir@BP generated more singlet oxygen after X-ray irradiation. In in vivo experiments, with X-ray irradiation, RGD-Ir@BP effectively inhibited nasopharyngeal carcinoma tumor growth but with minor side effects. Additionally, based on untargeted metabolomics analysis, the combined treatment specifically down-regulated the tumor proliferative mark of prostaglandin E2 in cancer cells. In general, this study provides a design strategy of high-performance coordination-driven BP-based nanosensitizer in cancer radiotherapy.

Engineering EHD1-Targeted Natural Borneol Nanoemulsion Potentiates Therapeutic Efficacy of Gefitinib against Nonsmall Lung Cancer.

Despite the effective targeting of the epidermal growth factor receptor (EGFR), the use of gefitinib (GFT) for nonsmall cell lung cancer (NSCLC) treatment meets a failure because of the insufficient drug accumulation in the tumor region. Therefore, developing chemosensitizers of GFT with synergistic therapeutic effects is urgently needed for advanced cancer therapy. Herein, a natural chemosensitizer, natural borneol (NB), is reformulated as an oil-in-water nanoemulsion to enhance its solubility, distribution, and to ultimately increase the therapeutic index with GFT. The nanolization of NB (NBNPs) displays stronger targeted delivery and cytotoxicity than NB by selectively identifying eight specific protein targets in A549 NSCLC cells as revealed by the proteomic studies. Consistently, NBNPs realize stronger chemosensitization effects than NB with GFT by effectively regulating EGFR/EHD1-mediated apoptosis in A549 NSCLC cells. Owing to the satisfying synergistic effect between NBNPs and GFT, the combined therapy not only enhances the anticancer ability of GFT against NSCLC proliferation but also avoids heavy double toxicity in vivo. This finding demonstrates the effective synergism between NBNPs and GFT with clear mechanistic investigation and is expected to extend the application of NBNPs as a novel chemosensitizer for advanced cancer chemotherapy.

Sequentially Triggered Delivery System of Black Phosphorus Quantum Dots with Surface Charge-Switching Ability for Precise Tumor Radiosensitization.

Cancer radiotherapy suffers from drawbacks such as radiation resistance of hypoxic cells, excessive radiation that causes damage of adjacent healthy tissues, and concomitant side effects. Hence, radiotherapy sensitizers with improved radiotherapeutic performance and requiring a relatively small radiation dose are highly desirable. In this study, a nanosystem based on poly(lactic- co-glycolic acid) (PLGA) and ultrasmall black phosphorus quantum dots (BPQDs) is designed and prepared to accomplish precise tumor radiosensitization. The PLGA nanoparticles act as carriers to package the BPQDs to avoid off-target release and rapid degradation during blood circulation. The nanosystem that targets the polypeptide peptide motif Arg-Gly-Asp-Gys actively accumulates in tumor tissues. The 2,3-dimethylmaleic anhydride shell decomposes in an acidic microenvironment, and the nanoparticles become positively charged, thereby favoring cellular uptake. Furthermore, glutathione (GSH) deoxidizes the disulfide bond of cystamine and sequentially triggers release of BPQDs, rendering tumor cells sensitive to radiotherapy. The treatment utilizing the PLGA-SS-D@BPQDs nanosystem and X-ray induces cell apoptosis triggered by overproduction of reactive oxygen species. In the in vivo study, the nanosystem shows excellent radiotherapy sensitization efficiency but negligible histological damage of the major organs. This study provides insights into the design and fabrication of surface-charge-switching and pH-responsive nanosystems as potent radiosensitizers to achieve excellent radiotherapy sensitization efficacy and negligible toxic side effects.

Designing multifunctional cancer-targeted nanosystem for magnetic resonance molecular imaging-guided theranostics of lung cancer.

The integration of diagnosis and therapy is an effective way to improve therapeutic effects for cancer patients, which has acquired widely attentions from researchers. Herein, a multifunctional drug-loaded nanosystem (F/A-PLGA@DOX/SPIO) has been designed and synthesized to reduce the side effects of traditional chemotherapy drugs and realize simultaneous tumor diagnosis and treatment. The surface modification of folic acid (FA) and activatable cell-penetrating peptide (ACPP) endows the nanosystem with excellent cancer targeting capabilities, thus reducing toxicity to normal organs. Besides, the F/A-PLGA@DOX/SPIO nanosystem can serve as an excellent magnetic resonance imaging (MRI) T2-negative contrast agent. More importantly, according to in vitro experiments, the F/A-PLGA@DOX/SPIO nanosystem can promote the overproduction of reactive oxygen species (ROS) within A549 lung cancer cells, inducing cell apoptosis, greatly enhancing the antineoplastic effect. Furthermore, with the help of MRI technology, the targeting imaging of the F/A-PLGA@DOX/SPIO nanosystem within tumors and the dynamic monitoring of medicine efficacy can be realized. Therefore, this study provided a multifunctional drug-loaded F/A-PLGA@DOX/SPIO targeted nanosystem for magnetic resonance molecular imaging-guided theranostics, which has excellent potential for the application in tumor diagnosis and therapy.

BSA-based Cu2Se nanoparticles with multistimuli-responsive drug vehicles for synergistic chemo-photothermal therapy.

Functionalized-nanoparticles have been developed as novel therapeutic delivery platform for simultaneous drug loading and therapy over the past decade. Rationally-designed biocompatible nanosystem simultaneously with multistimuli-responsive property and synergistic therapeutic potential are highly desirable for modern biological applications. Herein, Cu2Se nanoparticles (Cu2SeNPs) with suitable size have been functionalized by bull serum albumin (BSA) through a simply, facile and controllable method. As a result, Cu2SeNPs modified by BSA (BSA-Cu2SeNPs) showed excellent biocompatibility and stability. The strong absorbance of BSA-Cu2SeNPs at near infrared region imparts them with high photothermal efficiency. Then loading doxorubicin (DOX, anticancer drug) on the surface of BSA-Cu2SeNPs, and consequently, a novel multifunctional nanosystem of BSA-Cu2SeNPs-DOX is designed. The BSA-Cu2SeNPs can achieve high DOX loading capacity (approximately 157 µg DOX per mg of Cu2Se). Furthermore, a rational and precise release of DOX from the BSA-Cu2SeNPs-DOX could be easily realized under the stimulates of the pH and temperature, which remarkably improved antitumor efficacy of combined chemotherapy and photothermal therapy triggered by 808 nm NIR laser. Thus, the BSA-Cu2SeNPs-DOX could serve as an ideal nanoplatform for cancer diagnosis and treatment in future. The results of cell experiments show that the BSA-Cu2SeNPs-DOX exhibited favorable selective cellular uptake cells. Under the NIR laser irradiation, BSA-Cu2SeNPs-DOX could induce the excessive expression of ROS, eventually leading to the death of U251 cells. Both in vitro and in vivo experiments indicate that the nanosystem of BSA-Cu2SeNPs-DOX showed excellent synergistic therapeutic effect and multistimuli-responsive drug vehicle, which will exert huge potential for future clinical application.

Cancer-targeted design of bioresponsive prodrug with enhanced cellular uptake to achieve precise cancer therapy.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of novel anticancer drugs to enhance the cancer targeting effects and biocompatibility, and decrease toxic side effects. Camptothecin (CPT) demonstrated strong anticancer activity in clinical trials but also notorious adverse effects. In this study, we presented a smart targeted delivery system (Biotin-ss-CPT) that consists of cancer-targeted moiety (biotin), a cleavable disulfide linker (S-S bond) and the active drug CPT. Biotin-ss-CPT was found to exhibit potent effects on the migration of cancer cells and induced apoptosis by induction of ROS-mediated mitochondrial dysfunction and perturbation of GSH/GPXs system, as well as activation of caspases. In vivo tumor suppression investigation including toxicity evaluation and pathology analysis, accompanied by MR images showed that Biotin-ss-CPT can be recognized specifically and selectively and taken up preferentially by cancers cells, followed by localization and accumulation effectively in tumor site, then released CPT by biological response to achieve high therapeutic effect and remarkably reduced the side effects that free CPT caused, such as liver damage, renal injury, and weight loss to realize precise cancer therapy. Taken together, our results suggest that biotinylation and bioresponsive functionalization of anticancer drugs could be a good way for the discovery of next-generation cancer therapeutics.

Nutritionally Available Selenocysteine Derivative Antagonizes Cisplatin-Induced Toxicity in Renal Epithelial Cells through Inhibition of Reactive Oxygen Species-Mediated Signaling Pathways.

Discovery of nutritionally available agents that could antagonize cisplatin-induced nephrotoxicity is of great significance and clinical application potential. 3,3'-Diselenodipropionic acid (DSePA) is a seleno-amino acid derivative that exhibits strong antioxidant activity. Therefore, this study aimed to examine the protective effects of DSePA on cisplatin-induced renal epithelial cells damage as well as the molecular mechanisms. The results revealed that DSePA effectively inhibited cell apoptosis induced by cisplatin through suppressing the caspase activation and poly(ADP-ribose) polymerase cleavage. In addition, DSePA blocked the cisplatin-induced mitochondrial dysfunction, as evidenced by the loss of mitochondrial membrane potential and reduction of mitochondrial mass. The results of western blot analysis showed that DSePA reversed the expression level of Bcl-2 family proteins altered by cisplatin. The cisplatin-activated AKT pathway was also modulated by DSePA. Moreover, these results indicate that DSePA could protect HK-2 cells from cisplatin-induced toxicity in renal epithelial cells by inhibiting intracellular reactive oxygen species-mediated apoptosis while showing an unobvious effect on its anticancer efficacy. Taken together, this study demonstrates that selenocysteine could be further developed as novel nutritionally available agents to antagonize cisplatin-induced nephrotoxicity during cancer therapy.

Cancer-Targeted Selenium Nanoparticles Sensitize Cancer Cells to Continuous γ Radiation to Achieve Synergetic Chemo-Radiotherapy.

Cancer radiotherapy with 125 I seeds demonstrates higher long-term efficacy and fewer side effects than traditional X-ray radiotherapy owing to its low-dose and continuous radiation but is still limited by radioresistance in clinical applications. Therefore, the design and synthesis of sensitizers that could enhance the sensitivity of cancer cells to 125 I seeds is of great importance for future radiotherapy. Selenium nanoparticles (SeNPs) have been found to exhibit high potential in cancer chemotherapy and as drug carriers. In this study, we found that, based on the Auger-electron effect and Compton effect of Se atoms, cancer-targeted SeNPs in combination with 125 I seeds achieve synergetic effects to inhibit cancer-cell growth and colony formation through the induction of cell apoptosis and cell cycle arrest. Detailed studies on the action mechanisms reveal that the combined treatments effectively activate intracellular reactive oxygen species (ROS) overproduction to regulate p53-mediated DNA damage apoptotic signaling pathways and mitogen-activated protein kinase (MAPK) phosphorylation and to prevent the self-repair of cancer cells simultaneously. Taken together, the combination of SeNPs with 125 I seeds could be further exploited as a safe and effective strategy for next-generation cancer chemo-radiotherapy in clinical applications.

Transferrin-functionalized nanographene oxide for delivery of platinum complexes to enhance cancer-cell selectivity and apoptosis-inducing efficacy.

Rational design and construction of delivery nanosystems for anticancer metal complexes is a crucial strategy to improve solubility under physiological conditions and permeability and retention behavior in tumor cells. Therefore, in this study, we designed and synthesize a transferrin (Tf)-conjugated nanographene oxide (NGO) nanosystem as a cancer-targeted nanocarrier of Pt complexes (Tf-NGO@Pt). This nanodelivery system exhibited good solubility under physiological conditions. Moreover, Tf-NGO@Pt showed higher anticancer efficacy against MCF human breast cancer cells than the free Pt complex, and effectively inhibited cancer-cell migration and invasion, with involvement of reactive oxygen species overproduction. In addition, nanolization also enhanced the penetration ability and inhibitory effect of the Pt complex toward MCF7 breast cancer-cell tumor spheroids. The enhancement of anticancer efficacy was positively correlated with increased cellular uptake and cellular drug retention. This study provides a new strategy to facilitate the future application of metal complexes in cancer therapy.

Functionalized Selenium Nanosystem as Radiation Sensitizer of 125I Seeds for Precise Cancer Therapy.

Although radiotherapy has been extensively applied in cancer treatment, external beam radiation therapy is still unable to avoid damage to adjacent normal tissues in the process of delivering a sufficient radiation dose to the tumor sites of patients. To overcome this limitation, chemoradiotherapy, as a combination of chemotherapy and radiotherapy of a radioactive seed, has been proposed to decrease the damage to tumor-surrounding tissues and enhance the radiosensitivity of solid tumors. In this study, we designed and synthesized folic acid-conjugated selenium nanoparticles (FA@SeNPs) as a cancer-targeting agent that could be synergistically enhanced by radioactive 125I seeds to realize anticancer efficacy and inhibited colony formation ability. Interestingly, when compared with X-ray irradiation, 125I seeds demonstrate a larger synergistic effect with the FA@SeNPs, drastically increasing reactive oxygen species overproduction to trigger apoptosis and influencing the cell cycle distribution in human breast cancer cells, inducing DNA damage and activating the mitogen-activated protein kinase and p53 signaling pathways. Moreover, this combination treatment demonstrates better in vivo antitumor activity and lower systemic toxicity. Therefore, this study demonstrates a new strategy for using functionalized SeNPs as a radiation sensitizer for 125I seeds for cancer therapy.

Designing Core-Shell Gold and Selenium Nanocomposites for Cancer Radiochemotherapy.

Radiotherapy is an important regime for treating malignant tumors. There is interest in the development of radiosensitizers to increase the local treatment efficacy under a relatively low and safe radiation dose. In this study, we designed Au@Se-R/A nanocomposites (Au@Se-R/A NCs) as nano-radiosensitizer to realize synergistic radiochemotherapy based on the radiotherapy sensitization property of Au nanorods (NRs) and antitumor activity of Se NPs. In vitro studies show that the combined treatment of A375 melanoma cells in culture with NCs and X-ray induces cell apoptosis through alteration in expression of p53 and DNA-damaging genes and triggers intracellular ROS overproduction, leading to greatly enhanced anticancer efficacy. Further studies using clinically used radiotherapy equipment demonstrate that the combined treatment of NCs and X-ray significantly inhibits the tumor growth in vivo and shows negligible acute toxicity to the major organs. Taken together, this study provides a strategy for clinical translation application of nanomedicne in cancer radiochemotherapy.

Ruthenium complexes with phenylterpyridine derivatives target cell membrane and trigger death receptors-mediated apoptosis in cancer cells.

Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs.