Tumor-bearing Mice Research Articles

Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity

BackgroundAlthough immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate...

Biomimetic Metallacage Nanoparticles with Aggregation-Induced Emission for NIR-II Fluorescence Imaging-Guided Synergistic Immuno-Phototherapy of Tumors.

The integration of theranostics, which combines diagnostics with therapeutics, has markedly improved the early detection of diseases, precise medication management, and assessment of treatment outcomes. In the realm of oncology, organoplatinum-based supramolecular coordination complexes (SCCs) that can coload therapeutic agents and imaging molecules have emerged as promising candidates for multimodal theranostics of tumors. To address the challenges of tumor-targeted delivery and multimodal theranostics for SCCs, this study employs a cell membrane cloaking strategy to fabricate biomimetic metallacage nanoparticles (MCNPs) with multimodal imaging capabilities and homologous targeting capabilities. Specifically, a photosensitizer molecule (BTTP) containing AIE-active groups was assembled into a metallacage of C-BTTP through Pt-N coordination. This process endows the metallacage with strong NIR-II fluorescence in the aggregated state and significantly superior ROS generation compared to that of the precursor ligand. After being encapsulated with F127, the MCNPs were further cloaked with U87 cancer cell membranes, creating biomimetic MCNPs that achieve tumor-targeting capabilities. Verified by in vitro and in vivo experiments, MCNPs enable multimodal imaging and initiate immunotherapy under photothermal and photodynamic stimulation, leading to synergistic antitumor effects. Furthermore, the evaluation of immunogenic cell death and dendritic cell maturation rate in U87 tumor-bearing mice confirmed the mechanism of photothermal and photodynamic synergistic immunotherapy. This study provides an innovative strategy for enhancing the tumor-targeting and therapeutic efficiency of SCCs, offering a versatile strategy for efficient and minimally invasive theranostics of tumors. The development of such biomimetic nanoparticles represents a significant advancement in the field of nanomedicine, potentially transforming cancer treatment through personalized and targeted therapies.

A Smart Nanomedicine Unleashes a Dual Assault of Glucose Starvation and Cuproptosis to Supercharge αPD-L1 Therapy.

Combination therapy has become a promising strategy for promoting the outcomes of anti-programmed death ligand-1 (αPD-L1) therapy in lung cancer. Among all, emerging strategies targeting cancer metabolism have shown great potency in treating cancers with immunotherapy. Here, alteration in glucose and copper metabolisms is found to synergistically regulate PD-L1 expression in lung cancer cells. Thus, an intelligent biomimetic nano-delivery system is synthesized by camouflaging lung cancer cell membranes onto glucose oxidase-loaded Cu-LDHs (CMGCL) for cancer metabolism targeted interference. Such novel nanomedicine is able to induce lung cancer cell cuproptosis and PD-L1 upregulation significantly via self-amplified cascade reactions. Meanwhile, with a decent cancer cell membrane coating, CMGCL exhibited great biosafety, tumor-targeted efficiency and anti-tumor effects in LLC lung tumor-bearing mice models. Additionally, a combination of CMGCL can sensitize the therapeutic effects of αPD-L1, substantially promoting tumor inhibition in both subcutaneous and lung metastasis LLC-bearing mice models. Overall, these findings highlight the potential connections between glucose metabolism and cell cuproptosis, offering a promising approach for treating lung cancer by integrating starvation, cuproptosis, and immunotherapy.

Durable antitumor response via an oncolytic virus encoding decoy-resistant IL-18

BackgroundInterleukin-18 (IL-18), or interferon (IFN)-γ-inducing factor, potentiates T helper 1 and natural killer cell activation as well as CD8+ T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part...

V-domain immunoglobulin suppressor of T-cell activationand programmed death receptor 1 dual checkpoint blockade enhances antitumour immunity and survival in glioblastoma.

The current therapy cannot meet the needs of glioblastoma (GBM). V-domain immunoglobulin suppressor of T-cell activation (VISTA) is significantly up-regulated in GBM patients; however, its therapeutic potential in GBM is still unclear. Flow cytometry was used to detect the expression of VISTA and the co-expression pattern of VISTA and programmed death receptor 1 (PD-1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of α-VISTA monotherapy and α-VISTA combined with α-PD-1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data. Compared with normal mice, the frequency of VISTA expression and co-expression of VISTA and PD-1 on tumour-infiltrating lymphocytes (TILs) in tumour-bearing mice was increased. Anti-VISTA monotherapy significantly up-regulated multiple immune stimulation-related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD-1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8+ T cells played an important role in this process. In addition, we found that the expression of VISTA and PD-1 was significantly up-regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD-1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD-1 may achieve clinical transformation in GBM.

A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma

Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a “cold” tumor to a “hot” one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC.

STING agonists and PI3Kγ inhibitor co-loaded ferric ion-punicalagin networks for comprehensive cancer therapy

Nanoparticles-based drug delivery system has been a promising approach for the treatment of colorectal cancer (CRC), which can be combined with chemotherapy, targeted therapy and immunotherapy to improve the treatment of CRC. 2′3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is an agonist of the STING signaling pathway activating antitumor immunity. IPI-549 is a small-molecule inhibitor for phosphatidylinositol 3-kinase γ (PI3Kγ), which can induce M1 macrophages polarization to provide pro-inflammatory microenvironment to suppress tumors. Here, we developed a ferric ion-punicalagin network (Fe-PU), which can be not only used as an inducer of ferroptosis, but also serve as a carrier to load cGAMP and IPI-549 to obtain nanohybrid (Fe-PU/CD-IPI). In order to improve the delivery effect and targeted ability to CRC, a cyclic arginine-glycine-aspartic acid peptide linked-bovine serum albumin were utilized to modify Fe-PU/CD-IPI to prepare nanohybrid Fe-PU/CD-IPI@cBSA. The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo.

CaCO3-complexed pH-responsive nanoparticles encapsulating mitoxantrone and celastrol enhance tumor chemoimmunotherapy

Modulating the immunosuppressive tumor microenvironment (TME) while enhancing antitumor immune responses is a promising strategy. In this study, we designed an acid-sensitive nanosystem (MCCaNPs) to demonstrate effective immunotherapy against cancer through the systemic delivery of immune-stimulating chemotherapy combinations. A pH-responsive nanoplatform containing CaCO3 was prepared by the double emulsion method, and mitoxantrone (MIT) and celastrol (CEL) were simultaneously encapsulated as immunogenic cell death (ICD) inducers. Due to the acid responsiveness of CaCO3, the nanoparticles rapidly consume H+ to relieve the acidic tumor microenvironment and explosively release CEL and MIT, showing inherent immunomodulatory activity in collaborative tumor chemoimmunotherapy. MIT and CEL synergistically trigger stronger ICD by inducing tumor cells to release calreticulin (CRT), high mobility group box 1 protein (HMGB1). Following the intravenous administration of MCCaNPs, the local tumor microenvironment(TME) was reprogrammed in mice-bearing tumors. This reprogramming was characterized by a significant increase in the density of tumor-infiltrating cytotoxic T lymphocytes(CTLs), ultimately prolonging survival. Therefore, this research proposes a promising approach to trigger immunogenic cell death collaboratively, aiming to boost the tumor CTLs infiltration for anticancer immunotherapy.

Chitosan-coated PLA/poloxamer nanoparticles stimulate immunologic cancer cell death and synergistic chemo-immunotherapeutic efficacy

Cancer, a key factor in declining global life expectancy, has driven the integration of chemotherapy and immunotherapy to address multidrug resistance and influence the tumor microenvironment. We developed a novel vaccine delivery carrier, a chitosan-coated polylactic acid/poloxamer nanoparticle (CPP NP), designed to co-encapsulate an anticancer drug and antigen without any chemical conjugation process, enabling effective and synergistic cancer chemo-immunotherapy. The CPP NP achieved synergistic efficacy through paclitaxel (PTX), an immunogenic cell death-inducing chemotherapeutic agent; ovalbumin (OVA), which promotes dendritic cell maturation; and enhanced cellular uptake facilitated by chitosan. The PTX and OVA-loaded CPP NPs (PTX/OVA@CPP NPs) were stable in PBS for four weeks and resuspended well after lyophilization without any cryoprotectants. Moreover, PTX and OVA from the NPs exhibited a sustained release rate and pH-responsive release pattern within different cellular microenvironments. Importantly, PTX@CPP NPs exhibited much higher anticancer efficacy across various cancer cell lines, even multidrug-resistant cells, compared to free PTX and PTX@PP NPs without the chitosan coating. In antigen-presenting cells, OVA@CPP NPs led to higher IL-2 secretion and cellular uptake compared to free OVA and OVA@PP NPs. Furthermore, in a tumor-bearing mouse model, PTX/OVA@CPP NPs exhibited strong synergistic tumor suppression and triggered OVA antigen-specific responses, promoting an antitumor immune response. These findings demonstrate that PTX/OVA@CPP NPs show potential as new chemo-immunotherapeutic agents for effective cancer treatment.

Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization

Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.

Broussoflavonol F exhibited anti-proliferative and anti-angiogenesis effects in colon cancer via modulation of the HER2-RAS-MEK-ERK pathway

BackgroundA prenylated flavonoid, broussoflavonol F (BFF), was isolated from Macaranga genus with cytotoxicities against various cancer cells, though its underlying mechanisms have not been fully elucidated. HypothesisThis study aimed to investigate the anti-tumor and anti-angiogenesis activities of BFF and its underlying mechanisms in colon cancer. MethodIn the in vitro study, the cytotoxic effects of BFF in human colon cancer HCT-116 and LoVo cells were examined using MTT assay, BrdU assay and colony formation assay. The anti-proliferative effects of BFF in these cells were assessed via cell apoptosis and cell cycle analysis using flow cytometry. The anti-angiogenesis effects of BFF in human endothelial HEMC-1 cells were also detected using scratch wound healing assay and tube formation assay. While the in vivo effects of BFF in colon cancer were further examined in zebrafish embryos and HCT116 tumor-bearing mice. The underlying mechanisms of BFF were predicted using network pharmacology analysis, and Western blotting was performed to validate both in vitro and in vivo results. ResultsBFF exhibited cytotoxicities on 5 colon cancer cell lines, as well as anti-proliferative activities via inducing apoptosis and cell cycle arrest at the G0/G1 phase in HCT116 and LoVo cells. BFF at 1.25-5 µM also suppressed cell proliferation in these two colon cancer cell lines by downregulating HER2, RAS, p-BRAF, p-MEK and p-Erk protein expressions. In addition, BFF at 2.5-5 µM could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of NRP1a, PDGFba, PDGFRb, KDR, FLT1 and VEGRaa. Besides, BFF exhibited anti-angiogenesis activity via inhibiting cell proliferation, motility and tube formation in HMEC-1 cells. Furthermore, intraperitoneal administration of BFF (10 mg/kg) suppressed tumor growth and decreased the expression of tumor proliferation marker Ki-67 and angiogenesis marker CD31 in the tumor tissues in HCT116 tumor-bearing mice. BFF treatment could also significantly decrease expressions of RAS, p-BRAF, p-MEK and p-Erk in the tumor section, which are consistent with the in vitro results. ConclusionsThis study revealed the anti-tumor and anti-angiogenesis effects of BFF in colon cancer. This is the first report of the in vitro and in vivo anti-proliferative activity of BFF in colon cancer through regulating the HER2-RAS-MEK-ERK pathway. These findings further support the research development of BFF as an anti-cancer agent in colon cancer.

Injectable nanocomposite hydrogel with cascade drug release for treatment of uveal melanoma

Uveal melanoma (UM) is the most common malignant intraocular tumor with the trait of distant metastases. Currently, the standard clinical therapy results in suboptimal outcomes due to ineffective inhibition of tumor metastasis. Thus, developing novel therapeutic modalities for UM remains a critical priority. Herein, we have developed an injectable nanocomposite hydrogel (HA-DOX/LAP gel) through integrating hyaluronic acid-based drug-loaded nanoparticles into an alginate-dopamine gel, delivering the chemotherapeutic drugs, lapatinib and doxorubicin for combinational treatment of UM. HA-DOX/LAP gel is fabricated in situ by a simple injection of the mixed precursor solution into tumor sites and maintains in vivo for more than 21 days. The entrapped drug-loaded nanoparticles can gradually release from HA-DOX/LAP gel, enhancing tumor targeting and penetration, and synchronously releasing lapatinib and doxorubicin into the acidic intracellular environment to synergistically destroy UM cells. In vivo anti-tumor studies conducted in MuM-2B tumor models demonstrated that HA-DOX/LAP gel significantly impedes tumor growth, diminishes postoperative recurrence, and prolongs overall survivals of UM tumor-bearing mice through only single injection. Remarkably, the escaped drug-loaded nanoparticles effectively reduce the risk of tumor metastases. Our findings provide new insights for the development of multifunctional nanocomposite-incorporating combination therapy against UM by targeting tumor recurrence and metastases.

Enhanced transcytosis and therapeutic efficacy of paclitaxel nanoparticles: Pyridylboronic acid modification and sialic acid targeting

Efficient drug delivery and deeper penetration into tumors have become a primary focus of anti-tumor nanomedicine. In this study, pyridylboronic acid (BPA), as a targeting ligand for sialic acid, which is highly expressed on the surface of tumor cells, was conjugated with DSPE-PEG2k-NH2 to synthesize DSPE-PEG2k-BPA and used to encapsulate PTX. The resultant PTX@DSPE-PEG2k-BPA nanoparticles (DPB NPs) showed a mean particle size of 189.0 ± 3.5 nm, with a high drug loading content of 48.75 % and a rod-like morphology. In contrast to PTX@DSPE-mPEG2k nanoparticles (DP NPs), DPB NPs displayed enhanced cellular uptake and targetability to 4T1 tumor cells. Interestingly, BPA modification could also enhance transcytosis through the endoplasmic reticulum-Golgi pathway, thus improving penetration and accumulation of nanoparticles in tumors. An in vivo study on 4T1 tumor-bearing mice demonstrated that DPB NPs achieved a faster and more accumulation in tumors than DP NPs after intravenous administration, led to significantly improved therapeutic efficacy with a higher tumor inhibition rate (74.27 % vs 50.58 %, p < 0.01). In conclusion, the modification of BPA presents a strategy for the development of drug delivery systems that exhibit dual functionalities: active targeting and transcytosis.

Innovations in radiotherapy for tongue squamous cell carcinoma

Radiotherapy sensitivity is associated with the prognosis of patients with tongue squamous cell carcinoma (TSCC). In the present study, we proposed to explore the specific mechanism of interventional radiology (IR) therapy for TSCC in vitro and in vivo. TSCC cells were treated with 6 Gy IR and tumor bearing mice were treated with 20 Gy × 1 IR. DIA quantitative proteomics along with bioinformatics analysis were conducted in TSCC cells to investigate differential proteins related to IR and relation of which involved in TMEM147 and SPHK1 was confirmed by immunoprecipitation. Cell proliferation, apoptosis, autophagy& autophagy flux along with calcium signaling pathway detection were performed in vitro and in vivo. Our results showed that IR induced increasing calcium levels accompanied by up-regulated TMEM147 and down-regulated SPHK1 along with enhancing autophagy together with apoptosis. The effect of calcium overloading induced by IR on autophagy and apoptosis was dependent on increasing TMEM147 and decreasing SPHK1. However, IR-induced autophagy and apoptosis tended to be independent of only increasing calcium levels when down-regulating TMEM147 or up-regulating SPHK1 expression in vitro and in vivo. Our study suggested that calcium-mediated TMEM147/SPHK1 may promote autophagy and apoptosis to improve radiotherapy sensitivity in TSCC.

A dendritic cell vaccine for both vaccination and neoantigen-reactive T cell preparation for cancer immunotherapy in mice

Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficult isolation of neoantigen-specific T cells limits the clinical application of ACT. Here, we propose a method to prepare neoantigen-reactive T cells (NRT) for ACT following immunization with a tumor lysate-loaded dendritic cell (DC) vaccine. We show that the DC vaccine not only induces a neoantigen-reactive immune response in lung cancer-bearing mice in vivo, but also facilitate NRT cell preparation in vitro. Adoptive transfer of the NRTs as combinatorial therapy into DC vaccine-immunized, LL/2 tumor-bearing mice allows infiltration of the infused NRTs, as well as the enrichment of neoantigen reactive, non-ACT/NRT T cells into the tumor microenvironment with the function of these neoantigen-reactive T-cell receptors validated in vitro. In summary, we propose a method for preparing NRTs that increases ACT efficacy and paves the way to the design of personalized immunotherapies.

M2 macrophage-derived exosomes promote cell proliferation, migration and EMT of non-small cell lung cancer by secreting miR-155-5p.

Tumor-associated macrophages (TAMs) are a type of highly plastic immune cells in the tumor microenvironment (TME), which can be classified into two main phenotypes: classical activated M1 macrophages and alternatively activated M2 macrophages. As previously reported, M2-polarized TAMs play critical role in promoting the progression of non-small cell lung cancer (NSCLC) via secreting exosomes, but the detailed mechanisms are still largely unknown. In the present study, the THP-1 monocytes were sequentially induced into M0 and M2-polarized macrophages, and the exosomes were obtained from M0 (M0-exos) and M2 (M2-exos) polarized macrophages, respectively, and co-cultured with NSCLC cells (H1299 and A549) to establish the exosomes-cell co-culture system in vitro. As it was determined by MTT assay, RT-qPCR and Transwell assay, in contrast with the M0-exos, M2-exos significantly promoted cell proliferation, migration and epithelial-mesenchymal transition (EMT) process in NSCLC cells. Next, through screening the contents in the exosomes, it was verified that miR-155-5p was especially enriched in the M2-exos, and M2-exos enhanced cancer aggressiveness and tumorigenesis in in vitro NSCLC cells and in vivo xenograft tumor-bearing mice models via delivering miR-155-5p. The detailed molecular mechanisms were subsequently elucidated, and it was found that miR-155-5p bound with HuR to increase the stability and expression levels of VEGFR2, which further activated the tumor-promoting PI3K/Akt/mTOR signal pathway, and M2-exos-enhanced cancer progression in NSCLC cells were apparently suppressed by downregulating VEGFR2 and PI3K inhibitor LY294002 co-treatment. Taken together, M2-polarized TAMs secreted miR-155-5p-containing exosomes to enhanced cancer aggressiveness of NSCLC by activating the VEGFR2/PI3K/Akt/mTOR pathway in a HuR-dependent manner.

Unveiling potent bioactive compounds and anti-angiogenic pathways in Gekko swinhonis Guenther for gastric cancer therapy

Ethnopharmacological relevanceGekko swinhonis Guenther, commonly referred to as Gecko in the following text, belongs to the genus Gekko within the family Gekko. Its dried whole body is a widely utilized traditional Chinese medicine, demonstrating significant efficacy in the treatment of gastrointestinal malignancies, particularly gastric cancer (GC). Nevertheless, the composition of the gecko is complex, necessitating further research into its active ingredients for the treatment of GC. Aim of the studyIsolation and characterization of the most active components in Gecko based on their anti-GC mechanisms of vascular endothelial cell inhibition and anti-neovascularization. Materials and methodsWe utilized the enzymatic hydrolysate of Geckos to investigate its effectiveness and underlying mechanisms. Initially, we assessed its efficacy in ectopic and in-situ GC tumor-bearing mouse models. Subsequently, we evaluated the effectiveness of peptides, aliphatics, and small molecules derived from Gecko using CCK-8 and 3D tumor spheroid assays. The activities of peptides S1-S4 were further examined through these experiments. Finally, we screened, synthesized, and investigated five potential peptides for their pharmacodynamics in the CCK-8 assay and in the in-situ GC model mice. ResultsThe Gecko can inhibit the formation of blood vessels in the tumor microenvironment, providing a localized treatment for GC. The peptide components significantly inhibit vascular endothelial cells and impede the formation of new blood vessels, with the S2 peptide sections (0.3 KD - 3 KD) demonstrating the most potent inhibitory activity against angiogenesis. One of the active peptides effectively suppresses the growth of in-situ GC in nude mice through angiogenesis inhibition and also modulates immunity, all while exhibiting excellent biosafety. ConclusionsWe have achieved a significant breakthrough in the local treatment of GC using Gecko. Through pharmacodynamic experiments and a systematic process of isolation and identification, we identified the most effective anti-GC ingredients of Gecko, based on their mechanisms of inhibiting vascular endothelial cells and promoting anti-angiogenesis. Furthermore, we synthesized a lead peptide that demonstrates promising therapeutic efficacy and safety.

Highly Efficient and Long-Lasting Chemiluminescence-Functionalized Nanohydrogel for Imaging-Guided Precise Piperlongumine Chemotherapy.

A major challenge for imaging-guided precise chemotherapy remains the ability to track the in situ real-time variation of the reactive oxygen species (ROS) level during treatment with prooxidation antitumor drugs. Chemiluminescence (CL) is widely used as an in vivo imaging tool with an excellent signal-to-noise ratio and high biological safety. However, suffering from flash-type and poor water solubility, most of the reported CL probes for ROS detection are unsuitable for in vivo long-term tracking. Herein, we designed a water-soluble CL nanohydrogel (L-012/Co2+@NGs) by cross-linking of vinyl-derived β-cyclodextrin monomer (MAH-β-CD) and loaded with luminol analog L-012 and cobalt ions (Co2+). In vitro studies reveal that L-012/Co2+@NGs exhibit long-lasting CL emission (up to 4 h) due to the slow diffusion of hydrogen peroxide in the nanohydrogel. High catalytic efficiency from the accelerated reduction of Co3+ to Co2+ through Tris and chelation of Co2+, as well as protection of the β-CD cavity against the active intermediate of L-012, enables L-012/Co2+@NGs to exhibit a 722-fold CL signal turn-on ratio and a nanomolar limit of detection (8.9 nmol/L). Piperlongumine (PL) was selected as a model of prooxidation drugs. The long-term and highly efficient CL strategy was designed for monitoring the local dynamic changes of ROS in PL-treated tumor-bearing mice for 150 min. The CL signal increased over time until reaching its maximum with a ∼6-fold increase at 15 min and then decreased slowly. The CL-functionalized nanohydrogel platform with good biocompatibility offers a great opportunity for imaging-guided precise tumor chemotherapy of PL and other prooxidation antitumor drugs.

Study on the biosafety and targeting efficiency of Escherichia coli outer membrane vesicles in breast tumor.

To seek out the targeting of Escherichia coli outer membrane vesicles (E. coli OMVs) in breast tumor-bearing mice and their biosafety in healthy mice. Ultrafiltration in conjunction with ultracentrifugation was utilized to concentrate E. coli OMVs, and characterize them. Subcutaneous breast tumors were induced in BALB/c mice to serve as an experimental model, and the biodistribution of E. coli OMVs in both tumor-bearing and healthy mice was monitored using an in vivo fluorescence imaging system. Utilizing frozen sections, the infiltration of E. coli OMVs in tumor tissues was appraised at the 24-hour post-injection. Healthy BALB/c mice were randomly divided into control group and vesicles group. Following the intravenous injection of E. coli OMVs, monitoring encompassed variations in body weight, blood routine indices, serum levels of AST, ALT, and BUN, organ indices (heart, liver, spleen, lung, and kidney), along with tissue histopathology over a 14-day period. The spherical E. coli OMVs had a diameter of (155.8 ± 3.1) nm and exhibited the expression of outer membrane proteins OmpA and OmpC. Upon assessment, it was evident that the E. coli OMVs persisted in the tumor tissues even 24h post-injection. An evident decrease in the body weight of the vesicles group, distinct from the control group, was observed on the second day after injection (P < 0.001); in contrast, no considerable differences were noted at subsequent time points (P > 0.05). Following the injection, the vesicles group displayed notable reductions in WBC and PLT as relative to the control group (P < 0.0001) on the initial day, however, there were no noteworthy distinctions as opposed to the control group for other hematological indices; No notable variances in hematological indices between the two groups were observed on the seventh and fourteenth day (P > 0.05). Over the 14 days, no substantial differences were observed in the serum levels of BUN, AST, ALT, and organ indices within the vesicles group as opposed to the control group (P > 0.05). Furthermore, there were no obvious abnormal changes in tissue morphology. 0.5mg/kg of E. coli OMVs can safely and effectively target 4T1 breast tumor in mice.

Unwanted disorders and xenogeneic graft-versus-host disease in experimental immunodeficient mice: How to evaluate and how to report.

Human-derived tumor models are essential for preclinical development of new anticancer drug entities. Generating animal models bearing tumors of human origin, such as patient-derived or cell line-derived xenograft tumors, is dependent on immunodeficient strains. Tumor-bearing immunodeficient mice are susceptible to developing unwanted disorders primarily irrelevant to the tumor nature; and if get involved with such disorders, reliability of the study results will be undermined, inevitably confounding the research in general. Therefore, a rigorous health surveillance and clinical monitoring system, along with the establishment of a strictly controlled barrier facility to maintain a pathogen-free state, are mandatory. Even if all pathogen control and biosafety measures are followed, there are various noninfectious disorders capable of causing tissue and multiorgan damage in immunodeficient animals. Therefore, the researchers should be aware of sentinel signs to carefully monitor and impartially report them. This review discusses clinical signs of common unwanted disorders in experimental immunodeficient mice, and how to examine and report them.