Inside Tumor Research Articles

Inverse heat transfer prediction of the thermal parameters of tumors during cryosurgery

An inverse heat transfer approach for predicting the moving freezing front and the temperature distribution inside tumors during cryosurgery is presented. By recording the time-varying temperature at the surface of the diseased tissues, the inverse method is able to estimate simultaneously the blood perfusion rate and the metabolic heat generation of the tumor. Once these thermal properties are determined, the temperature field and the moving freezing front are predicted with a direct method. The direct problem is solved with the one-dimension Pennes bioheat equation and the enthalpy method. The inverse model rests on the Levenberg-Marquardt Method (LMM) combined to the Broyden Method (BM). The following effects on the predictions of the inverse method are investigated: (i) the initialization of the unknown thermal properties; (ii) the thermal properties of the diseased tissues; (iii) the duration of cryosurgery; (iv) the temperature of the cryoprobe; (v) the noise level on the recorded temperatures; and (vi) the total number of recorded data. It is shown that the proposed inverse method remains accurate and stable for all cases investigated. Recommendations are made for the initialization of the parameters of the inverse method and for the total number of measurements.

Hydrogen nanobubbles: A novel approach toward radio-sensitization agents.

Ocular melanoma is a rare kind of eye malignancy that threatens the patient's eyesight. Radiotherapy and surgical removal are the most commonly used therapeutic modalities, and nanomedicine has lately entered this field. Brachytherapy using Ruthenium-106 (106 Ru) ophthalmic plaques has been used for decades to treat ocular melanoma, with the applicator placed on the patient's eyes until the prescribed dose reaches the tumor apex. To investigate the efficiency of hydrogen nanobubbles (H2 -NBs) employment during intraocular melanoma brachytherapy using a 106 Ru electron emitter plaque. The Monte Carlo (MC) simulation and experimental investigation using a 3D-designed phantom and thermoluminescence dosimetry (TLD) were employed. Various concentrations of H2 -NBs with a diameter of 100nm were simulated inside tumor tissue. The results were presented as deposited energy and dose enhancement factor (DEF). An equivalent Resin phantom of the human eyeball was made using AutoCAD and 3D-Printer technologies. The glass-bead TLDs dosimeter were employed and placed inside the phantom. Using a 1% concentration of H2 -NBs, a DEF of 93% and 98% were achieved at the tumor apex of 10mm from the experimental setup and MC simulation, respectively. For simulated concentrations of 0.1%, 0.3%, 0.5%, 1%, and 4% H2 -NBs, a maximum dose enhancement of 154%, 174%, 188%, 200%, and 300% were achieved, respectively, and a dose reduction was seen at about 3mm from the plaque surface. H2 -NBs can be used as an absorbed dose enhancer in 106 Ru eye brachytherapy because of their unique physical characteristics. Reducing plaque implantation time on the patient's eye, reducing sclera absorbed dose, and decreasing the risk of patients' healthy organs irradiation are reported as some of the potential benefits of using H2-NBs.

Constructing pH-Responsive and Tunable Azo-Phenol-Based o-Nitrobenzyl Photocages.

Multiple triggered-release strategies are widely utilized to control the release of caged target molecules. Among them, photocages with conditional triggers provide extra layers of control in photorelease. In this work, a series of pH-responsive photocages was designed that could be triggered under irradiation and specific intracellular pH values. pH-sensitive phenolic groups were conjugated with o-nitrobenzyl (oNB) to form azo-phenolic NPX photocages with tunable pKa. These azo-phenol-based oNB photocages showed differentiable photoreleasing profiles at pH 5.0, 7.2 and 9.0. By attaching fluorogenic cargos, it was shown that one of the photocages, NPdiCl, could be used to differentiate between acidic pH 5.0 and neutral pH 7.2 in cells under artificial pH conditions. Finally, NPdiCl was identified as a promising pH-responsive photocage for photoreleasing cargo inside acidic tumor cells.

A Tetramethylpyrazine Releasing Hydrogel can Potentiate CAR-T Cell Therapy against Triple Negative Breast Cancer by Reprogramming Tumor Vasculatures

Irregular vasculature of solid tumors has proven to be a pivotal factor restricting their response to chimeric antigen receptor-T (CAR-T) cell therapy because it is tightly associated with hypoxia and other biological barriers. Herein, an injectable hydrogel composed of poly (ethylene glycol) dimethacrylate (PEGDMA) and ferrous chloride (FeCl2) responding to endogenous hydrogen peroxides (H2O2) is developed to enable sustained intratumoral release of Chinese herbal extracts tetramethylpyrazine (TMP). TMP is selected due to its potency in activating vascular endothelial growth factor (VEGF) expression and the endothelial nitric oxide synthase/nitric oxide (eNOS/NO) axis inside vascular endothelial cells. Upon being fixed inside tumors with the PEGDMA based hydrogel, TMP can remodel tumor vasculature by simultaneously promoting angiogenesis and dilating tumor vasculature and thus attenuate tumor hypoxia in two murine xenografts bearing human triple negative breast cancer (TNBC). Resultantly, treatment with TMP fixation potentiates the tumor suppression effect of intravenously injected epidermal growth factor receptor expressing CAR-T (HER-1-CAR-T) cells toward two TNBC tumor xenografts by promoting their tumor infiltration, survival, and effector function. This study highlights a concise yet effective approach to reinforce the therapeutic potency of CAR-T cells towards targeted solid tumors by simply remodeling tumor vasculature.

Combined chemo and photo therapy of programmable prodrug carriers to overcome delivery barriers against nasopharyngeal carcinoma

Indocyanine green (ICG) has been employed in medical diagnostics due to its superior photophysical characteristics. However, these advantages are offset by its quick body clearance and inferior photo-stability. In this work, programmable prodrug carriers for chemotherapy/PDT/PTT against nasopharyngeal carcinoma (NPC) were created in order to increase photo-stability and get around biochemical hurdles. The programmable prodrug carriers (PEG-PLA@DIT-PAMAM) that proactively penetrated deeply into NPC tumors and produced the deep phototherapy and selective drug release under laser irradiation was created by dendrimer-DOX/ICG/TPP (DIT-PAMAM) and PEGylated poly (α-lipoic acid) (PLA) copolymer. Long circulation times and minimal toxicity to mammalian cells are two benefits of PEG-coated carriers. The overexpressed GSH on the tumor cell or vascular endothelial cell of the NPC disintegrated the PEG-g-PLA chains and released the DIT-PAMAM nanoparticles after the carriers had reached the NPC tumor periphery. Small, positively charged DIT-PAMAM nanoparticles may penetrate tumors effectively and remain inside tumor for an extended period of time. In addition, the induced ROS cleaved the thioketal linkers for both DOX and nanoparticles and product hyperthermia (PTT) to kill cancer cells under laser irradiation, facilitating faster diffusion of nanoparticles and more effective tumor penetration with a programmable publication of DOX. The programmable prodrug carries showed high photo-stability high photo-stability, which enabled very effective PDT, PTT, and tumor-specific DOX release. With the goal of combining the effects of chemotherapy, PDT, and PTT against NPC, this research showed the great efficacy of programmable prodrug carriers.

Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2 S Donor Conjugate with Complexed Fe2.

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2 S donor conjugate, complexed with Fe2+ , termed AAN-PTC-Fe2+ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2 S, an inhibitor of catalase, an enzyme that detoxifies H2 O2 . Fe2+ and H2 S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+ , the AAN sequence, or the ability to generate H2 S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2 S-amplified, enzyme-responsive platform for synergistic cancer treatment.

Enzyme‐Triggered Chemodynamic Therapy via a Peptide‐H2S Donor Conjugate with Complexed Fe2+

AbstractInducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+, CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide‐H2S donor conjugate, complexed with Fe2+, termed AAN‐PTC–Fe2+. The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2S, an inhibitor of catalase, an enzyme that detoxifies H2O2. Fe2+ and H2S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+, the AAN sequence, or the ability to generate H2S. AAN‐PTC–Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2S‐amplified, enzyme‐responsive platform for synergistic cancer treatment.

Abstract 5877: Intratumoral lymphocyte networks harbor TCF1+ PD1+ progenitor CD8 T cells in lung cancer

Abstract Cancer immunotherapies that activate cytotoxic T cell responses against tumors have been remarkably effective in some patients, but the determinants of response remain unclear. To investigate how spatial organization of T cells might influence immunotherapy response, we developed a tissue-based cyclic immunofluorescence (t-CyCIF) platform to characterize preclinical genetically engineered mouse models (GEMMs) of cancer. We optimized a 21-antibody panel delineating major myeloid and lymphoid cell subsets, that included key markers for characterizing T cell phenotypes and function. The panel was used to characterize the Kras/p53-mutant GEMM of lung adenocarcinoma, treated with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB) therapy or a neoantigen-targeted long-peptide vaccine. Spatial profiling by t-CyCIF identified intratumoral lymphocyte networks (“lymphonets”) as a key feature associated with a productive immune response against lung tumors. Lymphonets were predominantly composed of B cells and conventional CD4 T cells, but harbored tumor-reactive CD8 T cell populations. TCF1+ PD1+ progenitor CD8 T cells, a subset previously correlated with patient response to ICB, were almost exclusively localized to lymphonets inside tumors. Lymphonets of similar composition harboring TCF1+ PD1+ cells were also found in early-stage human lung adenocarcinomas. In response to ICB and vaccine therapies in mice, cytotoxic CD8 T cells (Granzyme B+/Perforin+) colocalized with TCF1+ PD1+ cells in lymphonets, likely having differentiated from this progenitor pool. Notably, vaccination further induced a highly proliferative (Ki67hi) and cytotoxic (GranzymeBhiPerforinhi) population of CD8 T cells localized outside of tumors that we posit enter tumors without passing through the intratumoral progenitor cell state. Upon becoming dysfunctional, marked by loss of Granzyme B/Perforin expression and upregulation of inhibitory receptors, CD8 T cells were excluded from lymphonets and localized predominantly to the tumor margin. Altogether, these results shed light on the spatial dynamics associated with a productive response to immunotherapies and open avenues for exploration into the function of lymphonets in supporting cytotoxic CD8 T cell responses in tumors. Citation Format: Megan L. Burger, Giorgio Gaglia, Claire C. Ritch, Danae Rammos, Yang Dai, Grace E. Crossland, Sara Z. Tavana, Simon Warchol, Alex M. Jaeger, Santiago Naranjo, Shannon Coy, Ajit J. Nirmal, Robert Krueger, Jia-Ren Lin, Hanspeter Pfister, Peter K. Sorger, Tyler Jacks, Sandro Santagata. Intratumoral lymphocyte networks harbor TCF1+ PD1+ progenitor CD8 T cells in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5877.

Abstract 2329: Disulfiram metabolite modulates NK and T cell cytotoxicity against metastatic colorectal cancer through tumor derived NKG2D ligands

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, contributing to one million deaths yearly. While survival is expected in early-stage disease, the 5-year survival rate is only 15% in metastatic CRC (mCRC). Frequently patients develop resistance to their chemotherapy regimens resulting in CRC metastatic lesions to appear in the lungs, liver, and brain. In recent years, the development of immunotherapy has become a promising avenue for the treatment of cold-tumor environments such as CRC. Indeed, dense infiltration of lymphocytes in CRC correlates with longer patient survival. Thus, patients suffering from mCRC would benefit from the combination of classical chemotherapy/radiotherapy with small immunomodulatory molecules capable of overcoming cancer cell resistance to therapy through chemo- and radio-sensitization. Recently, Antabuse’s metabolite dithiocarb-copper complex (CuET) was found to have anti-cancer activity. Here, we report for the first time on the immunomodulatory properties of CuET in the context of T/NK cell antitumor response in mCRC. Methods: To assess CuET anticancer activity in vitro, we performed survival curve, colony-formation, and migration-invasion assays in the murine colorectal cancer cell lines MC-38 and CT-26, and in the human KRAS mutant HCT116 cell line. We assessed in vivo efficacy of CuET in ectopic and metastatic MC-38 and CT-26 models in respective C57BL/6 and BALB/c mice. We characterized tumor growth, mice survival, and tumor immunohistochemistry. We evaluated CuET’s immunomodulatory properties through immunophenotyping of mouse and human T/NK cell receptors as well as corresponding tumor cell ligands after CuET treatment. We assessed CuET’s effect on the functional anticancer cytotoxicity of human PBMC-derived T/NK cells. Results: In vitro, CuET significantly inhibits viability, clonogenicity, and migration of tumor cells MC-38, CT-26, and HCT116 with IC50 values in the nanomolar range. In vivo, systemic treatment with CuET significantly reduces tumor growth in mice and prolongs survival (p=0.0041) when compared to controls. CuET significantly inhibits MC-38 liver metastasis growth in C57BL/6 mice. CuET recruits macrophages and T lymphocytes inside tumor cores and induces apoptosis. CuET induces the expression of NKG2D activating receptors in NK and T lymphocytes, as well as the expression of the corresponding ligands MICA/B and ULBP1/2 on tumor cells, enhancing the T/NK cell cytotoxic response anticancer. Conclusion: CuET enhances the functional antitumor cytotoxic activity of NK and T lymphocytes in mice and in human PBMC. In summary, our findings demonstrate that Antabuse-derived copper-diethyldithiocarbamate, CuET, is a potent immunomodulator which could benefit patients with mCRC. Citation Format: Daciana Catalina Dumut, Ivo Frydrych, Miroslav Popper, Dusan Garic, Radu Alexandru Paun, Amanda Centorame, Olivia Canavan, Juhi Shah, Martin Mistrik, Petr Dzubak, Jiri Bartek, Marian Hajduch, Juan Bautista DeSanctis, Danuta Radzioch. Disulfiram metabolite modulates NK and T cell cytotoxicity against metastatic colorectal cancer through tumor derived NKG2D ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2329.

Nanodrug removes physical barrier to promote T-cell infiltration for enhanced cancer immunotherapy.

The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co-delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ-released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors.

Copper Single-Atom Jellyfish-like Nanomotors for Enhanced Tumor Penetration and Nanocatalytic Therapy

Single-atom catalysts with extraordinary catalytic activity have been receiving great attention in tumor therapy. However, most single-atom catalysts lack self-propulsion properties, restricting them from actively approaching cancer cells or penetrating the interior of tumors. Herein, we design N-doped jellyfish-like mesoporous carbon nanomotors coordinated with single-atom copper (Cu-JMCNs). It is a combination of single-atom nanocatalytic medicine and nanomotor self-propulsion for cancer therapy. The Cu single atom can catalyze H2O2 into toxic hydroxyl radical (•OH) for chemodynamic therapy (CDT). Near-infrared light triggers Cu-JMCNs to achieve self-thermophoretic motion because of the jellyfish-like asymmetric structure and photothermal property of carbon, which significantly improves the cellular uptake and the penetration of three-dimensional tumors. In vivo experiments indicate that the combination of single-atom Cu for CDT and near-infrared light propulsion can achieve over 85% tumor inhibition rate. This work sheds light on the development of advanced nanomotors with single-atom catalysts for biomedical applications.

Effect of porous heat transfer model on different equivalent thermal dose methods considering an experiment-based nanoparticle distribution during magnetic hyperthermia

Magnetic fluid hyperthermia damages malignant cells by keeping the therapeutic temperature within a specific range after magnetic nanoparticles (MNPs) are exposed to an alternating magnetic field. The temperature distribution inside bio-tissue is usually predicted by a classic Pennes bio-heat transfer equation, which considers a heat source due to a homogeneous distribution for MNPs. Aiming at this problem, this study compares the Pennes model to a porous heat transfer model, named local thermal non-equilibrium equation, by considering an experiment-based MNPs distribution, and evaluates the thermal damage degree for malignant tissue by two different thermal dose methods. In addition, this study evaluates the effect of porosity and different blood perfusion rates on both effective treatment temperature and equivalent thermal dose. Simulation results demonstrate that different bio-heat transfer models can result in significant differences in both the treatment temperature profile and the thermal damage degree for tumor region under the same power dissipation of MNPs. Furthermore, scenarios considering a temperature-dependent blood perfusion rate or a lower porosity can have a positive effect on the temperature distribution inside tumor, while having a lower value in the maximum equivalent thermal dose in both thermal dose evaluation methods.

Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7

Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.

Polyethylenimine-CO2 adduct templated CaCO3 nanoparticles as anticancer drug carrier

BackgroundDue to their porous structure and capability to degrade under acidic conditions, CaCO3 nanoparticles in vaterite form can be used as carriers to effectively deliver drugs to low-pH sites such as tumors. The usually used intravenous administration requires long-term vaterite phase and colloidal stability for storage and blood circulation. While passive accumulation in tumors can be achieved via the enhanced permeation and retention effect, active accumulation requires reactive groups on vaterite nanoparticles to conjugate targeting molecules. Both requirements are hard to achieve in one simple and economical vaterite formulation. Herein, we used polyethylenimine (PEI)-based CO2 adduct as both a CO2 source and a template for vaterite mineralization to generate PEI-CO2@CaCO3 colloidal particles, with reactive amino groups from the PEI template.ResultsThe obtained nanoparticles with a hydrodynamic diameter of 200–300 nm have a vaterite phase and colloidal stability in an aqueous solution for over 8 months. These nanoparticles could effectively load anticancer drug doxorubicin via coprecipitation and be surface-modified with polyethylene glycol (PEG) and folic acid for long-term blood circulation and tumor targeting purposes, respectively. After being endocytosed, the PEI-CO2 adduct accelerates the dissolution of drug-loaded nanoparticles to generate CO2 bubbles to break the lysosomes, leading to rapid doxorubicin delivery inside tumor cells. The degradation of PEI-CO2 in the CaCO3 nanoparticles could also release PEI and CO2 and may contribute to the disruption of normal cellular functions. As a result, the drug-loaded PEI-CO2@CaCO3 nanoparticles strongly suppressed tumor growth in mice with HeLa tumor xenografts.ConclusionsA new and effective vaterite drug carrier for anticancer therapy has been developed using PEI-CO2 adduct as both a CO2 source and vaterite template for CaCO3 mineralization. This delivery system illustrates an application of CO2 generation materials in drug delivery and has the potential for further development.

Prognostic Value and Immunological Role of the Interleukin 24 Gene in Pan-Cancer Using the Kaplan-Meier Plotter and GEPIA by Genomic Data Commons and R Programming Software

There exists an exclusive cytokine and tumor suppressor gene, which is called Interleukin 24 (IL-24), in interleukin 10 (IL-10) family with antitumor and immune-activating properties. However, pan-cancer analysis of IL-24 for identifying survival prognosis and tumor immune infiltration level remains lacking. This study utilized multiple online data analysis approaches, including TIMER, Oncomine, GEPIA and the Kaplan-Meier Plotter, for analyzing the differences in expression level, survival and tumor immune infiltration of IL-24 from a pan-cancer perspective. The expression dissection expounded IL-24 was under conveyed inside brain and prostate cancers, etc., but overexpressed in breast, colorectal and gastric cancers, etc. Also, the survival analysis indicated that IL-24 expression was positively linked to subsisting inside breast carcinoma, sarcoma, and lung adenocarcinoma, and negatively correlated with stomach adenocarcinoma, kidney renal papillary cell carcinoma, and uveal melanoma. Then, we selected breast cancer and stomach adenocarcinoma as representative cancers for further study and investigation.We found that IL-24 is obviously associated with the immune cellular infiltration inside breast tumor and stomach adenocarcinoma, where IL-24 is significantly linked to the CD4+ T cell and CD8+ T cell infiltration inside breast cancer. As to the subtypes of breast cancer, IL-24 is evidently linked to CD8+ T cells, B cells and CD4+ T cells in BRCA-basal and BRCA-luminal subtypes. Furthermore, we discovered that IL-24 expression is negatively associated with the tumor mutation burden (TMB) and that there is a higher survival rate with IL-24 overexpression in breast cancer patients with a low TMB. This finding suggests that IL-24 can be a substantial biomarker to predict prognostic value and evaluation of infiltrated immune constituents in several cancers.

Abstract B049: Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior

Abstract Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. However, how the necrotic core promotes tumor cell dissemination and metastasis remains unclear. Foundational models for cancer metastasis research include mouse, zebrafish, and chick embryo, but identifying tumor cells in transit is painstaking. Here we used a rat model of breast cancer metastasis to increase detection of dissemination events. Owing to the large size and higher blood volume of rats, we collected 10 times more circulating tumor cells (CTCs) than from mice. In the rat model, tumor dissemination was temporally correlated with the emergence of necrosis in the tumor interior. These findings were corroborated by longitudinal study of CTC abundance and tissue necrosis markers in blood plasma from patients with metastatic breast cancer. Further, we observed that dilated blood vessels were located next to necrotic regions of the tumor and that their increase was concurrent with the initiation of intratumoral necrosis and increase in CTC abundance. Bulk RNA sequencing of mouse-to-rat xenograft tumor necrotic core compared to the non-necrotic rim revealed distinct tumor-specific and host-specific transcripts in the necrotic interior. We identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the peri-necrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, peri-necrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promoted vascular permeability and supported vascular remodeling in the peri-necrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core. Tumor dissemination events are localized spatially to dilated peri-necrotic vessels in the tumor interior, and tumor dissemination is dependent functionally on the expression of a factor, Angptl7, produced by peri-necrotic tumor cells. Our findings in breast cancer models, in conjunction with recent clinical observations, provide strong evidence for tumor dissemination from the tumor interior. Citation Format: Ami Yamamoto, Yin Huang, Brad A. Krajina, Margaux McBirney, Andrea E. Doak, Carolyn L. Wang, Michael C. Haffner, Kevin J. Cheung. Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B049.

Synergistic Functional Nanomedicine Enhances Ferroptosis Therapy for Breast Tumors by a Blocking Defensive Redox System

The upregulation of dihydroorotate dehydrogenase (DHODH) redox systems inside tumor cells provides a powerful shelter against lipid peroxidation (LPO), impeding ferroptosis-induced antitumor responses. To solve this issue, we report a strategy to block redox systems and enhance ferroptotic cancer cell death based on a layered double hydroxide (LDH) nanoplatform (siR/IONs@LDH) co-loaded with ferroptosis agent iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR). siR/IONs@LDH is able to simultaneously release IONs and siR in a pH-responsive manner, efficiently generate toxic reactive oxygen species (ROS) via an Fe2+-mediated Fenton reaction, and synergistically induce cancer cell death upon the acceleration of LPO accumulation. In vivo therapeutic evaluations demonstrate that this nanomedicine has excellent performance for tumor growth inhibition without any detectable side effects. This work thus provides a new insight into nanomaterial-mediated tumor ferroptosis therapy.

Chemical-NIR dual-powered CuS/Pt nanomotors for tumor hypoxia modulation, deep tumor penetration and augmented synergistic phototherapy

The complex tumor microenvironment (TME) with the characteristics of severe hypoxia, enriched hydrogen peroxide (H2O2) and dense nature significantly restricted the therapeutic efficacy of nanomedicine in cancer treatment. Synthetic micro/nanomotors have shown multiple versatility in modulating the abnormal TME and overcoming the limited penetration in solid tumor. Herein, we constructed a chemical-NIR dual-propelled nanomotor based on CuS/Pt Janus nanoparticles with IR820 encapsulation for hypoxia alleviation, deep tumor penetration and augmented synergistic photodynamic (PDT) and photothermal therapy (PTT). The deposited Pt effectively catalyzed tumor endogenous H2O2 into oxygen, which extremely relieved the tumor hypoxia state and allowed the chemical propulsion of nanomotors. Under NIR irradiation, the Janus nanomotors exhibited more obvious movement via efficient photothermal conversion. Such autonomous motion significantly improved the tumoral accumulation of nanomotors and facilitated much deeper penetration inside tumor in vivo. In addition, enriched oxygen also promoted the generation of reactive oxygen species (ROS) for augment of PDT, which achieved satisfied antitumor effect in combination with the PTT treatment. Therefore, this strategy based on CuS/Pt Janus nanomotors would provide an innovative dimension for considerable applications in effective cancer management.

Hypoxia-Triggered Bioreduction of Poly(N-oxide)-Drug Conjugates Enhances Tumor Penetration and Antitumor Efficacy.

PEGylation prolongs the blood circulation time of drugs; however, it simultaneously reduces the tumor penetration of drugs due to the nonfouling function and bulky hydrodynamic volume of PEG, leading to unsatisfactory outcomes in the treatment of solid tumors. Herein, we report the in situ growth of a bioreducible polymer of poly(N-oxide) from an important protein drug of interferon alpha (IFN) to generate site-specific IFN-poly(N-oxide) conjugates with higher bioactivity than a clinically used PEGylated IFN of PEGASYS. An IFN-poly(N-oxide) conjugate is screened out to have a circulating half-life as long as 51 h, which is similar to that of PEGASYS but 96-fold greater than that of IFN. However, the conjugate greatly outperforms PEGASYS and IFN in tumor penetration and antitumor efficacy in mice bearing melanoma. This enhanced tumor penetration is ascribed to the adsorption-mediated transcytosis of the conjugate whose poly(N-oxide) is biologically reduced into poly(tertiary amine), under hypoxia, which can be further protonated in the acidic tumor microenvironment. These novel findings demonstrate that poly(N-oxide)s are not only long-circulating but also bioreducible under hypoxia and are of great promise as next-generation carriers to deliver drugs into the interior of solid tumors to enhance their antitumor efficacy.

Adaptive PID Control Approach Considering Simulated Annealing Algorithm for Thermal Damage of Brain Tumor During Magnetic Hyperthermia

Magnetic nanofluid hyperthermia (MNH) damages malignant cells by the heat generated by magnetic nanoparticles (MNPs) exposed to an alternating magnetic field during therapy. The key point for magnetic hyperthermia is to maintain the treatment temperature to a safe range for bio-tissue, in which malignant tissue will be damaged due to its higher heat sensitivity but not the healthy tissue. However, the therapeutic system for MNH should be a non-linear one since the treatment temperature is generally determined by many certain and uncertain factors, which result in the difficulty to modulate the temperature to a specific range in a practical application. This study proposes a control method for a MNH system by introducing a proportional-integral-derivative control (PID) algorithm, and dynamically optimizes the PID coefficients for the proposed system by considering simulated annealing algorithm during therapy. The treatment temperature distribution for bio-tissue is obtained by solving an improved Pennes bio-heat transfer equation using finite element method. The simulation results demonstrate that the proposed control system can effectively modulate the power dissipation for MNPs and further exactly regulate the transient treatment temperature to an expected value. In addition, this proposed system can also automatically adapt to different cases during therapy, in which the nanofluid concentration distribution inside tumor region changes with nanofluid injection strategy.