Subcutaneous Tumor Research Articles

Investigation of the Efficacy of Nowarta110 in the Treatment of HPV-16 and HPV-18 Oncogenically-transformed Human Cells and Cancer-implanted Animal Models.

Cervical cancer is the third leading cause of cancer-related death in women worldwide. Nearly all cases of cervical cancer are due to infection with human papillomavirus (HPV). Nowata110 has shown breakthrough therapeutic efficacy in phase II clinical study against plantar warts, with no reported side effects. This study evaluated the effectiveness of Nowarta110 in killing cultured HPV-transformed cancer cells and its anti-cancer effects in mice, using both vaginally engrafted and subcutaneously implanted animal cancer models. Nowata110 is a novel compound composed of colloidal silver and fig extract. The cytotoxic properties of Nowarta110 were evaluated on HPV-16 and HPV-18-transformed human cancer cells (ARPE-19/HPV-16 and HeLa cells, respectively). The therapeutic potential of Nowarta110 in vivo was evaluated following the engraftment of ME-180 epidermoid carcinoma cells in the mouse vagina or their subcutaneous implantation. Nowarta110 treatment was initiated when the tumor reached an approximate volume of 65 mm3 Results: Our data showed that HPV16-expressing human retinal pigmented epithelial cells are susceptible to Nowarta110-induced cell death, with a reduction in cell viability observed at 1% Nowarta110 and a complete absence of viable cells at 5% Nowarta110. In HPV18-expressing HeLa cells, Nowarta110 caused significant and rapid cell death at a dose of 5%, whereas lower doses of 1% did not produce the same effects. The results from animal studies indicated that Nowarta110 effectively induced tumor regression in both the intravaginal and subcutaneous tumor models. Nowarta110 effectively induced cell death in HPV-16 and HPV-18-transformed human cancer cells. It also effectively induced tumor regression in mouse models with intravaginally engrafted or subcutaneously implanted cancer cells. Considering the high prevalence of HPV-induced cervical dysplasia and cancer and the lack of treatment, clinical studies to promote the implementation of Nowarta110 are warranted.

Low-Intensity Focused Ultrasound-Responsive Phase-Transitional Liposomes Loaded with STING Agonist Enhances Immune Activation for Breast Cancer Immunotherapy.

Background: Pharmacologically targeting the STING pathway offers a novel approach to cancer immunotherapy. However, small-molecule STING agonists face challenges such as poor tumor accumulation, rapid clearance, and short-lived effects within the tumor microenvironment, thus limiting their therapeutic potential. To address the challenges of poor specificity and inadequate targeting of STING in breast cancer treatment, herein, we report the design and development of a targeted liposomal delivery system modified with the tumor-targeting peptide iRGD (iRGD-STING-PFP@liposomes). With LIFU irradiation, the liposomal system exploits acoustic cavitation, where gas nuclei form and collapse within the hydrophobic region of the liposome lipid bilayer (transient pore formation), which leads to significantly enhanced drug release. Methods: Transmission electron microscopy (TEM) was used to investigate the physicochemical properties of the targeted liposomes. Encapsulation efficiency and in vitro release were assessed using the dialysis bag method, while the effects of iRGD on liposome targeting were evaluated through laser confocal microscopy. The CCK-8 assay was used to investigate the toxicity and cell growth effects of this system on 4T1 breast cancer cells and HUVEC vascular endothelial cells. A subcutaneous breast cancer tumor model was established to evaluate the tumor-killing effects and therapeutic mechanism of the newly developed liposomes. Results: The liposome carrier exhibited a regular morphology, with a particle size of 232.16 ± 19.82 nm, as indicated by dynamic light scattering (DLS), and demonstrated low toxicity to both HUVEC and 4T1 cells. With an encapsulation efficiency of 41.82 ± 5.67%, the carrier exhibited a slow release pattern in vitro after STING loading. Targeting results indicated that iRGD modification enhanced the system's ability to target 4T1 cells. The iRGD-STING-PFP@liposomes group demonstrated significant tumor growth inhibition in the subcutaneous breast cancer mouse model with effective activation of the immune system, resulting in the highest populations of matured dendritic cells (71.2 ± 5.4%), increased presentation of tumor-related antigens, promoted CD8+ T cell infiltration at the tumor site, and enhanced NK cell activity. Conclusions: The iRGD-STING-PFP@liposomes targeted drug delivery system effectively targets breast cancer cells, providing a new strategy for breast cancer immunotherapy. These findings indicate that iRGD-STING-PFP@liposomes could successfully deliver STING agonists to tumor tissue, trigger the innate immune response, and may serve as a potential platform for targeted immunotherapy.

Ultrabright and ultrafast afterglow imaging in vivo via nanoparticles made of trianthracene derivatives.

Low sensitivity, photobleaching, high-power excitation and long acquisition times constrain the utility of afterglow luminescence. Here we report the design and imaging performance of nanoparticles made of electron-rich trianthracene derivatives that, on excitation by room light at ultralow power (58 μW cm-2), emit afterglow luminescence at ~500 times those of commonly used organic afterglow nanoparticles. The nanoparticles' ultrabright afterglow allowed for deep-tissue imaging (up to 6 cm), for ultrafast afterglow imaging (at short acquisition times down to 0.01 s) of naturally behaving mice with negligible photobleaching, even after re-excitation for over 15 cycles, and for the accurate visualization of subcutaneous and orthotopic tumours and of plaque in carotid arteries. We also show that an afterglow nanoparticle that is activated only in the presence of granzyme B allowed for the tracking of granzyme-B activity in the context of therapeutic monitoring. The high sensitivity and negligible photobleaching of the organic afterglow nanoparticles offer advantages for real-time in vivo monitoring of physiopathological processes.

Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression.

Lung cancer is one of the most common malignant tumors in the world, with high incidence rate and mortality. Monocarboxylate transporter (MCT) 1 has been found to be widely expressed in various tumors and plays a crucial role in regulating energy metabolism. Emodin, as an important traditional Chinese medicine in China, has been reported to inhibit the progression of lung cancer. However, its potential mechanism has not been fully elucidated. The effects of emodin and MCT1 inhibitor AZD3965 on the proliferation, migration, and invasion of lung cancer cells were detected using cell counting kit-8 (CCK-8) assay, wound-healing assay, and transwell small chamber assay. The content of glucose, lactate, and pyruvate in the cell culture medium was detected using a glucose, lactate, and pyruvate detection kit, and also detected protein expression using western blotting. In addition, to investigate the effects of emodin and AZD3965 on lung cancer in vivo, we constructed nude mice subcutaneous transplant tumor model by subcutaneous injection of lung cancer cells. The results showed that emodin and AZD3965 could inhibit the proliferation, migration, and invasion of lung cancer cells. At the same time, they could inhibit the expression of MCT1 in lung cancer cells and promote the release of lactate, but did not affect the content of glucose and pyruvate. In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer.

ZSTK474 targeting PIK3R3 inhibits the Wilms' tumor through G0 / G1 phase arrest.

Wilms' tumor (WT), also known as nephroblastoma, is the predominant form of primary malignant renal cancer. The unfavorable prognoses linked to anaplastic nephroblastoma and recurrent nephroblastoma emphasize the crucial requirement for the exploration of innovative treatment modalities for WT. Our study conducted one-way Cox regression and Kaplan-Meier analyses using TARGET-WT nephroblastoma data to identify differentially expressed genes in nephroblastoma and evaluate their prognostic relevance. Utilizing the Connectivity Map database, ZSTK474 emerged as a viable therapeutic option for WT. The effect of ZSTK474 on WT and related underlying mechanisms were further investigated through in vitro and in vivo investigations. The in vivo experiment results indicated that ZSTK474 effectively inhibited subcutaneous tumor growth in WT mice. CCK-8 assays revealed two nephroblastoma cell lines exhibited half-inhibitory concentrations of 2μM and 2.51μM for ZSTK474, respectively. ZSTK474 was shown to inhibit the migration and invasion capabilities of WT cells in both Transwell and wound healing assays. Flow cytometry apoptosis and TUNEL assays demonstrated that ZSTK474 induced apoptosis in WT cells. Cell cycle analysis revealed that ZSTK474 led to the induction of G0/G1 phase arrest. Sequencing of ZSTK474-treated WiT49 cells suggested that the impact of ZSTK474 on WT might be mediated by the PI3K/Akt pathway, specifically by inhibiting PIK3R3. Knock-down of PIK3R3 confirmed that ZSTK474 downregulated PIK3R3, reducing Akt phosphorylation, cyclin D and CDK4 levels and elevating P21 expression in nephroblastoma cells. However, current research has limitations, including a lack of understanding of the long-term effects and potential resistance mechanisms of new therapies. This research provides insight into the potential of ZSTK474 and other PI3K inhibitors for treating nephroblastoma.

Colorectal Cancer Cell-Derived Extracellular Vesicles Promote Angiogenesis Through JAK/STAT3/VEGFA Signaling

Background: Angiogenesis plays a crucial role in the growth of colorectal cancer (CRC). Recent studies have identified extracellular vesicles (EVs) in the tumor microenvironment as important mediators of cell-to-cell communication. However, the specific role and mechanisms of CRC-derived EVs in regulating tumor angiogenesis remain to be further investigated. Methods: EVs were isolated from the conditioned medium of the CRC cells using ultracentrifugation. We investigated the effects of HT-29-derived EVs on tumor growth and angiogenesis in a subcutaneous HT-29 CRC tumor model in mice. Additionally, we evaluated the impact of HT-29-derived EVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, bioinformatics analysis was performed to identify relevant signaling pathways, and pathway inhibitors were used to block the activation of these pathways, aiming to elucidate their roles in angiogenesis. Results: We found that HT-29-derived EVs can promote tumor growth and angiogenesis in vivo, as well as significantly enhance the proliferation, migration, and tube formation of HUVECs. Bioinformatics analysis revealed that HT-29-derived EVs may regulate angiogenesis through the JAK/STAT3 signaling pathway. Specifically, we observed that CRC-derived EVs promoted the phosphorylation of STAT3 (p-STAT3) and the expression of VEGFA in the nucleus of HUVECs. Treatment with the STAT3 inhibitor Stattic reduced the nuclear expression of p-STAT3, which impaired its function as a transcription factor, thereby inhibiting VEGFA expression and the pro-angiogenic effects of CRC-derived EVs. Conclusions: EVs derived from CRC cells promote CRC tumor angiogenesis by regulating VEGFA through the JAK/STAT3 pathway in endothelial cells.

Pathology-Based Animal Cancer Registry of Abruzzo and Molise Regions (Central Italy): A Ten-Year Retrospective Study (2014–2023)

Pets have a crucial role in cancer research. Specifically, dogs and cats share the same environment as their owners and thus may serve as sentinels of naturally occurring tumors that are linked to the exposure to environmental hazards. Quantitative comparison of tumor types may reveal unusual cancer frequencies, providing directions for research and generation of hypotheses of cancer causation in a specific area and identification of risk factors. The aim of this study was to describe the data collected by the pathology-based animal cancer registry, managed by Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise (IZSAM), during 10 years of activity (2014–2023) and to assess its potential epidemiological relevance. Frequencies of tumor topography and morphology in dogs and cats were described, analyzed and compared. Proportional morbidity ratios (PMRs) were calculated, taking into consideration some potential risk factors such as species, breed, sex, diet and living environment. The database comprises 5311 tumors (n = 4719 in dogs and n = 592 in cats), with a higher prevalence in females (67.3% in dogs and 61.2% in cats). The mean age at the first diagnosis of tumors was similar between sexes and slightly lower in dogs compared to cats. PMRs highlighted certain risk and “protective” factors for the development of tumors in specific topography. The risk of developing tumors of the blood and hematopoietic system (PMR = 0.44; 95% CI: 0.21–0.94), skin and subcutaneous tissues (PMR = 0.70; 95% CI: 0.61–0.80), oral cavity and pharynx (PMR = 0.60; 95% CI: 0.24–0.89), urinary organs (PMR = 0.33; 95% CI: 0.11–0.99) and bones, joints and cartilage (PMR = 0.72; 95% CI: 0.22–0.98) was lower in non-neutered male dogs than in neutered male dogs. Non-spayed female dogs had a greater risk of developing tumors of the mammary gland (PMR = 1.75; 95% CI: 1.57–1.96), female sexual organs (PMR = 2.12; 95% CI: 1.01–4.36) and respiratory system (PMR = 2.25; 95% CI: 1.55–6.74) but less risk for cutaneous and subcutaneous tissue tumors (PMR = 0.44; 95% CI: 0.38–0.51) and blood/hematopoietic system tumors (PMR = 0.47; 95% CI: 0.26–0.85) compared to spayed female dogs. Compared with mixed breed, purebred dogs had a significantly greater risk of developing mammary gland tumors (PMR = 1.36; 95% CI: 1.20–1.54) and lower risk for respiratory (PMR = 0.15; 95% CI: 0.07–0.32), gastrointestinal (PMR = 0.63; 95% CI: 0.34–0.94) and oral (PMR = 0.59; 95% CI: 0.36–0.96) neoplasia. Non-neutered male cats had a lower risk of developing skin and subcutaneous tumors (PMR = 0.68; 95% CI: 0.50–0.92) compared with neutered cats. The risk of developing skin and subcutaneous tissues tumors was higher for dogs and cats that lived mostly outdoor (PMR dogs = 1.21; 95% CI: 1.10–1.33; PMR cats = 1.18; 95% CI: 1.08–1.47), while dogs that live mainly indoor had a greater risk to develop mammary gland tumors (PMR = 0.78; 95% CI: 0.68–0.89). Results described herein highlight the fundamental role of animal cancer registration initiatives. These efforts would contribute to the possibility of conducting multicentric collaborative studies to deepen the knowledge of the epidemiology of tumors in dogs and cats from a comparative perspective, thus fulfilling the One Health approach.

Mitochondria-Targeted Icaritin Nanoparticles Induce Immunogenic Cell Death in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor that is resistant to chemotherapy and immunotherapy. Icaritin (ICT), a traditional Chinese medicine, has been reported as an immunoregulatory agent for treating advanced unresectable HCC. ICT induces mitophagy to cause immunogenic cell death (ICD); however, the poor bioavailability of ICT limits its therapeutic efficacy and clinical use. Therefore, this study aimed to assess the effect of using the poly(2-(N-oxide-N,N-diethylamino) ethyl methacrylate)-b-poly(ε-caprolactone) copolymer (OPDEA-PCL) to encapsulate ICT into nanoparticles (ICT NPs). OPDEA-PCL/ICT NPs colocalized with the mitochondria, promoting the ICD induction effect of ICT in mouse HCC H22 cells. In the H22 subcutaneous tumor model, intravenously injected OPDEA-PCL/ICT NPs quickly accumulated in the tumor and efficiently activated systemic anticancer immunogenicity through their effects on mitophagy. The resulting tumor suppression rate was 60%, which was significantly higher than that of free ICT and poly(ethylene glycol) (PEG)-PCL/ICT NPs. Furthermore, mouse survival was also prolonged by nearly 2-fold with OPDEA-PCL/ICT NPs compared with PBS. In summary, this approach provides valuable insights into improving the immunotherapeutic efficacy of ICT for HCC.

Erianin inhibits the progression of pancreatic cancer by directly targeting AKT and ASK1

BackgroundPancreatic cancer is a malignant tumor of the digestive tract with a high mortality rate. Erianin has antitumor activity, but the regulatory targets and mechanism of action in pancreatic cancer are unclear. The objective of this study was to evaluate the anti-pancreatic cancer activity of Erianin and explore its underlying mechanisms.MethodsA network pharmacology approach was used to investigate the mechanism of action of Erianin in pancreatic cancer cells. Cell proliferation was analyzed using CCK8, colony-formation, and EdU proliferation assays. Cell migration was evaluated through wound healing and transwell assays, as well as determination of the protein expression levels of EMT markers and β-catenin. Apoptosis and the cell cycle were measured using flow cytometry and JC-1 staining, respectively. The protein expression levels of p-Rb, CyclinB1, P21, Cleaved-PARP, and Cleaved-Caspase3 were assessed using western blotting. RNA sequencing (RNA-seq) and bioinformatics analyses were performed to elucidate the mechanism underlying the action of Erianin in pancreatic cancer. Western blotting was used to examine the expression levels of key proteins in the AKT, JNK, and p38 MAPK signaling pathways. Molecular docking and CETSA were used to test hypotheses. The tumor-suppressive ability of Erianin in vivo was assessed using a tumor-bearing assay in nude mice.ResultsNetwork pharmacology revealed that Erianin inhibited pancreatic cancer through multiple pathways. Erianin significantly inhibited pancreatic cancer cell proliferation and migration while promoting intracellular ROS and inducing apoptosis. Mechanistically, Erianin inhibited pancreatic cancer cell proliferation by regulating the AKT/FOXO1 and ASK1/JNK/p38 MAPK signaling pathways. In vivo experiments showed that Erianin inhibited subcutaneous tumor growth and promoted tumor tissue apoptosis in nude mice.ConclusionsThe component-target-pathway network revealed that Erianin exerted anti-cancer effects through multiple components, targets, and pathways. Erianin inhibited the proliferation and migration of pancreatic cancer cells and induced apoptosis through the AKT/FOXO1 and ASK1/JNK/p38 MAPK signaling pathways. These results indicate that Erianin is a promising agent for pancreatic cancer treatment.

Preclinical Positron Emission Tomography with Body Conforming Animal Molds for Cloud-Based Automated Image Analysis in Mice.

Positron Emission Tomography (PET) is a molecular imaging modality that can be used to investigate a multitude of pharmacological questions, such as biomarker modulation, receptor occupancy, and biodistribution of compounds of interest. In biodistribution studies, experimental subjects are often longitudinally imaged after receiving the test article. The images are then analyzed to derive the compound's distribution profile in various organs at different timepoints. This constitutes a crucial step in drug development to understand the distribution and potentially binding profile of an investigative compound. Standard/manual methods of PET imaging-based biodistribution analyses, however, are labor-intensive and time-consuming and are often associated with high inter-operator variability. Further, it is challenging to keep the animals' positions consistent across different timepoints. To address these shortcomings, a series of mouse Body Conforming Animal Molds (BCAMs) were used to enable rigid and consistent positioning of animals during PET/CT imaging acquisition. Further, a Software-as-a-Service (SaaS) platform consisting of a cloud-based Organ Probability Map (OPM) and an artificial intelligence-powered segmentation tool were employed to enable reliable and automated quantitation of in vivo PET imaging data. The workflow presented here includes (1) prepping mice for imaging with the BCAMs, including the proper implantation of subcutaneous tumors to be compatible with the molds, (2) acquiring PET/CT images with BCAMs using the G8 scanner, and 3) performing automated organ segmentation and biodistribution analysis using the cloud-based SaaS. [18F]FDG was used as an exemplar tracer here, but other biomarkers and/or radio-labeled compounds can be readily adapted into the workflow. This procedure can be executed accurately and effectively with minimal training, and the automated PET data analysis yielded satisfactory results consistent with the manual method.

Quercetin regulates sensitivity to X-ray radiation of hepatocellular carcinoma through miR-216a-3p.

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with limited therapeutic options, and enhancing radiosensitivity remains a key challenge in improving treatment outcomes. Quercetin (Que) can inhibit the progression of hepatocellular carcinoma (HCC); however, its effect on HCC radiosensitivity remains unclear. This research investigates the role of Que in regulating HCC growth and radiosensitivity, aiming to provide a scientific foundation for enhancing the clinical efficacy of radiation therapy in HCC. The CCK-8 assay was used to determine the optimal treatment conditions for Que and X-rays. Changes in cell growth, cycle arrest, invasion, migration, the relative proportion of JC-1 red and green fluorescence (mitochondrial membrane potential), and the levels of ROS, MDA, SOD, and GSH-Px (oxidative stress) were assessed using flow cytometry, Transwell assays, JC-1 staining, Western blot, and ELISA, respectively, under Que, X-ray, and co-treatment conditions. The effect of miR-216a-3p knockdown on the action of Que was also explored, and the potential pathways by which Que regulates HCC growth and radiosensitivity were investigated in conjunction with in vivo subcutaneous transplantation tumor experiments. The in vitro treatment parameters for Que and X-rays were 100 µM and 4 Gy. Que combined with X-ray therapy enhanced HCC cell radiosensitivity, reduced proliferation, invasion, and migration, and promoted oxidative stress and apoptosis. Que was found to upregulate miR-216a-3p in HCC cells. Rescue experiments with miR-216a-3p knockdowns demonstrated that Que regulates HCC cell radiosensitivity via miR-216a-3p. In vivo research further showed that Que increased tumor sensitivity to X-rays by upregulating miR-216a-3p, thereby inhibiting HCC growth. In conclusion, Que has been shown to enhance HCC radiosensitization by upregulating miR-216a-3p and inhibiting HCC progression. Que may be a promising agent for increasing the radiosensitivity of HCC.

Blestriarene C exerts an inhibitory effect on triple-negative breast cancer through multiple signaling pathways.

Breast cancer is the most common cancer worldwide, the leading cause of cancer death in women, and the fifth leading cause of cancer death. Triple negative breast cancer (TNBC), with high metastasis and mortality rates, is the most challenging subtype in breast cancer treatment. There is an urgent need to develop anti-TNBC drugs with significant efficacy, low side effects and good availability. In early drug screening, blestriarene C was found to have inhibitory effects on TNBC cells. In this article, we further explore the mechanisms associated with blestriarene C for breast cancer. In this article, we take the approach of network pharmacology combined with in vivo and in vitro experiments. Network pharmacology analysis was used to predict the active components in Baiji, and to investigate the hub targets and related mechanisms of BC in TNBC treatment. The mechanism of anti-TNBC in vitro was evaluated by CCK-8 assay, cell apoptosis and cell cycle assays, wound healing assay, WB assay, and molecular docking analysis. The inhibition effect in vivo was test in subcutaneous tumor models established in mice. Through network pharmacology analysis and experiments, we screened out BC as the main active ingredient, and found that BC could inhibit the Ras/ERK/c-Fos signaling pathway while downregulating the expression of HSP90AA1 and upregulating the expression of PTGS2, thereby promoting apoptosis, causing S-phase cycle arrest, and inhibiting the proliferation and migration of BT549 cells. The in vivo results illustrated that BC inhibited the growth of TNBC tumors and has a high safety profile. By integrating network pharmacology with in vitro and in vivo experiments, this study demonstrated that BC inhibited the proliferation and migration of TNBC cells by inhibiting the Ras/ERK/c-Fos signaling pathway, promoting apoptosis, and causing S-phase cycle arrest. This study provides new evidence for the use of BC as a novel drug for TNBC treatment.

Euphorbia helioscopia inhibits proliferation, invasion, and migration and promotes apoptosis of non-small cell lung cancer cells

To investigate the effect of Euphorbia helioscopia on biological behaviors of non-small cell lung cancer (NSCLC) cells. NSCLC cell lines PC-9 and A549 treated with different concentrations of Euphorbia helioscopia preparations were examined for changes in proliferation, apoptosis, invasion and migration using CCK-8 assay, colony formation assay, flow cytometry, wound healing assay and Transwell assay. Western blotting was performed to detect the changes in protein expressions of Bax, Bcl-2, E-cadherin, vimentin, MMP2, and MMP9 in the treated cells. PC-9 cells were injected subcutaneously into BALB/C nude mice to establish a nude mouse subcutaneous tumor model. According to the growth of subcutaneous tumors, mice were randomly divided into control group: gavaged daily with saline; Euphorbia helioscopia-treated group: gavaged daily with Euphorbia helioscopia 65 mg/mL, and Euphorbia helioscopia granules were dissolved in saline; cisplatin-treated group: injected intraperitoneally with cisplatin 4 mg/kg every 5 days, 6 mice per group. The subcutaneous tumor volume and mass changes of mice were measured, and the toxic effects of Euphorbia helioscopia on heart, liver, spleen, lung and kidney as well as the therapeutic effects of Euphorbia helioscopia were observed in the mice bearing tumor. Euphorbia helioscopia granules concentration-dependently inhibited the proliferation and survival of PC-9 and A549 cells, significantly promoted cell apoptosis, suppressed invasion and migration abilities of the cells, up-regulated the expression levels of E-cadherin and Bax, and down-regulated the expressions of Bcl-2, vimentin, MMP2, and MMP9. In the tumor-bearing mice, treatment with Euphorbia helioscopia significantly inhibited tumor growth without producing obvious toxicity in the vital organs. Euphorbia helioscopia can inhibit proliferation, invasion, and migration and induces apoptosis of NSCLC cells in vitro.

In vivo delivery of PBAE/ZIF-8 enhances the sensitivity of colorectal cancer to doxorubicin through sh-LncRNA ASB16-AS1.

The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.

MARCHF1 promotes breast cancer through accelerating REST ubiquitylation and following TFAM transcription.

Breast cancer has become the leading cause of death in women. Membrane associated ring-CH-type finger 1 (MARCHF1) is associated with the development of various types of cancer, but the exact role of MARCHF1 in breast cancer remains unclear. In our study, the higher MARCHF1 expression was observed in tumor samples of patients with breast cancer and then the role of MARCHF1 in breast cancer was further evaluated. Overexpression of MARCHF1 contributed to proliferation of cancer cells and inhibition of oxidative stress. Knockdown of MARCHF1 reduced breast cancer cell proliferation, increased mitochondrial dysfunction induced by oxidative stress, eventually aggravating cell death. In vivo, MARCHF1 promoted the tumor growth and oppositely, MARCHF1 silencing suppressed the tumor development. Moreover, MARCHF1 interacted with repressor Element-1 silencing transcription factor (REST) and facilitated its ubiquitylation and degradation. Subsequently, REST negatively regulated the transcription of mitochondrial transcription factor A (TFAM). The subcutaneous tumor formation assay in nude mice also supported these conclusions. In details, knockdown of MARCHF1 upregulated the protein expression of REST and downregulated the mRNA level of TFAM. On the contrary, MARCHF1 overexpression exhibited opposite effects. Thus, MARCHF1 is conducive to the progression of breast cancer via promoting the ubiquitylation and degradation of RSET and then the transcription of TFAM. Downregulating MARCHF1 could provide a novel direction for treating breast cancer.

Photosensitizing metal–organic framework nanoparticles combined with tumor-sensitization strategies can enhance the phototherapeutic effect upon medullary thyroid carcinoma

Photodynamic therapy (PDT) utilizing metal-organic frameworks (MOFs) has developed as a new and efficacious treatment for malignant tumors located on the surface of the human body. In order to achieve more effective PDT treatment outcomes, the traditional method has been to increase the intensity of the laser irradiation, but this approach can easily lead to tissue burns. In this study, we developed a new type of nanoparticle, F68-PKI@PCN224, aims to achieve effective PDT upon medullary thyroid carcinoma (MTC) which is an uncommon form of thyroid cancer that originates in the parafollicular cells of the thyroid and the therapeutic outlook for patients with MTC remains unsatisfactory. F68-PKI@PCN224 combines the antitumor features of PDT with mammalian target of rapamycin (mTOR) inhibitor PKI-587 (PKI). The tumor sensitization, slow release, and pH response features of F68-PKI@PCN224 was demonstrated by a series of in vitro and in vivo experiments / assays. F68-PKI@PCN224 achieved the long-term activation and slow releasing of PKI and TCPP in MTC tumor tissues. During the process of generating PDT effects, F68-PKI@PCN224 enhanced the tumor's sensitivity to PDT, direct laser irradiation of MTC cells or subcutaneous tumor tissues. As a result, low-dose phototherapy achieves a higher anti-tumor effect upon F68-PKI@PCN224 compared with TCPP. This study reveals the synergistic effect between tumor sensitization by mTOR inhibitor and PDT and initially unveils the mechanism of action of these nanoparticles.

PET Imaging Using 89Zr Labeled StarPEG Nanocarriers Reveals Heterogeneous Enhanced Permeability and Retention (EPR) in Prostate Cancer.

The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors, and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET-imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed-starPEG40kDa with or without talazoparib (TLZ), a potent PARPi, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared to CT26, a known EPR-high MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545, moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 subcutaneous xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in subcutaneous and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.

Ranking Magnetic Colloid Performance for Magnetic Particle Imaging and Magnetic Particle Hyperthermia

AbstractMagnetic particle imaging (MPI) is an emerging modality that can address longstanding technological challenges encountered with magnetic particle hyperthermia (MPH) cancer therapy. MPI is a tracer technology compatible with MPH for which magnetic nanoparticles (MNPs) provide signal for MPI and heat for MPH. Identifying whether a specific MNP formulation is suitable for both modalities is essential for clinical implementation. Current models predict that functional requirements of each modality impose conflicting demands on nanoparticle magnetic properties. This objective here is to develop a measurement and ranking scheme based on end‐use performance to streamline evaluation of candidate MNP formulations. The measured MPI point‐spread function (PSF) and specific loss power (SLP) is combined to generate a single numerical value for comparison on a relative ranking scale, or figure of merit (FoM). 12 aqueous iron‐containing formulations are evaluated, including FDA‐approved (parenteral) iron‐containing colloids. MNPs with high (Synomag‐D70: 123.4), medium (Synomag‐D50: 63.2), and low (NanoXact: 0.147) FoM values are selected for in vivo validation of the selection scheme in subcutaneous 4T1 tumors. Results demonstrate that the proposed ranking accurately assessed the relative performance of MNPs for MPI and MPH. Data demonstrated that image quality and tumor temperature rise increased with FoM ranking, validating predictions. It isshown that the MPI signal correlated with MNP concentration in tissue. Computational heat transfer models anchored on tumor MPI data harmonized with experimental results to within an average of 2 °C when MNP content estimated from MPI data is included. Computational studies emphasized the importance of post‐injection MNP quantitation and MPI spatial resolution.

Oncolytic Coxsackievirus B3 Strain PD-H Is Effective Against a Broad Spectrum of Pancreatic Cancer Cell Lines and Induces a Growth Delay in Pancreatic KPC Cell Tumors In Vivo

Pancreatic cancer is one of the deadliest cancers globally, with limited success from existing therapies, including chemotherapies and immunotherapies like checkpoint inhibitors for patients with advanced pancreatic ductal adenocarcinoma (PDAC). A promising new approach is the use of oncolytic viruses (OV), a form of immunotherapy that has been demonstrated clinical effectiveness in various cancers. Here we investigated the potential of the oncolytic coxsackievirus B3 strain (CVB3) PD-H as a new treatment for pancreatic cancer. In vitro, PD-H exhibited robust replication, as measured by plaque assays, and potent lytic activity, as assessed by XTT assays, in most pancreatic tumor cell lines, outperforming two other coxsackievirus strains tested, H3N-375/1TS and CVA21. Thus, H3N-375/1TS showed efficient replication and lytic efficiency in distinctly fewer tumor cell lines, while most tumor cells were resistant to CVA21. The oncolytic efficiency of the three OV largely correlated with mRNA expression levels of viral receptors and their ability to induce apoptosis, as measured by cleaved caspase 3/7 activity in the tumor cells. In a syngeneic mouse model with subcutaneous pancreatic tumors, intratumoral administration of PD-H significantly inhibited tumor growth but did not completely stop tumor progression. Importantly, no virus-related side effects were observed. Although pancreatic tumors respond to PD-H treatment, its therapeutic efficacy is limited. Combining PD-H with other treatments, such as those aiming at reducing the desmoplastic stroma which impedes viral infection and spread within the tumor, may enhance its efficacy.

A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-driven Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, and KRAS mutations occur in 25-30% of NSCLC. Our approach to developing a therapeutic with the potential to target KRAS mutant NSCLC was to identify a new target involved in modulating signaling proteins in the RAS pathway. Glutathione S-Transferase P (GSTP) known as a Phase II detoxification enzyme has more recently been identified as a modulator of MAP kinase-related cell-signaling pathways. Therefore, developing a GSTP siRNA may be an effective therapeutic approach to treat KRAS mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle (LNP) comprising GSTP siRNA (NDT-05-1040). Here, studies using a panel of KRAS mutant NSCLC cell lines demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA inhibitor. Our Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of MAPK and PI3K pathway components while upregulating apoptotic signaling cascade. Our in vivo studies revealed statistically significant higher distribution of NBF-006 to the lungs and tumor as compared to liver. In the subcutaneous and orthotopic tumor models, NBF-006 led to a statistically significant and dose dependent anti-tumor growth inhibition. Further, quantitative image analysis of PCNA and PARP staining showed that NBF-006 decreased proliferation and induced apoptosis, respectively, in tumors. Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P <0.005) as compared to the vehicle control group. Together, these preclinical studies supported advancement of NBF-006 into clinical studies.