Enhancing oncolytic virus efficiency with methionine and N-(3-aminoprolil)methacrylamide modified acrylamide cationic block polymer.

Oncolytic virus ablation of tumor cells has the advantages of high tumor selectivity, strong immunogenicity, and low side effects. However, the recognition and clearance of oncolytic viruses by the immune system are the main factors limiting their anti-tumor efficiency. As a highly biosafe and highly modifiable oncolytic virus vector, acrylamide can improve the long-term circulation of oncolytic viruses. Still, it is limited in its uptake efficiency by tumor cells. Herein, we constructed an N-hydroxymethyl acrylamide-b-(N-3-aminopropyl methacrylamide)-b-DMC block copolymer (NMA-b-APMA-b-DMA, NAD) as an oncolytic virus carrier, which not only improves the long-term circulation of oncolytic viruses in the body but also shows excellent stability for loading an oncolytic virus. The data shows that there was no obvious difference in the transfection effect of the NAD/Ad complex with or without neutralizing antibodies in the medium, which meant that the cationic carrier mediated by NAD/Ad had good serum stability. Only 10 micrograms of NAD carrier are needed to load the oncolytic virus, which can increase the transfection efficiency by 50 times. Cell experiments and mouse animal experiments show that NAD vectors can significantly enhance the anti-tumor effect of oncolytic viruses. We hope that this work will promote the application of acrylamide as an oncolytic virus vector and provide new ideas for methods to modify acrylamide for biomedical applications.

Multifunctional nanoplatform based on tetragonal BaTiO3-Au@polydopamine for computed tomography imaging-guided photothermal synergistic and enhanced piezocatalytic cancer therapy.

Non-centrosymmetric tetragonal barium titanate nanocrystals have the potential to serve as piezoelectric catalysts in cancer therapy. When exposed to ultrasound irradiation, BaTiO3 can generate reactive oxygen species with a noninvasive and deep tissue-penetrating approach. However, the application of BaTiO3 in cancer nanomedicine is limited by their biosafety, biocompatibility, and dosage efficiency. To explore the potential application of BaTiO3 in nanomedical cancer treatment, we introduced ultra-small Au nanoparticles onto the surface of BaTiO3 to enhance the piezoelectric catalytic performance. Additionally, we also coated the BaTiO3 with polydopamine to improve their biosafety and biocompatibility. This led to the preparation of a novel multifunctional BaTiO3-based nanoplatform called BTAPs. In vitro and in vivo experiments demonstrated that the incorporation of Au dopants and polydopamine coating successfully improved the piezoelectric catalysis properties and biocompatibility of BaTiO3. Compared with unmodified BaTiO3, BTAPs achieved a similar piezoelectric catalytic effect at a low dose (0.3 mg ml-1 in vitro and 10 mg kg-1 in vivo). Moreover, BTAPs also exhibited enhanced properties in computed tomography imaging and photothermal effects in vivo. Therefore, BTAPs offer valuable insights into the advantages and limitations of piezoelectric catalytic nanomedicine in cancer treatment.

Protein-coated cobalt oxide-hydroxide nanospheres deliver photosensitizer IR780 iodide for near-infrared light-triggered photodynamic/photothermal/chemodynamic therapy against colon cancer.

Phototherapy has garnered worldwide attention for its minimal invasiveness, controllability, and spatial selectivity in treating cancer. One promising approach involves the use of near-infrared dye IR780, which demonstrates both photodynamic therapy (PDT) and photothermal therapy (PTT) effects under 808 nm laser irradiation. However, this hydrophobic dye's toxicity and limited tumor targeting ability severely hamper its suitability for cancer applications. Herein, a biocompatible nanoplatform CoOOH-IR780@BSA (CoIRB) is developed to efficiently deliver IR780 and provide multi-mode treatments for colon tumors. Due to the nanocarrier coating, CoIRB nanoparticles demonstrated reliable dispersion and stability, and their biotoxicity was substantially reduced for safer blood circulation, which overcame the biological barrier of IR780. The nanoplatform has also shown considerable results in phototherapy in vivo and in vitro experiments, with successful inhibition of MC38 tumor growth through intravenous administration. Additionally, the introduction of cobalt ions could induce Fenton-like reactions to activate the production of toxic hydroxyl radicals (˙OH), exerting an assisted chemodynamic therapy (CDT) effect. Notably, these nanodrugs also exhibited potential as scavengers of reductive glutathione (GSH) and hydrogen sulfide (H2S), leading to amplifying oxidative damage of reactive oxygen species (ROS). Overall, the versatile therapeutic platform, CoIRB, has opened up considerable prospects as a biotherapeutic option for combining PDT/PTT/CDT against colon cancer.

A multifunctional nanotheranostic agent based on Lenvatinib for multimodal synergistic hepatocellular carcinoma therapy with remarkably enhanced efficacy.

Lenvatinib (LT), a first-line molecular targeted therapeutic drug for hepatocellular carcinoma (HCC), has been replacing the status of Sorafenib (SF) as the clinically preferred and irreplaceable treatment for a decade. To overcome the low drug utilization and limited single efficacy of LT, ultrasmall copper sulfide nanocrystals (Cu2-xS NCs), and ultrasmall gold nanoparticle (AuNPs) were evenly wrapped into galactosamine conjugated poly(lactide-co-glycolide) (PLGA) as the drug delivery nanoparticles (CAL@PG) by nanoprecipitation. The CAL@PG NPs exhibited excellent stability under physiological conditions, whereas they released LT rapidly in the unique tumor microenvironment (TME) and high temperature, which could be provided by the near-infrared-II (NIR-II) photothermal effect of Cu2-xS NCs. Moreover, the temperature elevation, regenerated hydrogen peroxide (H2O2), and lower pH of TME could substantially boost the reaction potency of copper Fenton-like chemistry. More importantly, this combined therapy significantly improved the efficacy of LT, provided a multifunctional LT delivery system, and enriched the nanoparticle-augmented multimodal synergistic HCC therapy modality.

New anti-cancer explorations based on metal ions.

Due to the urgent demand for more anti-cancer methods, the new applications of metal ions in cancer have attracted increasing attention. Especially the three kinds of the new mode of cell death, including ferroptosis, calcicoptosis, and cuproptosis, are of great concern. Meanwhile, many metal ions have been found to induce cell death through different approaches, such as interfering with osmotic pressure, triggering biocatalysis, activating immune pathways, and generating the prooxidant effect. Therefore, varieties of new strategies based on the above approaches have been studied and applied for anti-cancer applications. Moreover, many contrast agents based on metal ions have gradually become the core components of the bioimaging technologies, such as MRI, CT, and fluorescence imaging, which exhibit guiding significance for cancer diagnosis. Besides, the new nano-theranostic platforms based on metal ions have experimentally shown efficient response to endogenous and exogenous stimuli, which realizes simultaneous cancer therapy and diagnosis through a more controlled nano-system. However, most metal-based agents have still been in the early stages, and controlled clinical trials are necessary to confirm or not the current expectations. This article will focus on these new explorations based on metal ions, hoping to provide some theoretical support for more anti-cancer ideas.

Application of nanotechnology in the early diagnosis and comprehensive treatment of gastrointestinal cancer.

Gastrointestinal cancer (GIC) is a common malignant tumour of the digestive system that seriously threatens human health. Due to the unique organ structure of the gastrointestinal tract, endoscopic and MRI diagnoses of GIC in the clinic share the problem of low sensitivity. The ineffectiveness of drugs and high recurrence rates in surgical and drug therapies are the main factors that impact the curative effect in GIC patients. Therefore, there is an urgent need to improve diagnostic accuracies and treatment efficiencies. Nanotechnology is widely used in the diagnosis and treatment of GIC by virtue of its unique size advantages and extensive modifiability. In the diagnosis and treatment of clinical GIC, surface-enhanced Raman scattering (SERS) nanoparticles, electrochemical nanobiosensors and magnetic nanoparticles, intraoperative imaging nanoparticles, drug delivery systems and other multifunctional nanoparticles have successfully improved the diagnosis and treatment of GIC. It is important to further improve the coordinated development of nanotechnology and GIC diagnosis and treatment. Herein, starting from the clinical diagnosis and treatment of GIC, this review summarizes which nanotechnologies have been applied in clinical diagnosis and treatment of GIC in recent years, and which cannot be applied in clinical practice. We also point out which challenges must be overcome by nanotechnology in the development of the clinical diagnosis and treatment of GIC and discuss how to quickly and safely combine the latest nanotechnology developed in the laboratory with clinical applications. Finally, we hope that this review can provide valuable reference information for researchers who are conducting cross-research on GIC and nanotechnology.

Ionizing Radiation-Induced Tumor Cell-Derived Microparticles Prevent Lung Metastasis by Remodeling the Pulmonary Immune Microenvironment.

PURPOSE: The majority of cancer-related deaths are attributed to metastasis rather than localized primary tumor progression. However, the factors that regulate the premetastatic niche (PMN) and metastasis have not yet been clearly elucidated. We investigated the antimetastatic effects of irradiated tumor cell-derived microparticles (RT-MPs) and highlighted the role of innate immune cells in PMN formation. METHODS AND MATERIALS: Mice were treated 3 times with isolated RT-MPs, followed by tumor cell injection via the tail vein. The hematoxylin and eosin staining was performed to assess the number of tumor nodules in the lungs, and in vivo luciferase-based noninvasive bioluminescence imaging was conducted to detected tumor burden. The mechanisms of RT-MPs mediated PMN formation was evaluated using flow cytometry, transwell assay, and reverse transcription-polymerase chain reaction. RESULTS: RT-MPs inhibited tumor cell colonization in the lungs. Neutrophils phagocytosed RT-MPs and secreted CCL3 and CCL4, which induced monocytes chemotaxis and maturation into macrophages. RT-MPs promoted the transition of neutrophils and macrophages into antitumor phenotypes, hence inhibiting cancer cell colonization and proliferation. CONCLUSIONS: RT-MPs inhibited PMN formation and lung metastasis in a neutrophil- and macrophage-dependent but T cell-independent manner.

Comprehensive Bioinformatics Analysis of Gasdermin Family of Glioma.

Pyroptosis is a programmed cell death mediated by gasdermins (GSDMs). The prognostic value of pyroptosis-related genes in different tumor types has been gradually demonstrated recently. However, the prognostic impact of GSDMs expression in glioma remains unclear. Here, we present a comprehensive bioinformatic analysis of gasdermin family member gene expression, producing a prognostic model for glioma and creating a competing endogenous RNA (ceRNA) network. The mRNA expression profiles and clinical information of glioma patients were downloaded from TCGA and CGGA. A risk score based on the gasdermin family was constructed in the TCGA cohort and validated in CGGA. The Jurkat cell was used to verify the relationship between pyroptosis and activation-induced cell death (AICD). We identify a significant association between the expression of GSDMD and GSDME and the glioma stage. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to construct a prognostic gene model based on the four prognostic gasdermin family genes (GSDMC, GSDMD, GSDME, and PJVK). This model was able to predict the overall survival of glioma patients with high accuracy. We show that gasdermin family genes are expressed primarily by immune cells, endothelial cells, and neuronal cells in the tumor microenvironment, rather than by malignant tumor cells. T cells were significantly activated in high-risk patients; however, the activation-induced cell death (AICD) pathway was also significantly activated, suggesting widespread expiration of cytotoxic T lymphocytes (CTLs), facilitating tumor progression. We also identify the lncRNA/miR-296-5p/GSDMD regulatory axis as an important player in glioma progression. We have conducted a comprehensive bioinformatic analysis identifying the importance of gasdermin family members in glioma; a prognostic algorithm containing four genes was constructed.

Relieving immunosuppression during long-term anti-angiogenesis therapy using photodynamic therapy and oxygen delivery.

Angiogenesis is an irreplaceable therapeutic cancer target, where anti-angiogenesis are drugs that are limited by their hydrophobicity and low therapeutic effects. What is more, the long-term shutdown of tumor blood vessel density also aggravates hypoxia and causes immunosuppression in the tumor microenvironment (TME). In order to solve these shortcomings, we developed a single therapeutic agent based on a bovine serum albumin nanocarrier that can co-deliver the anti-angiogenic drug Sorafenib ("S") and the photosensitizer Ce6 ("C") along with a molecular oxygen supply based on MnO2 ("M") as a convenient one-pot formulated nanoscale agent (SCM@BSA). Compared with anti-angiogenesis monotherapy, SCM@BSA can not only improve upon the solubility and therapeutic effects of anti-angiogenesis agents, but it also reshapes the immunosuppressive TME during anti-angiogenic therapy. Together, these results point out that SCM@BSA synthesized via a very simple method can solve the shortcomings usually experienced during long-term anti-angiogenic therapy.

Half-life determination of inorganic-organic hybrid nanomaterials in mice using laser-induced breakdown spectroscopy.

Inorganic or inorganic-organic hybrid nanomaterials have great potential for applications in the biomedical fields. Biological half-life is an essential pharmacokinetic parameter for these materials to function in vivo. Compared to inductively coupled plasma mass spectrometry (ICP-MS), which is the gold standard, laser-induced breakdown spectroscopy (LIBS) is a faster and more efficient elemental detection method. We investigated an efficient way to quantify the metabolic rate using LIBS. Nanoparticle platforms, such as manganese dioxide-bovine serum albumin (MnO2-BSA) or boehmite-bovine serum albumin (AlO(OH)-BSA) were injected into mice through intravenous administration for LIBS spectrum acquisition. First, the spectral background was corrected using the polynomial fitting method; The spectral interference was eliminated by Lorentz fitting for each LIBS spectrum simultaneously. The support vector regression (SVR) was then used for LIBS quantitative analyses. Finally, the LIBS results were compared with the ICP-MS ones. The half-lives of MnO2-BSA calculated by LIBS and ICP-MS were 2.49 and 2.42 h, respectively. For AlO(OH)-BSA, the half-lives detected by LIBS and ICP-MS were 3.46 and 3.57 h, respectively. The relative error of LIBS is within 5% compared to ICP-MS. The results demonstrate that LIBS is a valuable tool for quantifying the metabolic rates with a high degree of accuracy.

Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming.

Radiotherapy (RT) is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. The mechanism underlying the radiation-induced bystander effect (RIBE) is not understood and not therapeutically exploited. We suggest that the RIBE is predominantly mediated by irradiated tumor cell-released microparticles (RT-MPs), which induce broad antitumor effects and cause immunogenic death mainly through ferroptosis. Using a mouse model of malignant pleural effusion (MPE), we demonstrated that RT-MPs polarized microenvironmental M2 tumor-associated macrophages (M2-TAMs) to M1-TAMs and modulated antitumor interactions between TAMs and tumor cells. Following internalization of RT-MPs, TAMs displayed increased programmed cell death ligand 1 (PD-L1) expression, enhancing follow-up combined anti-PD-1 therapy that confers an ablative effect against MPE and cisplatin-resistant MPE mouse models. Immunological memory effects were induced.

Co-delivery of Bee Venom Melittin and a Photosensitizer with an Organic-Inorganic Hybrid Nanocarrier for Photodynamic Therapy and Immunotherapy.

Photodynamic therapy (PDT) is a clinical cancer treatment modality based on the induction of therapeutic reactive oxygen species (ROS), which can trigger immunogenic cell death (ICD). With the aim of simultaneously improving both PDT-mediated intracellular ROS production and ICD levels, we designed a serum albumin (SA)-coated boehmite ("B"; aluminum hydroxide oxide) organic-inorganic scaffold that could be loaded with chlorin e6 (Ce6), a photosensitizer, and a honey bee venom melittin (MLT) peptide, denoted Ce6/MLT@SAB. Ce6/MLT@SAB was anchored by a boehmite nanorod structure and exhibited particle size of approximately 180 nm. Ce6/MLT@SAB could significantly reduce hemolysis relative to that of free MLT, while providing MLT-enhanced PDT antitumor effects in vitro. Compared with Ce6@SAB, Ce6/MLT@SAB improved Ce6 penetration of cancer cells both in vitro and in vivo, thereby providing enhanced intracellular ROS generation with 660 nm light treatment. Following phototreatment, Ce6/MLT@SAB-treated cells displayed significantly improved levels of ICD and abilities to activate dendritic cells. In the absence of laser irradiation, multidose injection of Ce6/MLT@SAB could delay the growth of subcutaneous murine tumors by more than 60%, compared to controls. When combined with laser irradiation, a single injection and phototreatment with Ce6/MLT@SAB eradicated one-third of subcutaneous tumors in treated mice. The addition of an immune checkpoint blockade to Ce6/MLT@SAB phototreatment further augmented antitumor effects, generating increased numbers of CD4+ and CD8+ T cells in tumors with concomitant reduction of myeloid-derived suppressor cells.

Enhancing magnetic resonance/photoluminescence imaging-guided photodynamic therapy by multiple pathways.

Mitochondria, which are a major source of adenosine triphosphate (ATP) and apoptosis regulators, are the key organelles that promote tumor cell proliferation, and their dysfunction affects tumor cell behavior. Additionally, mitochondria have been shown to play a central role in the biosynthesis of protoporphyrin IX (PpIX), which is a widely used photosensitizer that has been used for tumor detection, monitoring and photodynamic therapy. Nevertheless, photosensitizers administrated exogenously are often restricted by limited bioavailability.δ-Aminolevulinic acid (δ-ALA) is a naturally occurring delta amino acid that can be converted in situ to PpIX via the heme biosynthetic pathway in mitochondria. Because δ-ALA is the precursor for PpIX, δ-ALA-based photodynamic therapy (PDT) shows promise in treating cancer. However, the accumulation of δ-ALA within endosomal system limits the production of PpIX and eventually impedes its effectiveness. Theranostic nanoparticles (NPs) capable of endosomal escape are expected to optimize the endogenous biosynthetic yield. In this study, δ-ALA was improved with triphenylphosphoniumcation (TPP+), a high net position cation that functions in endosomal escape and as a mitochondria-targeting ligand, and was further modified with bovine serum albumin stabilized manganese dioxide (MnO2). The tumor microenvironment (TME) responsive MnO2 in this system can elevate oxygen content to relieve hypoxia. Both enhanced photosensitizer yield and elevated oxygen contributing to the final therapeutic effect. Moreover, the enhancement of magnetic resonance imaging (MRI) (r1 = 5.410 s-1mM-1) stemming from the degradation of MnO2 by the TME could serve as a guide prior to treatment for accurate location, while in situ hysteretic photoluminescence imaging derived from PpIX can be utilize as a supervisor for prognosis evaluation. This systematic design could broaden the biomedical application and highlight the considerable therapeutic promise of PDT.

Microwave-assisted preparation of paramagnetic zwitterionic amphiphilic copolymer hybrid molybdenum disulfide for T1-weighted magnetic resonance imaging-guided photothermal therapy.

Magnetic resonance imaging (MRI)-guided photothermal therapy (PTT) has recently attracted tremendous attention. In this study, a paramagnetic zwitterionic amphiphilic copolymer (PZAC) was successfully prepared and utilized as a multifunctional surfactant to form micelles in diethylene glycol to coordinate with a molybdenum disulfide precursor (MoS2). Uniform spherical MoS2 nanohybrids (MoS2@PZAC) were first prepared by a microwave-assisted solvothermal process, which is simpler, easier and more efficient than hydrothermal methods or exfoliation processes. In this nanoplatform, MoS2 serves as a phototherapeutic agent possessing a high photothermal conversion efficiency (33.8%), while PZAC acts as a T1-weighted MRI contrast agent. This nanoplatform has the advantages of ultralow toxicity, prolonged circulation time and bio-imaging guided capability. The cytotoxicity assessment showed the good cytocompatibility of MoS2@PZAC. Furthermore, MoS2@PZAC could effectively kill cancer cells upon 2 W cm-2 808 nm laser irradiation for 10 min in both in vitro and in vivo experiments. This work provides a novel and efficient solution to synthesize a multifunctional and uniform theranostic agent, and the results show that the as-prepared MoS2@PZAC can be used as a promising theranostic agent for T1-weighted MRI-guided PTT of cancer cells.

Sorafenib and indocyanine green co-loaded in photothermally sensitive liposomes for diagnosis and treatment of advanced hepatocellular carcinoma.

Sorafenib (SF), as an irreplaceable first-line drug to help advanced hepatocellular carcinoma (HCC) patients to prolong their lives, has already been used in clinical practice for several years. However, this treatment causes several side effects, and few alternatives to SF treatment exist. Herein, we designed NIR fluorescence imaging-guided photothermally sensitive nanoliposomes based on co-encapsulation of SF and the clinical photothermal and photodynamic therapy agent Indocyanine Green (ICG) to solve the problems of SF-based treatment in advanced HCC. As expected, in vitro and in vivo drug release studies on SF-ICG liposomes (SILs) demonstrated SF release from SILs compared with free SF at the same concentration. In addition, in vivo NIR fluorescence imaging and anti-tumor treatment using SILs have been demonstrated by using Hep3B tumor-bearing xenograft nude mice. All detailed experimental evidence suggested that biocompatibility, biotoxicity, and anti-tumor effects were improved by using SILs instead of free SF. In conclusion, our designed SILs could present a novel and suitable SF-based treatment strategy for advanced HCC therapy in the future.

Bio-inspired synthesis of PEGylated polypyrrole@polydopamine nanocomposites as theranostic agents for T1-weighted MR imaging guided photothermal therapy.

Polypyrrole nanoparticle (PPy) based theranostic agents for magnetic resonance imaging (MRI) guided photothermal therapy (PTT) have received increasing attention in recent years. However, the limitations of cost and biocompability still offer us opportunities to improve these agents. Considering the versatile character of polydopamine (PDA), PEGylated PPy@Fe3+-chelated PDA nanocomposites (PPDEs) were designed and prepared in an easy way. PPDE with a uniform core-shell structure could be obtained by adjusting the ratio of dopamine and PPys. In this nanocomplex, the shells confer the nanoparticles with good biocompability and MRI signal enhancing ability. Moreover, the PPy cores play a role in photothermal ablation of tumors. Compared with pure PDA nanoparticles, the PPDEs have higher NIR absorbance and better photothermal capability benefitting from the high photothermal conversion of the cores. Additionally, the obtained PPDEs provide significant MRI signal enhancement for both in vitro and in vivo imaging with high longitudinal relaxivity (r1 = 5.055 mM-1 s-1). After intravenous injection, the PPDEs exhibited valid tumor accumulation, as revealed by MRI and verified by biodistribution analysis. Under NIR irradiation, the PPDEs showed highly effective photothermal ablation of 4T1 cells. Notably, excellent biocompability of the PPDEs was confirmed by a relevant MTT assay and histologic analysis. This work achieved an example of exploiting the inherent advantages of PPy and PDA within a single unit and exploring its potential for T1 MRI-guided PTT.