Tumor Site Research Articles

Advances in nano-preparations for improving tetrandrine solubility and bioavailability.

Tetrandrine (TET) is a natural bis-benzylisoquinoline alkaloid isolated from Stephania species with a wide range of biological and pharmacologic activities; it mainly serves as an anti-inflammatory agent or antitumor adjuvant in clinical applications. However, limitations such as prominent hydrophobicity, severe off-target toxicity, and low absorption result in suboptimal therapeutic outcomes preventing its widespread adoption. Nanoparticles have proven to be efficient devices for targeted drug delivery since drug-carrying nanoparticles can be passively transported to the tumor site by the enhanced permeability and retention (EPR) effects, thus securing a niche in cancer therapies. Great progress has been made in nanocarrier construction for TET delivery due to their outstanding advantages such as increased water-solubility, improved biodistribution and blood circulation, reduced off-target irritation, and combinational therapy. Herein, we systematically reviewed the latest advancements in TET-loaded nanoparticles and their respective features with the expectation ofprovidingperspective and guidelines for future research and potential applications of TET.

RADT-04. ASSESSMENT OF CLINICAL AND NEUROLOGICAL ALTERATIONS BEFORE RADIATION THERAPY IN CHILDREN WITH MALIGNANT BRAIN TUMORS

Abstract BACKGROUND Young patients with malignant brain tumors show neurocognitive alterations as both consequences of the tumor and of treatments received. A prospective study of longitudinal radiation damages after focal RT was activated in 2017. We present the first analysis correlating tumor localization, symptoms, neurological/endocrinological impairments, surgery/ies if adopted, and cognitive assessments at the time of enrollment. METHODS Sixty-six children eligible for focal RT were enrolled and underwent a neurocognitive assessment based on standardized tests (“impaired”/“non-impaired”). The database included demographical, clinical and pathological variables. The latter, together with MRI morphological scans, were used to define different kind of damage scores. The pattern of associations between clinical variables and damage scores was investigated. RESULTS Patients median age was 8 years; the most frequent tumor was Ependymoma (41%) and Posterior Fossa (29%) was the prevalent tumor site. All but 5 children (with Germ Cell Tumors), had undergone surgery and 32 had undergone chemotherapy before irradiation and evaluations. Ad-hoc scores of neurological deficits and endocrine alterations were created to characterize each patient. Moreover, structural abnormalities were quantified in a score for each cortical/subcortical region. Patients with posterior fossa Ependymomas and infratentorial tumors showed higher neurological damage scores. Endocrine alterations were more serious in supratentorial tumors, specifically in patients with Craniopharyngioma and Germ Cell tumors of the sellar region and ventricular system. Deficit scores were not associated to the presence of hydrocephalus and surgery, unlike endocrine alteration scores. The median number of child’s structural damaged areas was equal to 2 (IQR: 2-3). Tumor sites of patients with an impaired or non-impaired full-scale IQ or visual-perception index, was found to be different. CONCLUSIONS The analysis of baseline evaluations highlights damages preexisting to irradiations and generated by multiple factors. In light of these findings, damages over time could be better investigated by distinguishing multiple generating factors.

IMG-24. MAPK-ALTERED PEDIATRIC LOW-GRADE GLIOMA: MRI HINTS TO EXPLAIN THE INTERPLAY BETWEEN GLIOMA AND IMMUNE CELLS

Abstract BACKGROUND In MAPK-altered pediatric low-grade glioma (pLGG), immune infiltration may be involved in treatment response. It is debated whether tumor immune cell infiltration is due to expansion of endogenous resident microglia or to the active recruitment of bone marrow-derived microglial progenitors from the bloodstream. This study aimed to investigate the relation between neuroradiological features of MAPK-altered pLGG and treatment response to MAPK-inhibitors (MAPKi). METHODS We conducted a retrospective analysis of all patients with unresectable BRAF-V600E mutated brain pLGG, radiotherapy naïve, treated with MAPKi at our institution since 2015. MRI studies were reviewed by two experienced neuroradiologist and tumor response assessed according to RAPNO criteria. RESULTS 12 patients were enrolled (9 female). Median age at treatment start was 6.2 years (range 2.7–14.3 years). Four were pilocytic astrocytomas, 6 gangliogliomas, and 2 desmoplastic infantile gangliogliomas. Five patients received MAPKi as first line, 7 following other chemotherapy lines. Median follow-up was 4.1 years (range 2.5–8.7 years). Tumor response was associated with contrast enhancement (CE): 9 out of 10 patients with CE at treatment onset had at least partial response and subsequent CE resolution, while both 2 out of 2 patients without CE showed stable disease. A 4-year old contrast enhancing-ganglioglioma who reached partial response and CE resolution with MAPKi, presented disease progression four days after treatment withdrawal; treatment re-start determined tumor and CE reduction after only 7 days. CONCLUSIONS We hypothesize that brain-blood barrier breakage is induced by tumor infiltration of bloodstream immune cells, and that this trafficking is stimulated by tumor cell secreted products and determined by microglial progenitors shift from the bloodstream to the tumor site. MAPKi treatment may incite blood-brain barrier reconstitution as it reduces the trafficking between tumor site and bloodstream. ACKNOWLEDGEMENT This work was supported by grant number NET-2018-12366666 NeuroArtP3 from the Italian Ministry of Health.

A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

Clinicopathological Characteristics and the First Mutational Analysis of Gastrointestinal Stromal Tumors From Mexico: A Single Institution Experience.

Background Gastrointestinal stromal tumors (GISTs) arise from Cajal's interstitial cell precursors and display a variety of genetic mutations, primarily in the KIT and PDGFRA genes. These mutations are linked to tumor location, prognosis, and response to treatment. This study delves into the mutational patterns of GISTs in a Mexican population and their impact on overall survival (OS) and disease-free survival (DFS). Methodology This retrospective study examined 42 GIST cases diagnosed at the Oncology Hospital of the National Medical Center XXI Century between January 2018 and December 2020. Clinical, histological, and immunohistochemical data were gathered, and mutational analysis of KIT and PDGFRA genes was conducted using second-generation sequencing. Results The study group consisted of 52.4% females and 47.6% males, with an average age of 62.6 years. The most common tumor site was the stomach (59.5%), followed by the small intestine (26.2%). KIT mutations were detected in 71.4% of cases, predominantly involving exon 11. PDGFRA mutations were observed in 7.1% of cases. Recurrence was noted in 9.5% of patients, all with high-risk tumors. No significant link was identified between specific mutations and OS or DFS. Conclusions This investigation sheds light on the genetic landscape of GISTs in the Mexican population. While no significant association was established between particular mutations and survival outcomes, the study emphasizes the importance of molecular profiling in treatment decision-making. Further studies with larger sample sizes and longer follow-up periods are necessary to validate these results and explore their clinical relevance.

DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG), including Diffuse intrinsic pontine glioma (DIPG), is an aggressive brain tumor in children with limited treatment options. Recent developments of phase 1 clinical trials have shown early promise for chimeric antigen receptor (CAR) T cells in patients with DMG/DIPG. However, several barriers such as the absence of tumor-specific antigens, restricted trafficking to the tumor site, and poor persistence hinder the full therapeutic potential of CAR T cell therapy in DMG/DIPG. METHODS To safely target the glioma-associated antigens (GAAs) without attacking nomal tissues expressing the same antigens, we adopted a novel synthetic Notch (synNotch) receptor system and engineered T cell circuits employing a “prime-and-kill” strategy. In this system, a synNotch receptor recognizing the priming antigen, Brevican (BCAN), exclusively expressed on cells in the central nervous system (CNS) but not on non-CNS cells, locally induces the expression of a tandem CAR against GAAs, ephrin type A receptor (EphA2) and interleukin-13 receptor a2 (IL13Ra2), there by homogenously eliminating DMG/DIPG cells. RESULTS The α-BCAN synNotch⋄α-EphA2/IL-13Rα2 CAR (B-SYNC) T cells efficiently killed DMG/DIPG (BT-245, SF8628, SU-DIPGXIII, and SU-DIPGXVII) cells in vitro in the presence of priming cells (K562 cells expressing BCAN). Moreover, a single intravenous infusion of B-SYNC T cells significantly (P< 0.001) prolonged the survival of immunodeficient mice bearing aggressive, orthotopic SF8628 DIPG xenografts and completely eradicated the tumor in more than 50% (4/7) of mice. Strikingly, we observed excellent homing, priming, activation, and persistence of B-SYNC T cells in the brain stem of mice bearing SF8628 xenografts. In contrast, constitutively active α-EphA2/IL-13Rα2 CAR T cells or untransduced T cells demonstrated a failure to migrate to the brain stem and improve the survival of mice. CONCLUSIONS Collectively, our findings strongly support the development of clinical trials evaluating the efficacy of B-SYNC T cells in DMG/DIPG patients.

Zinc-Based ROS Amplifiers Trigger Cancer Chemodynamic/Ion Interference Therapy Through Self-Cascade Catalysis.

Nanozyme-mediated chemodynamic therapy has emerged as a promising strategy due to its tumor specificity and controlled catalytic activity. However, the poor efficacy caused by low hydrogen peroxide (H2O2) levels in the tumor microenvironment (TME) poses challenges. Herein, an H2O2 self-supplying nanozyme is constructed through loading peroxide-like active platinum nanoparticles (Pt NPs) on zinc peroxide (ZnO2) (denoted as ZnO2@Pt). ZnO2 releases H2O2 in response to the acidic TME. Pt NPs catalyze the hydroxyl radical generation from H2O2 while reducing the mitigation of oxidative stress by glutathione, serving as a reactive oxygen (ROS) amplifier through self-cascade catalysis. In addition, Zn2+ released from ZnO2 interferes with tumor cell energy supply and metabolism, enabling ion interference therapy to synergize with chemodynamic therapy. In vitro studies demonstrate that ZnO2@Pt induces cellular oxidative stress injury through enhanced ROS generation and Zn2+ release, downregulating ATP and NAD+ levels. In vivo assessment of anticancer effects showed that ZnO2@Pt could generate ROS at tumor sites to induce apoptosis and downregulate energy supply pathways associated with glycolysis, resulting in an 89.7% reduction in tumor cell growth. This study presents a TME-responsive nanozyme capable of H2O2 self-supply and ion interference therapy, providing a paradigm for tumor-specific nanozyme design.

Multi-stimuli-responsive Hydrogels for Therapeutic Systems: An Overview on Emerging Materials, Devices, and Drugs.

The rising interest in hydrogels nowadays is due to their usefulness in physiological conditions as multi-stimuli-responsive hydrogels. To reply to the prearranged stimuli, including chemical triggers, light, magnetic field, electric field, ionic strength, temperature, pH, and glucose levels, dual/multi-stimuli-sensitive gels/hydrogels display controllable variations in mechanical characteristics and swelling. Recent attention has focused on injectable hydrogel-based drug delivery systems (DDS) because of its promise to offer regulated, controlled, and targeted medication release to the tumor site. These technologies have great potential to improve treatment outcomes and lessen side effects from prolonged chemotherapy exposure.

Advances in 2,3-Dimethylmaleic Anhydride (DMMA)-Modified Nanocarriers in Drug Delivery Systems.

Cancer represents a significant threat to human health. The cells and tissues within the microenvironment of solid tumors exhibit complex and abnormal properties in comparison to healthy tissues. The efficacy of nanomedicines is inhibited by the presence of substantial and complex physical barriers in the tumor tissue. The latest generation of intelligent drug delivery systems, particularly nanomedicines capable of charge reversal, have shown promise in addressing this issue. These systems can transform their charge from negative to positive upon reaching the tumor site, thereby enhancing tumor penetration via transcytosis and promoting cell internalization by interacting with the negatively charged cell membranes. The modification of nanocarriers with 2,3-dimethylmaleic anhydride (DMMA) and its derivatives, which are responsive to weak acid stimulation, represents a significant advance in the field of charge-reversal nanomedicines. This review provides a comprehensive examination of the recent insights into DMMA-modified nanocarriers in drug delivery systems, with a particular focus on their potential in targeted therapeutics. It also discusses the synthesis of DMMA derivatives and their role in charge reversal, shell detachment, size shift, and ligand reactivation mechanisms, offering the prospect of a tailored, next-generation therapeutic approach to overcome the diverse challenges associated with cancer therapy.

An antioxidative-enhanced endoplasmic reticulum-targeted cyanine dye for efficient tumor immunotherapy

Excessive generation of reactive oxygen species (ROS) triggers intense endoplasmic reticulum (ER) stress, emerging as a key mechanism for arousing autoimmune therapy. Therefore, the development of an ER-targeted ROS generator is crucial for advancing self-immunotherapy. However, despite a clear demand for ER-targeting ROS generators, the high-efficiency agents are still limited. In this study, the pentamethine cyanine dye (Cy5) is used as a parent structure to explore the efficient ER-targeted immune activator. Three variants (PCy5-H, PCy5-Cl, and PCy5-2Cl) were synthesized by introducing benzene, chlorobenzene, and dichlorobenzene structures at the meso-position of the Cy5 scaffold. The electron-withdrawing groups (EWGs) effectively reduce the electron density on the conjugate chain, facilitating the intersystem crossing (ISC) process and enhancing the antioxidant capability. Consequently, the antioxidant properties and ROS generation capacity of PCy5-2Cl were enhanced. Furthermore, encapsulating PCy5-2Cl into liposomes significantly improves its retention at the tumor site, inducing robust ER stress. Upon accumulation at the ER sites in tumor cells, PCy5-2Cl nanoparticles induced strong ER stress under near-infrared (NIR) light irradiation. Exposure to necrotic fragments reverses the immunosuppressive microenvironment within the tumor, ultimately promoting dendritic cell maturation and infiltration of cytotoxic T lymphocytes (CTLs). As a result, significant inhibition is observed in both primary and distant tumors, underscoring the efficacy of this EWGs modification strategy for enhancing tumor immunotherapy.

Syngeneic mesenchymal stem cells loaded with telomerase-dependent oncolytic adenoviruses enhance anti-metastatic efficacy.

Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable.

Autophagy‐Inducing MoO3‐x Nanowires Boost Photothermal‐Triggered Cancer Immunotherapy

AbstractAutophagy could play suppressing role in cancer therapy by facilitating release of tumor antigens from dying cells and inducing immunogenic cell death (ICD). Therefore, discovery and rational design of more effective inducers of cytotoxic autophagy is expected to develop new strategies for finding innovative drugs for precise and successful cancer treatment. Herein, we develop MoO3‐x nanowires (MoO3‐x NWs) with high oxygen vacancy and strong photothermal responsivity to ablate tumors through hyperthermia, thus promote the induction of cytotoxic autophagy and severe ICD. As expected, the combination of MoO3‐x NWs and photothermal therapy (PTT) effectively induces autophagy to promote the release of tumor antigens from the ablated cells, and induces the maturation and antigen presentation of dendritic cells (DCs), subsequently activates cytotoxic T lymphocytes (CTLs)‐mediated adaptive immunity. Furthermore, the combination treatment of MoO3‐x NWs with immune checkpoint blockade of PD‐1 could promote the tumor‐associated macrophages (TAMs) polarization into tumor‐killing M1 macrophages, inhibit infiltration of Treg cells at tumor sites, and alleviate immunosuppression in the tumor microenvironment, finally intensify the anti‐tumor activity in vivo. This study provides a strategy and preliminary elucidation of the mechanism of using MoO3‐x nanowires with high oxygen vacancy to induce autophagy and thus enhance photothermal immunotherapy.

Autophagy-Inducing MoO3-x Nanowires Boost Photothermal-Triggered Cancer Immunotherapy.

Autophagy could play suppressing role in cancer therapy by facilitating release of tumor antigens from dying cells and inducing immunogenic cell death (ICD). Therefore, discovery and rational design of more effective inducers of cytotoxic autophagy is expected to develop new strategies for finding innovative drugs for precise and successful cancer treatment. Herein, we develop MoO3-x nanowires (MoO3-x NWs) with high oxygen vacancy and strong photothermal responsivity to ablate tumors through hyperthermia, thus promote the induction of cytotoxic autophagy and severe ICD. As expected, the combination of MoO3-x NWs and photothermal therapy (PTT) effectively induces autophagy to promote the release of tumor antigens from the ablated cells, and induces the maturation and antigen presentation of dendritic cells (DCs), subsequently activates cytotoxic T lymphocytes (CTLs)-mediated adaptive immunity. Furthermore, the combination treatment of MoO3-x NWs with immune checkpoint blockade of PD-1 could promote the tumor-associated macrophages (TAMs) polarization into tumor-killing M1 macrophages, inhibit infiltration of Treg cells at tumor sites, and alleviate immunosuppression in the tumor microenvironment, finally intensify the anti-tumor activity in vivo. This study provides a strategy and preliminary elucidation of the mechanism of using MoO3-x nanowires with high oxygen vacancy to induce autophagy and thus enhance photothermal immunotherapy.

An Asymmetric NIR-II Organic Fluorophore with an Ultra-Large Stokes Shift for Imaging-Guided and Targeted Phototherapy.

NIR-II imaging-guided phototherapy is an attractive, yet challenging, tumor treatment strategy. By monitoring the accumulation of phototherapy reagents at the tumor site through imaging and determining the appropriate therapy window, the therapeutic effect could be significantly improved. Probes with NIR-II (1000-1700 nm) fluorescence emission and a large Stokes shift hold great promise for fluorescence imaging with deep penetration, minimized self-quenching, and high spatiotemporal resolution. However, due to the lack of a suitable molecular framework, the design of a simple small-molecule dye with a large Stokes shift and NIR-II fluorescence emission has rarely been reported. Herein, we prepare an asymmetric D-π-A type NIR-II fluorescence probe (TBy). The probe is incapsulated in an amphiphilic polymer and modified with a fibronectin targeting peptide CREKA, which could recognize the fibrin-fibronectin complex overexpressed in multiple malignant tumors. The nanoparticles thus constructed (TByC-NPs) have maximum fluorescence emission at 1037 nm with a large Stokes shift of 426 nm, which is the largest Stokes shift among organic NIR-II fluorescent dyes reported in the literature. The TByC-NPs exhibit a good NIR-II imaging performance, active tumor targeting, and good photothermal and photodynamic capabilities. In vitro and in vivo studies verify that the TByC nanoplatform shows outstanding biocompatibility for NIR-II imaging-guided phototherapy and provides an excellent antitumor effect.

Final results of BrUOG 354: A randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas.

LBA5500 Background: Extra-renal clear cell cancer (CCC) are rare tumors that can arise from any organ. Gynecologic CCC can originate from the ovaries, endometrium, or cervix. Compared to serous carcinomas, ovarian CCC is associated with poorer outcomes to standard chemotherapy, warranting a focused evaluation for innovative therapies. We completed a two-stage two-arm phase 2 trial evaluating immunotherapy for extra-renal CCC and present the final results of treatment using nivolumab (N) monotherapy and in combination with ipilimumab (I) in this population. Methods: This is a randomized two-stage phase II study evaluating single-agent N (240mg IV every two weeks) or in combination with I (1mg/kg every six weeks) (N/I) in people with relapsed extra-renal CCC after at least one prior therapy (no prior immunotherapy). Measurable disease was required. In the first stage, volunteers were randomly assigned to N or N/I with stratification by tumor site (ovarian vs extra-ovarian). Treatment was continued until disease progression or unacceptable toxicity. Each arm was evaluated for overall response rate (ORR) separately at stage 1 using RECIST and iRECIST criteria. In January 2022, the N arm was closed, and subsequent volunteers were treated with N/I. The study completed enrollment in April 2023. Results: Between July 2018 and April 2023, 46 volunteers provided consent for the study and 44 were treated (14 N, 30 N/I). The median age was 57 (range, 18-75) years. Across the study, 75% were White, 9.1% Black, 4.5% were Asian, and 11.4% were Hispanic. All volunteers had a gynecologic primary, 36 (82%) with ovarian CCC. The median number of prior lines was 1 (range, 1-7). The Overall Response Rate (ORR) is 14.3% (2 Partial Responses) with N and 33% (4 Complete and 6 Partial Responses) with N/I. Four people continue on treatment with N/I as of December 2023. With a median follow up of 11.3 (range, 1.6-46.4) months, the median Progression-Free Survival is 2.2 (95% CI 1.2-3.4) months with N and 5.6 (95% CI 1.6-29.1) months with N/I. The median Overall Survival is 17 (95% CI 2.1-NR) and 24.6 (95% CI 5.9-NR) months, respectively. Serious treatment-related adverse events were recorded in 3 (21%) treated with N (all grade 3) and 14 (47%) treated with N/I (two of whom had grade 4 pancreatic enzyme elevations). No new safety signals were noted, and no treatment-related deaths were observed in either arm. Conclusions: Immunotherapy demonstrated important, meaningful, and durable activity in people with previously treated gynecologic CCC including four (12%) volunteers who achieved a complete response with N/I. N/I warrant further evaluation against standard treatment for people with ovarian CCC, given the historically chemotherapy-resistant nature of the disease. Clinical trial information: NCT03355976 .

Dual approach: micellar delivery of chlorambucil prodrug with concurrent glutathione depletion and GST inhibition for enhanced anticancer activity

Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and GSH S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally, in vivo tumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.

A Computational Framework for the Administration of 5-Aminovulinic Acid Before Glioblastoma Surgery.

5-Aminolevulinic Acid (5-ALA) is the only fluorophore approved by the FDA as an intraoperative optical imaging agent for fluorescence-guided surgery in patients with glioblastoma. The dosing regimen is based on rodent tests where a maximum signal occurs around 6h after drug administration. Here, we construct a computational framework to simulate the transport of 5-ALA through the stomach, blood, and brain, and the subsequent conversion to the fluorescent agent protoporphyrin IX at the tumor site. The framework combines compartmental models with spatially-resolved partial differential equations, enabling one to address questions regarding quantity and timing of 5-ALA administration before surgery. Numerical tests in two spatial dimensions indicate that, for tumors exceeding the detection threshold, the time to peak fluorescent concentration is 2-7h, broadly consistent with the current surgical guidelines. Moreover, the framework enables one to examine the specific effects of tumor size and location on the required dose and timing of 5-ALA administration before glioblastoma surgery.

Lipo/TK-CDN/TPP/Y6 nanoparticles inhibit cutaneous melanoma formation

Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumour immunity. Nevertheless, the systemic delivery of STING agonists to the tumour presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal therapy (PTT)/photodynamic therapy (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumours were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumour growth. Exploration of the mechanism of anti-tumour action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumour immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumour sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumours.

From bimodal to unimodal: The transformed incidence of osteosarcoma in the United States

BackgroundOsteosarcoma is the most common primary bone malignancy. It has classically been described as having a bimodal incidence by age. We sought to identify whether the bimodal incidence distribution still exists for osteosarcoma using the SEER and NIS databases. MethodsIncidence rates of primary osteosarcoma between 2000–2021 were analyzed by age at diagnosis, year of occurrence, sex, and tumor site from the SEER Research Data, 17 Registries, Nov 2023 Sub (2000–2021). The incidence of cases in 35–64 year-olds and 65 and above was compared statistically to determine if there is an increased incidence in the later ages. Incidence of tumors of the long bones of the lower limbs from the NIS discharge database 2012–2019 was also analyzed for comparison. ResultsOverall, 5,129 cases of osteosarcoma were reported in the SEER database. Across the 22 calendar year span, a consistent first peak appeared in the second decade of life. There was no consistent second peak in the 35+ age group. There were 86,100 discharges with long bone tumors analyzed in the NIS data which exhibited nearly identical patterns. ConclusionsOur analysis shows that the incidence of osteosarcoma is no longer bimodally distributed but rather unimodally distributed.

Carrier-Free Self-Assembled Nanomedicines for Promoting Apoptosis and Inhibiting Proliferation in Hepatocellular Carcinoma.

In order to improve the effectiveness of tumor treatment and reduce the toxic side effects of drugs, we formed carrier-free multifunctional nanoparticles (BI NPs) by noncovalent interaction of berberine hydrochloride and IR780. BI NPs possessed the synergistic effects of promoting apoptosis, inhibiting proliferation and metastasis of tumors, and phototherapeutic treatment. Dispersive and passive targeting ability retention (EPR) effects of BI NPs on tumor sites in vivo could be monitored by fluorescence imaging. In addition, BI NPs exhibited effective reactive oxygen species (ROS) generation and photothermal conversion capabilities, photodynamic therapy (PDT), and photothermal therapy (PTT). Importantly, BI NPs inhibit tumor suppression through the AMPK/PI3K/AKT signaling pathway to inhibit tumor proliferation and metastasis. BI NPs not only have efficient in vivo multimodal therapeutic effects but also have good biosafety and potential clinical applications.