Deep Tumor Research Articles

Cyclometalated N-Difluoromethylbenzimidazolylidene Platinum(II) Complexes with Built-in Secondary Coordination Spheres: Photophysical Properties and Bioimaging.

Bidentate Pt(II) complexes with cyclometalated N-heteroarene or N-heterocyclic carbene (NHC) ligands have been extensively studied as phosphorescent emitters over the past two decades. Herein, we introduce a difluoromethyl group (CF2H) into the wingtip of NHCs, where CF2H acts as a lipophilic hydrogen bond (HB) donor. Their cyclometalated Pt(II) complexes show excellent PLQYs (up to 93%) and phosphorescence lifetimes mainly due to the rigid structure with hydrogen bonding between the CF2H group and the adjacent O atom at the β-diketonate ligand. Bioimaging studies demonstrate high cellular uptake efficiency and deep tumor penetration capability of complex 7 in HeLa cells and multicellular tumor spheroids, highlighting their potential as bioimaging probes.

Dual-responsive nanoparticles for enhanced drug delivery in breast Cancer chemotherapy.

Drug delivery efficiency often affects chemotherapy outcome due to dense collagen barrier in tumor environment. Here, we report a nanoparticle capable of pH and glutathione dual-responsive drug delivery to enhance the efficacy of breast cancer chemotherapy. Maleiminated polyethylene glycol and polylactide block copolymer were synthesized as a core material, doxorubicin was encapsulated into the nanoparticle by self-assembly. Thiocollagenase and maleimide were connected on the nanoparticle surface by click chemistry, and further coated with chondroitin sulfate as a protective layer to form dual-responsive doxorubicin nanoparticle. The results showed that the nanoparticle had the ability to penetrate deep tumor tissue, to target on CD44 of cancer cell, and to release doxorubicin in cancer cell in response to pH and glutathione signals, demonstrating superior anticancer efficacy in breast cancer-bearing mice. In conclusion, the dual-responsive nanoparticle could be used as a drug carrier to enhance drug delivery in breast cancer chemotherapy.

TMOD-22. MULTIREGION BIOPSIES AND CORRESPONDING NEUROSPHERE CULTURES REVEAL SPATIAL DIVERGENCE IN GLIOBLASTOMA EVOLUTION

Abstract Spatial organization of normal tissues is key for their function, yet the role of distribution of distinct clones of cancer cells in tumor is not usually studied as a potential vulnerability in cancer. This is of particular interest in glioblastoma (GBM), in which extensive intratumor heterogeneity hampers effectiveness of treatment. To better understand tumor evolution and the complexity of cancer ecosystem in GBM, we performed profiling of biopsies collected from MRI-defined regions of the tumors, spanning the surface, tumor core and deep tumor margins, which drive local recurrence after surgery. To test how spatially distinct biopsies differ in their cancer cell composition and to assess the tumor microenvironment heterogeneity, we took advantage of 5-ALA metabolite fluorescence, which accumulates in GBM cells and allows the surgeon to visualize cancer under blue light. We used it to separate cancer cells (predominantly 5-ALAhigh) from tumor microenvironment (5-ALAlow) and subjected the fractions to bulk and single cell transcriptomics, respectively. We found a gradient of cellular states associated with location in the tumor, with the deep margin samples having more 5-ALAlow cancer cells and generally less defined phenotype. We have also developed neurosphere cultures from our collection of spatially distant biopsies. Despite the selection pressure of the in vitro culture conditions, cells from different regions of the tumor adopted different morphologies, suggesting retention of some of their differential features. The differences between cultures were reflected in metabolism, proliferation, and differential sensitivity to a drug panel. Whole exome sequencing and transcriptomic analysis were also performed to identify the selection bottleneck of culture conditions, establish evolutionary trajectory of the distinct regions and neurosphere cultures, and test how strongly our cultures represent both the 5-ALAhigh and 5-ALAlow subpopulations of GBM cells. Our study identified properties associated with different spatial locations within GBM tumors, which will help uncover the cellular and microenvironmental dependencies that could lead to novel therapeutic targets for this highly heterogeneous tumor.

CTNI-17. A PHASE 2 STUDY OF SAFETY AND EFFICACY OF CONCURRENT ACT001 AND RADIATION TREATMENT FOLLOWED BY ACT001 MAINTENANCE THERAPY IN NEWLY DIAGNOSED PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting NF-κB and STAT3 pathways, has shown activity in preclinical DIPG model and dose-finding study in patients with diffuse midline glioma. We further evaluated safety and activity of ACT001 in newly diagnosed DIPG patients and presented the interim data from exploratory stage of this phase 2 study. METHODS Eligible patients ≥ 5 and ≤ 15 years old were treated with concurrent ACT001 and standard radiation followed by ACT001 single agent treatment in this single arm, open label, multicenter phase 2 study. Tumor lesions were evaluated at baseline, 4 weeks and then every 8 weeks after the end of radiation therapy per RAPNO criteria with ORR as primary endpoint. Interim data analysis was performed when data from approximately 20 efficacy evaluable patients became available during the exploratory stage of this study. RESULTS Among 30 patients enrolled since Sept, 2023, 27 took at least one dose of ACT001 by April 30th, 2024, the data cutoff date (with exception for May 15th as the MRI cutoff date). While 3 patients were quickly taken off study due to a disease progression or consent withdrawal, 17 out of 27 patients finished at least one post-radiation MRI exam whereas MRI results are pending for 7 other patients by this interim analysis. Median age was 8 years old and male to female patient ratio is 17:10. The median LPS score is 70.0. Among 17 efficacy evaluable subjects, 8 patients exhibited partial response (6 confirmed) including one with a deep tumor reduction (-91.7%) noted three months after end of radiation. Among 9 other evaluable patients, 5 and 4 exhibited ongoing stable disease and progressive disease respectively. Subject 05001 was considered PD despite confirmed objective response for the target lesion upon development of new lesions. Two patients withdrew consent after finishing first post-radiation MRI scans despite initial tumor burden reduction which were both close to PR criteria. Patients tolerated concurrent ACT001 and radiation well. In total, 289 TEAE and 184 TRAE events were reported in 23 and 22 patients respectively. There were two ACT001-related grade 3 or 4 adverse events including one grade 4 hemorrhagic tumor necrosis (a SUSAR event and the only ACT001 related SAE) likely due to a therapeutic effect of ACT001 and one clinically insignificant grade 3 decreased lymphocyte count. Most common TRAE were manageable grade 1 or 2 events such as weight loss (15/184), vomiting (71/184), decreased lymphocyte count (13/184) and abdominal bloating (7/184). No study discontinuation occurred due to ACT001 or radiation related TRAEs. Conclusion. Concurrent ACT001 and radiation treatment was well tolerated. Preliminary evidence of anti-tumor activity was shown in about 50% efficacy evaluable DIPG patients. It is worthwhile to explore ACT001 and temozolomide combination in future study based on safety and efficacy signal from DIPG and recurrent GBM studies. The confirmatory stage of this study is in planning to further evaluate the anti-tumor efficacy signal of this NF-κB and STAT3 dual inhibitor.

Biomimetic Dual‐Driven Heterojunction Nanomotors for Targeted Catalytic Immunotherapy of Glioblastoma

AbstractThe existence of the blood–brain barrier (BBB) and the characteristics of the immunosuppressive microenvironment in glioblastoma (GBM) present significant challenges for targeted GBM therapy. To address this, a biomimetic hybrid cell membrane‐modified dual‐driven heterojunction nanomotor (HM@MnO2‐AuNR‐SiO2) is proposed for targeted GBM treatment. These nanomotors are designed to bypass the BBB and target glioma regions by mimicking the surface characteristics of GBM and macrophage membranes. More importantly, the MnO2‐AuNR‐SiO2 heterojunction structure enables dual‐driven propulsion through near‐infrared‐II (NIR‐II) light and oxygen bubbles, allowing effective treatment at deep tumor sites. Meanwhile, the plasmonic AuNR‐MnO2 heterostructure facilitates the separation of electron–hole pairs and generates reactive oxygen species (ROS), inducing immunogenic tumor cell death under NIR‐II laser irradiation. Furthermore, MnO2 in the tumor microenvironment reacts to release Mn2+ ions, activating the cGAS‐STING pathway and enhancing antitumor immunity. In vitro and in vivo experiments demonstrate that these dual‐driven biomimetic nanomotors achieve active targeting and deep tumor infiltration, promoting M1 macrophage polarization, dendritic cell maturation, and effector T‐cell activation, thereby enhancing GBM catalysis and immunotherapy through ROS production and STING pathway activation.

The short-term outcomes of laparoscopic enucleation of pancreatic tumors with exposing the Wirsung duct.

It is widely believed that the prerequisite for safely performing enucleation is that the distance between the tumor and the main pancreatic duct (MPD) is at least 2-3mm. However, enucleating a deep pancreatic tumor adjacent to the MPD remains challenging, particularly when exposure or repair of the MPD is necessary. This study reported our initial experience with this procedure and demonstrated the feasibility and safety of the MPD exposure or repair. Patients who underwent laparoscopic enucleation (LapEN) with exposing the MPD from January 2017 to August 2023 were collected and analyzed in this retrospective cohort study. Data from procedures of laparoscopic middle pancreatectomy (LMP) and LapEN for superficial tumors were collected for comparative analyses. A total of 26 patients were enrolled, 27 tumors were enucleated. Tumor located in the pancreatic head and neck (n = 20), and the body (n = 7). The mean tumor size, operating time, and blood loss were 2.3cm, 163min, and 63ml, respectively. MPD injuries occurred in 8 cases due to the need for complete tumor resection, which were repaired or reconstructed using 6-0 PDS-II with or not inserting a plastic stent. 10 cases (38.5%) developed surgical-related complications, seven (26.9%) were classified as Clavien-Dindo grade I, and three (11.5%) were Clavien-Dindo grade IIIa. Biochemical leakage occurred in 16 cases (61.5%), clinically relevant pancreatic fistula (CR-POPF) occurred in 10 cases (38.5%). Two patients (7.7%) experiencedpost-pancreatectomy hemorrhage. Further analyses indicated LapEN with MPD exposure had a longer operating time and higher incidence of CR-POPF compared to LapEN for superficial tumors, but a shorter operating time and less blood loss compared to LMP (P < 0.05). Laparoscopic enucleation with exposing the MPD is feasible and safe with the support of precise preoperative assessments, meticulous intraoperative dissection, well familiarity with the anatomy of the MPD, and excellent surgical skills.

Intratumoral lactic acid neutralization strategy for boosting chemoimmunotherapy using liposomal sodium bicarbonate

Glycolysis-related lactic acid overproduction creates an “ion-trapping” barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy. Therefore, normalization of tumor microenvironment via lactic acid neutralization can be a promising avenue for overcoming this therapeutic hurdle. In this study, the flexible liposomes loaded with sodium bicarbonate (NaHCO3@Flip) were used as a nano-adjuvant to boost chemoimmunotherapy. Their effects on assisting DOXIL and anti-PD-1 therapy were investigated. NaHCO3@Flip achieved deep tumor penetration, with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment. NaHCO3@Flip is biosafe and can enhance cellular uptake efficiency of doxorubicin (DOX) by overcoming the ion-trapping barrier and amplify immunogenic cell death induced by DOX. The combination therapy of liposomal DOX and NaHCO3@Flip demonstrated enhanced inhibition of tumor growth. NaHCO3@Flip can also synergize with PD-1 antibody therapy. NaHCO3@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.

An ultrasound-activated piezoelectric sonosensitizer enhances mitochondrial depolarization for effective treatment of orthotopic glioma

Despite the significant advancements in piezoelectric materials for sonodynamic therapy (SDT), the suppression of orthotopic glioma remains challenging, primarily due to the unclear mechanism and the restriction of blood-brain barrier (BBB). Herein, we proposed that layered piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) could effectively depolarize the mitochondrial membrane potential (ΔΨm) of glioma cells under ultrasound (US) exposure. The US-induced band bending in SBTO NPs enhanced redox ability, promoting an increase in reactive oxygen species (ROS) generation. The in vitro results proved that SBTO NPs selectively accumulated in mitochondria under US and induced apoptosis in a mitochondrial depolarization manner mediated by the generation of ROS and free charges. Furthermore, SBTO NPs could cross the BBB and then accumulate in gliomas through US/microbubbles (MBs) procedure and protein-mediated transport. The therapeutic effect of piezoelectric SBTO NPs mediated SDT was proved in the orthotopic glioma mouse model. As validated by the histopathological observation and the long-term evaluation, the good biocompatibility and biosafety of SBTO NPs make it possible for deep tumor therapy, and worthy for further preclinical study. Statement of significanceEmploying piezoelectric sonosensitizers for sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, the unclear mechanism and blood-brain barrier (BBB) limit the effectiveness of SDT in glioma. Herein, we developed piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) with a built-in electric field for glioma treatment and explored the underlying therapeutic mechanism. Notably, SBTO NPs selectively accumulated in mitochondria under ultrasound (US) and induced apoptosis in a mitochondrial depolarization manner, which is mediated by the generation of reactive oxygen species (ROS) and free charges. In an orthotopic glioma mouse model, SBTO NPs were delivered into the glioma through US/microbubbles and transferrin-mediated transport pathways, inhibiting tumor growth. This work provides a new paradigm for the treatment of orthotopic glioma and other tumor types.

Diradicaloid-Loaded Polypeptide Nanoparticles for Two-Photon NIR Phototheranostics.

Stable organic radicals, with unique electronic transitions from the ground state (D0) to the doublet excited state (D1), show promise as high-fluorescence quantum yield dyes. While organic small-molecule photosensitizers (PSs) have advanced for tumor photodynamic therapy (PDT), opportunities exist to enhance their performance and functionality. Herein, we synthesized Thiele's fluorocarbon derivative diradicaloid TFC-I with nearly 100% PLQY and integrated it into amphiphilic polypeptide nanoparticles, P-TI, using a precursor-doping approach. P-TI demonstrated notable features including high photostability, aggregation-induced emission, bright near-infrared fluorescence, substantial quantum yield (37% PLQY), robust near-infrared two-photon absorption (∼400 GM cross section), and superior ROS generation compared to commercial PSs. In vitro and in vivo experiments confirmed that P-TI performed well in mitochondria-targeted PDT, two-photon fluorescence imaging, and biosafety. This work highlights the use of organic stable radicals with precursor-doping for efficient PDT and deep tumor tissue imaging.

Mesoporous Microneedles Enabled Localized Controllable Delivery of Stimulator of Interferon Gene Agonist Nanoexosomes for FLASH Radioimmunotherapy against Breast Cancer.

The immunosuppressive nature of the tumor microenvironment (TME) contributes to radioresistance, thereby impairing the effectiveness of radiotherapy as a therapeutic intervention. Activation through the stimulator of interferon genes (STING) pathway shows potential in modulating immunogenicity. However, the therapeutic efficacy of STING agonists might be restricted by off-target effects and potential cytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous microneedles were employed for precise delivery of the STING agonist MSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration enabled by microneedles, EXOs can be continually released and accumulate within deep residual tumors. Once internalized, these EXOs release the encapsulated MSA-2, facilitating the activation of the STING pathway upon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy elevates the type I interferon level, promotes dendric cell maturation, and modulates the immunosuppressive TME, showing efficient antitumor efficacy in both primary/metastatic tumors. Furthermore, the induction of a potent immune response effectively prevented tumor recurrence. The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

MMP-2 Responsive Gold Nanorods Loaded with HSP-70 siRNA for Enhanced Photothermal Tumor Therapy.

Gold nanorods (Au NRs) are a valuable photothermal nanomaterial for tumor therapy. However, when treated with Au NRs for photothermal therapy, the expression of heat shock proteins in tumors will increase, which will induce heat resistance in tumor cells and reduce the photothermal therapeutic effect of Au NRs. By RNA interference, the expression of heat shock proteins would be effectively inhibited to improve the efficasy of tumor photothermal therapy. However, deep and noninvasive tissue penetration remains a great obstacle to applying siRNA successfully. Thus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced photothermal tumor therapy by RNA interference. In the AGC/HSP-70 siRNA complex, the Au-S bond modified the matrix metalloproteinase-2 (MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods. Moreover, the natural basic polysaccharide (chitosan) was reacted with the peptide by an amide bond for delivering heat shock protein 70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker could cause more Au NRs to accumulate in tumors to exert a photothermal effect and promote the penetration of HSP-70 siRNA and chitosan complexes into deep tumor tissues. In vitro experiments indicated that the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70 siRNA could promote the cellular uptake and perinuclear distribution of HSP-70 siRNA in tumor cells, which may be due to the smaller size and positive electricity of the complexes. All of these results ensured the efficient gene silencing effect of HSP-70 siRNA to enhance the photothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated by the gene silencing and cellular apoptotic experiments. In vivo experiments further proved that the AGC/HSP-70 siRNA nanoplatform efficiently improved the photothermal effect of Au NRs. In summary, this work proved that AGC/HSP-70 siRNA is a promising drug delivery strategy for enhancing the photothermal therapy of tumors by regulating the photothermal sensitivity of deep tumor cells as well as retaining more Au NRs in tumor tissues, and also provides a novel strategy for tumor photothermal therapy.

P10.22.B PREDICTING INTRAOPERATIVE 5-ALA-INDUCED TUMOR FLUORESCENCE VIA MRI AND DEEP LEARNING IN GLIOMAS WITH RADIOGRAPHIC LOWER-GRADE CHARACTERISTICS

Abstract BACKGROUND Lower-grade gliomas typically exhibit 5-aminolevulinic acid (5-ALA)-induced fluorescence in only 20-30% of cases, a rate that can be increased by doubling the administered dose of 5-ALA. Fluorescence can depict anaplastic foci, which can be precisely resected to avoid undergrading. We aimed to analyze whether a deep learning model can predict intraoperative fluorescence based on preoperative magnetic resonance imaging (MRI). Material and Methods: The MRI images of gliomas lacking high-grade characteristics (necrosis, extended contrast-enhancement, a.o.) consisted of T1, T1-post gadolinium, and FLAIR sequences. The preprocessed MRIs were fed into an encoder-decoder convolutional neural network (U-Net), pre-trained for tumor segmentation using those three MRI sequences. We used the outputs of the bottleneck layer of the U-Net in the Variational Autoencoder (VAE) as features for classification. We identified and utilized the most effective features in a Random Forest classifier using the principal component analysis (PCA) and the partial least square discriminant analysis (PLS-DA) algorithms. We evaluated the performance of the classifier using a 10-fold cross-validation procedure. RESULTS We evaluated a cohort of 163 glioma patients categorized as fluorescent (n=83) or non-fluorescent (n=80). Our proposed approach’s performance was evaluated using metrics such as mean balanced accuracy, mean sensitivity, and mean specificity. The optimal results were obtained by employing top-performing features selected by PCA, resulting in a mean balanced accuracy of 80% and mean sensitivity and specificity of 84% and 76%, respectively. CONCLUSION Our findings highlight the potential of a U-Net model, coupled with a random forest classifier, for intraoperative fluorescence prediction. We achieved good accuracy using advanced techniques such as deep learning-based tumor segmentation and Variational Autoencoder for radiomics feature extraction. While the model can still be improved, it has the potential for evaluating when to administer 5-ALA to gliomas lacking typical high-grade radiographic features.

Self‐Initiated Nano‐Micelles Mediated Covalent Modification of mRNA for Labeling and Treatment of Tumors

AbstractAs a promising gene therapy strategy, controllable small molecule‐mRNA covalent modification in tumor cells could be initiated by singlet oxygen (1O2) to complete the modification process. However, in vivo generation of 1O2 is usually dependent on excitation of external light, and the limited light penetration of tissues greatly interferes the development of deep tumor photo therapy. Here, we constructed a tumor‐targeting nano‐micelle for the spontaneous intracellular generation of 1O2 without the need for external light, and inducing a high level of covalent modification of mRNA in tumor cells. Luminol and Ce6 were chemically bonded to produce 1O2 by chemiluminescence resonance energy transfer (CRET) triggered by high levels of hydrogen peroxide (H2O2) in the tumor microenvironment (TME). The sufficient 1O2 oxidized the loaded furan to highly reactive dicarbonyl moiety, which underwent cycloaddition reaction with adenine (A), cytosine (C) or guanine (G) on the mRNA for interfering with the tumor cell protein expression, thereby inhibiting tumor progression. In vitro and in vivo experiments demonstrated that this self‐initiated gene therapy nano‐micelle could induce covalent modification of mRNA by 1O2 without external light, and the process could be monitored in real time by fluorescence imaging, which provided an effective strategy for RNA‐based tumor gene therapy.

MDM2 Testing In Lipomatous Tumors: An Institutional Experience with 1,161 Neoplasms

Abstract Introduction/Objective Amplifications of the MDM2 gene is a well-recognized central molecular event in atypical lipomatous tumors, well-differentiated liposarcomas, and dedifferentiated liposarcomas. However, given the fact that most adipocytic neoplasms are benign, the specific testing approaches that will maximize the detection of MDM2 amplified tumors in an accurate and cost-efficient manner remains unclear. The purpose of this study is to present our experience with MDM2 testing by FISH in a large cohort of lipomatous neoplasms. Methods/Case Report The pathologic database of an academic medical center was queried for all lipomatous tumors as well as all tumors for which MDM2 testing was performed during a three-year period. At our center, MDM2 testing for well differentiated adipocytic neoplasms is triggered by the so-called “traditional criteria”: a deep tumor and/or tumor size &amp;gt;10 cm and/or recurrence. We also take an expanded approach for a variety of indications that may include equivocal atypia or clinical/imaging concern, among others. Testing is also performed on overt malignancies for which dedifferentiated liposarcoma is a plausible consideration after review of morphologic features. Clinicopathologic data, including patient age of diagnosis, tumor size, depth of tumor, results from MDM2 testing [when performed], anatomic location(s) and recurrence [where applicable], were collected for each patient. Results (if a Case Study enter NA) 1161 cases were assessed, 456 of whom underwent MDM2 testing, and 108 of which were ultimately classified as MDM2 amplified. Standardized bivariable comparisons found that a deep tumor location (p=0.0014) and older age (p=0.0002), but not tumor size at the &amp;gt;10 cm cut off were associated with MDM2 positivity. However, a logistic regression model showed that neither size, depth or age were significantly associated with MDM2 positivity. Among the MDM2-positive cohort, 91% had tumor sizes &amp;lt;10 cm, 14% were superficial, 23% were non-recurrent and 15% were less than the median cohort patient age of 58 years. If the aforementioned “traditional criteria” were used as the sole basis for MDM2 testing, 50 (46.29%) of the 108 cases that were ultimately classified as MDM2 positive would not have been tested. Conclusion Our findings suggest that a strict adherence to “traditional criteria” may result in a significant subset of MDM2 positive tumors not being tested in lipomatous tumors. A more expansive approach that incorporates additional indications for testing, should be evaluated.

Morphology-Mediated Tumor Deep Penetration for Enhanced Near Infrared II Photothermal and Chemotherapy of Colorectal Cancer.

The low permeability and heterogeneous distribution of drugs (including nanomedicines) have limited their deep penetration into solid tumors. Herein we report the design of gold nanoparticles with virus-like spikes (AuNVs) to mimic viral shapes and facilitate tumor penetration. Mechanistic studies revealed that AuNVs mainly entered cells through macropinocytosis, then transported to the Golgi/endoplasmic reticulum system via Rab11-regulated pathway, and finally exocytosed through recycling endosomes, leading to high cellular uptake, effective transcytosis, and deep tumor penetration compared to gold nanospheres (AuNPs) and gold nanostars (AuNSs). The high tumor accumulation and deep tumor penetration of mitoxantrone (MTO) facilitated by AuNVs endowed effective chemophotothermal therapy when exposed to a near-infrared II laser, significantly reducing tumor sizes in a mouse model of colorectal cancer. This study reveals a potent mechanism of viral-like structures in tissue penetration and highlights their potential as effective drug delivery carriers.

Synthesis and optical properties of SnO2 nanostructure as a novel photosensitizer for deep tumor treatment in photodynamic therapy using UV light and X-ray radiation

Synthesis and optical properties of SnO2 nanostructure as a novel photosensitizer for deep tumor treatment in photodynamic therapy using UV light and X-ray radiation

Outcomes of a modified technique of partial parotidectomy and novel parotid tumour position classification from a single surgeon prospective database.

Conservative parotidectomy for benign tumours reduces facial nerve palsy, without increasing local recurrence. We report a modified technique of partial parotidectomy and using a novel description of tumour position, explore relationships between tumour position and histological margins, facial nerve palsy and local recurrence. A prospectively collected single surgeon parotidectomy database was analysed, including tumour location (superficial/deep lobe; central/peripheral) and outcomes. A partial parotidectomy identified the facial nerve and the proximal portion of its branches with a macroscopically clear resection margin. Mean follow up was 5.9 years for pleomorphic adenomas. Three hundred and three patients underwent parotidectomy; 257 (84.8%) were superficial and 46 (15.2%) deep lobe. Tumour position was recorded in 291: 236 (81.1%) were peripheral tumours and 55 (18.9%) central. Histological margin involvement was similar in central and peripheral tumours, both overall and for superficial and deep lobe tumours, but was commoner in central deep lobe tumours, (P = 0.003). Temporary partial facial nerve palsy occurred in 21 (6.9%), with one permanent partial nerve palsy (0.3%). Deep lobe tumours and total parotidectomy were associated with facial nerve palsy (P = 0.01). Facial nerve monitoring reduced the risk of palsy (P < 0.01). Local recurrence of pleomorphic adenomas was uncommon, occurring in 3 (2.0%) of 151 patients. This series confirms the safety and adequacy of more conservative partial parotidectomy for benign tumours, highlighting most tumours are peripheral, but not more prone to histological margin involvement or local recurrence, and with routine intraoperative facial nerve monitoring, is achieved with low facial nerve palsy rates.

A 3D wideband electromagnetic horn antenna applicator for biomedical applications

Abstract This paper proposes a new, compact, wideband 3D horn antenna for biomedical wireless applications such as cancer and tumor detection. In order to achieve the best penetration level, the antenna has been built and tuned to work in the low frequency range of 0.48–1.24 GHz, which can exhibit a high-resolution detection result. The proposed applicator is a double ridge horn antenna (DRHA). The layout and operation of the key needed components to assemble a wideband hyperthermia system are provided in this study. We assume a cylindrical human tissue phantom with wideband dispersive tissue properties, and simulation results are given. The resulting field maps are displayed in several planes to illustrate the energy localization process. The findings indicate that, in contrast to traditional narrowband systems, wideband operation may improve energy localization in deep tumor locations while eliminating hot spots. The suggested antenna was built and measured to verify the result.

ICAM‐1‐Expressing Extracellular Vesicles Enable Sequential Delivery Barrier‐Breaking and Microenvironment Modulating for Glioblastoma Stem Cell Inhibition

AbstractGlioma stem‐like cell (GSC) inhibition is a promising strategy for glioblastoma therapy. However, it is hampered by two main obstacles: first, delivery barriers, including the blood–brain barrier (BBB) and deep tumor‐penetrating obstacles, hinder sufficient drug accumulation in GSCs that often reside in hypoxic niches deep in glioblastoma; second, hypoxia and the immunosuppressive tumor microenvironment (TME) limit the therapeutic responses of GSC inhibition strategies. An intercellular cell adhesion molecule 1 (ICAM‐1)‐expressing M1 macrophage‐derived small extracellular vesicles loaded with a complex of bovine serum albumin, MnO2, and the small‐molecule inhibitor PTC209 (IsEV‐BMP) is constructed to achieve sequential barrier‐breaking delivery and simultaneous TME modulation to boost GSC inhibition. ICAM‐1 facilitates endothelial transcytosis‐mediated BBB crossing, microglial transcytosis‐mediated deep tumor penetration, and internalization of IsEV‐BMPs in GSCs. Hypoxia alleviation inhibits the binding of hypoxia‐inducible factor 1α (HIF‐1α) to hypoxia‐responsive elements on the gene promoters of cancer stem cell‐related markers and CD47 in GSCs, thereby improving PTC209 sensitivity and immune phagocytosis of GSCs. IsEV‐BMP achieves simultaneous microglial polarity transition and immuno‐microenvironmental modulation during microglial transcytosis‐mediated deep tumor penetration. This study provides a strategy to overcome the sequential delivery barrier for effective glioblastoma treatment.

Enhanced Sonodynamic Therapy for Deep Tumors Using a Self-Assembled Organoplatinum(II) Sonosensitizer.

Despite the promising advances in photodynamic therapy (PDT), it remains challenging to target and treat deep-seated solid tumors effectively. Herein, we developed an organoplatinum(II) complex (Pt-TPE) with self-assembly properties for sonodynamic therapy (SDT). Pt-TPE forms a nanofiber network structure through Pt-Pt and π-π stacking interactions. Notably, under ultrasound (US), Pt-TPE demonstrates unique self-assembly-induced singlet oxygen (1O2) generation due to a significantly enhanced singlet-triplet intersystem crossing (ISC). This generation of 1O2 occurs exclusively in the self-assembled state of Pt-TPE. Additionally, Pt-TPE exhibits sono-cytotoxicity against cancer cells by impairing mitochondrial membrane potential (MMP), inhibiting glucose uptake, and aerobic glycolysis. Furthermore, US-activated Pt-TPE significantly inhibits deep solid tumors in mice, achieving remarkable therapeutic efficacy even at penetration depths greater than 10 cm. This study highlights the potential of self-assembled metal complexes to enhance the efficacy of SDT for treating deep tumors.