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At least 19 recordsLinked to original sources

Biomaterial-Integrated Electroporation for Therapeutic Delivery: From Gene Editing to Tumor Ablation and Immune Modulation.

Electroporation has evolved from a membrane-permeabilization method into a versatile therapeutic platform for intracellular delivery, locoregional tumor intervention, and bioelectrically regulated treatment. Depending on pulse intensity and duration, electroporation operates in two distinct modes: reversible electroporation (RE), which transiently permeabilizes the plasma membrane to enable delivery of nucleic acids, proteins, and small molecules while preserving cell viability, and irreversible electroporation (IRE), which causes permanent membrane damage for non-thermal tissue ablation. Increasingly, the therapeutic scope of electroporation is being expanded through integration with biomaterials, including nanocarriers, hydrogels, soft conductors, and micro/nanoengineered bioelectronic interfaces. These material-assisted strategies improve cargo protection, field confinement, local retention, tissue conformity, and spatiotemporal control, thereby extending electroporation beyond conventional transfection toward gene editing, engineered cell manufacturing, electrochemotherapy, tumor ablation, immune modulation, and transdermal or localized delivery. In this Review, we summarize the biophysical principles of RE and IRE, discuss how biomaterials reshape electroporation performance across therapeutic settings, compare the design logic of major biomaterial-assisted electroporation platforms, and highlight key translational challenges, including pulse-material compatibility, manufacturing scalability, in vivo dosimetry, and regulatory complexity.

Humans

[Tumor ablation with focalized ultrasound. In vivo experiment with prostatic adenocarcinoma R3327 Mat-Ly-Lu].

Ultrasound can induce tissue lesions by a combination of thermal and mechanical effects related to the tissue absorption of the energy emitted at the focal point of the transducer. The effects of focused ultrasound were studied in vivo in Fisher/Copenhagen hybrid rats bearing Dunning R3327 experimental prostatic carcinoma. The experimental tumour was transplanted by subcutaneous injection into the abdomen of 20 mg of tumour tissue derived from the Mat-Ly-Lu strain. Treatment was performed under general anaesthesia. The animal, maintained in a sarcophage exposing the tumour, was immersed in degassed water ensuring the interface between the tumour and the 1 MHz transducer. The displacements of the transducer were guided by computerised ultrasound screening, allowing irradiation of the entire tumour. The energy was supplied by a 7.5 kW amplifier in the form of series of impulses of variable duration. 77 rats were treated and the tumour growth was compared to that of non-irradiated control rats. Comparative series demonstrated the following results: 1. Immediate tumour destruction was obtained with a very high acoustic intensity (9,000 Watts/cm2) and a brief exposure time. 2. A transient slowing of the tumour growth rate was observed for an acoustic intensity of between 3,500 and 5,500 Watts/cm2. 3. Partial or total necrosis of the tumour was obtained with intensities of between 300 and 2,750 Watts/cm2 and a long exposure time. Total tumour destruction was obtained in 30 of the 49 rats treated under these conditions. 14 animals developed a local recurrence, 9 animals did not develop a local recurrence but developed metastases and 7 animals obtained long-term survival without local recurrence or metastasis. Under certain experimental conditions, focused ultrasound, without any adjuvant treatment, was able to destroy the Dunning R3327 Mat-Ly-Lu strain experimental tumour and, in certain cases, induced complete cure of this experimental cancer.

Animals

Predictors of radiation response in lung cancer. A clinico-pathobiological analysis.

From February 1972 to July 1975, 200 lung cancer patients were seen at the University of Rochester Cancer Center's Division of Radiation Oncology; 40% had squamous cell tumors and 87.5% had advanced disease localized to the thorax. Of the 160 patients who completed treatment, 101 were treated with continuous therapy schedules, and 59 were treated with split-course schedules, and 59 were treated with split-course schedules; 40 patients did not complete treatment because of early metastatic disease or death. Radiation therapy was very effective in local tumor ablation. To assess local tumor response, doubling times were obtained in measurable lesions prior to treatment. The doubling times (DT) were 25 days for small cell cancers and 192 days for adenocarcinoma. More than 50% tumor shadow regression was a good prognosticator of local tumor response; this increased as the mean DT decreased. The order of kinetic increase in tumor ablation per histology was the opposite of the one-year survival results because of the metastatic spread patterns of the different tumors. Survival rates in lung cancer emerge as simplistic and inadequate to explain local radiation effectiveness. Survival is conditioned by stage, histology, and modality of treatment, total dose delivered, and local tumor response. Although the most effective treatment dose seems to be over 6000 rads, the most efficient schedules were split-course delivering lower tumor doses. This modality of treatment is proposed as the optimal schedule to be combined with other forms of therapy with the goal of achieving better survival.

Adenocarcinoma

Photodynamic therapy of chemically- and ultraviolet B radiation-induced murine skin papillomas by chloroaluminum phthalocyanine tetrasulfonate.

Photodynamic therapy (PDT) of cancer combines irradiation of tumors with visible light following selective uptake of the photosensitizer by the tumor cells. PhotofrinR-II (Pf-II) is the only photosensitizer which is in clinical use in PDT, whereas chloroaluminum phthalocyanine tetrasulfonate (AlPcTS) has also shown promise in preclinical studies. In most such studies, the effectiveness of the photosensitizers has been assessed in implanted tumor model systems rather than in model systems where tumors are allowed to grow in their own connective tissue matrix. In this study the pharmacokinetics, tumor ablation capability and cutaneous photosensitization response of AlPcTS have been assessed in mice bearing chemically- and ultraviolet B radiation (UVB)-induced benign skin papillomas. When tumor-bearing animals were injected intraperitoneally with AlPcTS (5 mg/kg body wt), maximum tumor:normal skin ratio of 2.4 was observed at 48 h, at which time the mice were irradiated within the absorption spectrum of the photosensitizer. In tumor ablation studies with SENCAR mice bearing chemically-induced skin tumors, AlPcTS resulted in greater than 80% ablation in tumor volume at 20 days post-irradiation. In cutaneous photosensitization response, AlPcTS produced only transient effects (no effect after 24 h) in SENCAR mice. Pharmacokinetics data, tumor ablation effects and cutaneous photosensitization response of AlPcTS were comparable in SKH-1 hairless mice bearing UVB-induced skin tumors. Our data indicate that AlPcTS produces significant photodynamic effects towards the ablation of murine skin tumors, and that it does not produce prolonged cutaneous photosensitivity.

Animals

High-Frequency Irreversible Electroporation Alters Proteomic Profiles and Tropism of Small Tumor-Derived Extracellular Vesicles to Promote Immune Cell Infiltration.

High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technique that disrupts the blood-brain barrier (BBB) in a focal and reversible manner. However, the mechanisms underlying this disruption remain poorly understood, particularly the role of small tumor-derived extracellular vesicles (sTDEVs) released from ablated tumor cells. In this study, we investigate the proteomic and functional alterations of sTDEVs released from F98 glioma and LL/2 Lewis lung carcinoma cells following H-FIRE ablation. Mass spectrometry analysis revealed 108 unique proteins in sTDEVs derived from ablative doses of H-FIRE, which are capable of disrupting the BBB in an in vitro model. Proteomic analysis of TDEVs highlights key changes in pathways related to integrin signaling, Platelet-derived growth factor receptor (PDGFR) signaling, and ubiquitination, which may underline their interactions with brain endothelial cells. These "disruptive" sTDEVs exhibit enhanced tropism for cerebral endothelial cells both in vitro and in vivo, where they persist in the brain longer than sTDEVs released after non-ablative H-FIRE doses. Notably, when introduced into a healthy Fischer rat model, disruptive sTDEVs are associated with increased recruitment of Iba1+ immune cells, suggesting a potential role in modulating post-ablation immune responses. However, despite their altered protein composition, these vesicles do not directly increase BBB permeability in vivo. This study is the first to demonstrate that electroporation-based tumor ablation significantly alters the composition and functionality of tumor-derived extracellular vesicles, potentially influencing the tumor microenvironment post-ablation. These findings have important implications for developing multimodal treatment strategies that combine H-FIRE with systemic therapies to enhance efficacy while managing the peritumoral microenvironment.

Animals

A photothermal ablation strategy for orthotopic ovarian cancer via mitochondria-dependent apoptosis.

Photothermal therapy (PTT) shows promise for ovarian cancer, but unclear cell death mechanisms slow its clinical use. Here, we report two-dimensional rhenium diselenide (ReSe₂) nanosheets as a stable, high-performance photothermal agent that triggers ovarian cancer cell apoptosis through a mitochondria-dependent pathway. Under near-infrared light, ReSe₂ generates local hyperthermia. This triggers a rapid burst of intracellular reactive oxygen species, collapses mitochondrial membrane potential, and shifts the balance between pro- and anti-apoptotic Bcl-2 family proteins. In an orthotopic mouse model, this defined apoptotic cascade strongly suppresses tumors with no detectable systemic toxicity. Our work not only elucidates a clear molecular mechanism for photothermal tumor ablation but also establishes ReSe₂-mediated PTT as a translatable therapeutic strategy, advancing the rational design of photothermal agents based on biological mechanism.

Apoptosis

Cardiac pathologic findings in patients treated with bone marrow transplantation.

Cardiac pathologic findings were analyzed in 22 necropsy cases from a series of 29 patients with leukemia, aplastic anemia, or metastatic cancer who had been treated with ablative therapy followed by bone marrow transplantation. Some cardiac alterations were similar to those that occur in patients with hematologic and neoplastic diseases not treated with bone marrow transplantation, and consisted of cardiomegaly, cardiac atrophy, hemorrhage, foci of necrosis due to shock associated with sepsis or hepatic failure, myocardial abscesses secondary to systemic candidiasis or staphylococcal infection, fibrinous pericarditis, and hemosiderosis. Other cardiac alterations were more specifically related to factors associated with transplantation procedure. Six patients exhibited a distinctive interstitial reactive change characterized by the presence of (1) moderate to large numbers of Anitschkow cells, occurring alone or in small cellular aggregates and histiocytes, histiocytic cells with nuclei of the Anitschkow type, lymphoid cells, and plasma cells, and (2) nuclei of the Anitschkow type in cardiac vascular and endocardial smooth muscle, endothelial and Schwann cells, and occasional cardiac muscle cells. This alteration may have been induced by abnormal immune mechanisms, as suggested by the observation that five of the six patients with interstitial change had clinical evidence of graft-versus-host disease. Two patients developed fatal congestive cardiac failure in the early post-transplant period and exhibited myocardial damage with histologic and post-transplant period features indicative of severe acute injury. Findings in these two patients consisted of necrotic muscle cells, which exhibited multiple contraction bands, diastase-resistant PAS staining, and intracellular fibrin deposits; microthrombi, which were composed of fibrin and occasionally of fibrin and platelets; and extravasated erythrocytes and fibrin strands in the interstitium. One of the two patients also exhibited unusual nuclear alterations, which were characterized by replacement of normal chromatin by palely stained fibrous and filamentous material. Clinicopathologic analysis strongly suggested that the fatal cardiotoxicity in both patients resulted primarily from effects of high doses of cyclophosphamide, which were administered as part of a four drug regimen that provided tumor ablation and immunosuppression for bone marrow transplantation. Our findings emphasize the need for less toxic antineoplastic and immunosuppressive therapy for use in bone marrow transplantation procedures.

Abscess

Management of advanced and recurrent facial carcinoma.

I report five cases of advanced and recurrent facial carcinoma to illustrate the extent to which such disease can develop and yet be compatible with life. Radical treatment approaches are used so as to maximize the chances for tumor ablation and survival as well as for restoration of function and cosmetics.

Aged

Detection of metastatic thyroid carcinoma after the administration of a therapeutic dose of 131-iodine.

A patient with thyroid cancer is described whose metastases were detected only after the administration of a large therapeutic dose of 131 Iodine. This suggests that very high doses of 131 Iodine might permit diagnoses of metastatic lesions not otherwise detected. This phenomenon may be explained by the improved counting statistics which occur with the use of a higher dose of the isotope. In such cases, exceedingly high doses of 131 Iodine might be necessary for successful tumor ablation.

Female

Organization of layers II-III connections in human visual cortex revealed by in vitro injections of biocytin.

In the search for cortical mechanisms subserving psychological phenomena, a better understanding of human cortical circuitry is crucial. In this report we describe aspects of intrinsic connectivity of supragranular layers in human visual cortex, revealed by extracellular injections of the anterograde tracer biocytin in vitro. Human cortical slices were obtained from visual association cortex in the posterior-medial portion of the dorsal bank of the occipital lobe, removed during neurosurgical tumor ablations. Small iontophoretic injections of biocytin into layers II-III revealed intense Golgi-like staining of axonal projections emanating from the injection sites. Vertically descending axons are grouped in bundles 20 microns in diameter which are spaced 15 microns apart. Some of these axons enter the white matter and send long oblique and horizontal collaterals. The main horizontal spread of the axons could be observed in layers II-III and V. The bulk of projections extends to a distance of 1.5 mm in layers II-III and 1.1 mm in layer V. Few individual axons could be observed at greater distances. In contrast, layer IV is almost devoid of horizontal connections, forming a clear gap between supra- and infragranular layers. Axon collaterals in the infragranular layers project mostly in a descending oblique direction with long horizontal collaterals in lower layer VI.

Axons

The mucoperiosteal palate flap for closure of oral cavity defects.

We have used a modification of a mucoperiosteal flap described by Lane for cleft palates in 3 patients with oral cavity defects from tumor ablations. The flap provides excellent lining for repairs when alternative flaps are unavailable. The vascularity of the flap and its texture allow a watertight closure which does not hinder the patient's ability to talk or eat.

Aged

Immediate facial rehabilitation in poor prognosis tumor patients.

Effective rehabilitation of facial paralysis in the poor prognosis tumor patient is best accomplished by the judicious and individualized use of that combination of static or static and dynamic procedures which will correct the major deformities present immediately and with minimal morbidity. This approach may be taken at the time of tumor ablation or later when the effects of paralysis become distressingly evident. In the rare patient whose disease is controlled, additonal dynamic rehabilitative efforts may be considered subsequently.

Aged

[Role of MRI in the diagnosis of endocrine tumors of the pancreas].

Eight patients affected with endocrine tumor of the pancreas were examined, within the same period of time, by MRI and CT. Results from those two examinations were similar for the detection of the primary tumor (succeeding to visualize the lesion 5 times out of 8) and the evaluation of locoregional and vascular extension. No tumor smaller than 3 cm was diagnosed by MRI. Most of cases the pancreatic tumor appeared as hypointense in T1 and hyperintense in T2 sequences. MRI was a little more efficient than CT for the detection of liver metastases. MRI seems to be an interesting method for the follow-up of those patients needing a regular and prolonged surveillance after primary tumor ablation.

Adenoma, Islet Cell

Is there a better way to deliver total body irradiation?

The available data suggest that the antileukemic, immunosuppressive and toxic effects of TBI are highly dose dependent and if TBI is given as single daily fractions at 5-10 cGy/minute, an optimal dose for the treatment of most leukemias is somewhere between 12 and 16 Gy. Giving radiation as a single dose rather than fractionating it increases both its immunosuppressive as well as its toxic effects. The relative anti-leukemic effects of single vs. fractionated irradiation are less clear, but available data support the view that fractionation does not substantially reduce the effects of TBI on myeloid tissue. Increasing the dose rate increases toxicities and, although data are not yet complete, likely increases both immunosuppressive and anti-tumor effects. The impact of total dose, dose fractionation and dose rate are highly interdependent and how best to manipulate these 3 factors to lead to an optimal combination is as yet unknown. Directing radiotherapy to sites of leukemia using monoclonal antibodies or other carriers such as growth factors is feasible and, although there are many aspects of this approach which have yet to be worked out, targeted radiotherapy may prove to be the best way to achieve the therapeutic goals of increased tumor ablation and immunosuppression without increased toxicities.

Bone Marrow Transplantation

Prolactin receptors in 7,12-dimethylbenz(a) anthracene-induced mammary tumors following endocrine ablation.

We have determined the effect of ovariectomy and hypophysectomy on prolactin receptors in 7,12-dimethylbenz(a)anthracene-induced mammary tumors. Growing tumors from intact rats show a wide range in the number of prolactin receptors. Ovariectomy causes a slight (approximately 30%) decrease in receptors regardless of whether tumors regress or continue to grow, while the affinity of the receptor for prolactin remains unchanged. Hypophysectomy, which causes a prompt 10-fold decrease in prolactin receptors in rat liver, causes only a slight reduction in prolactin receptors in tumors from these same animals. We conclude that autonomous and ovariectomy responsive 7,12-dimethylbenz(a)anthracene-induced mammary tumors cannot be distinguished on the basis of prolactin receptor sites and that endocrine regulation of prolactin receptors is distinctly different in normal liver and neoplastic mammary tissue.

9,10-Dimethyl-1,2-benzanthracene

Estrogen and prolactin receptor concentrations in rat mammary tumors and response to endocrine ablation.

Estrogen and prolactin receptor concentrations were measured in 24 carcinogen-induced rat mammary tumors and correlated with the tumor response to host ovariectomy or hypophysectomy. It was found that essentially all of the tumors contained some specific estrogen receptor, and all but three contained prolactin receptor. The values for each receptor comprised a continuum from very low to relatively high concentrations, suggesting that previous considerations of hormone dependence on the basis of presence or absence of hormone receptors may be oversimplified. The concentration of each receptor tended to be lower in the hormone-independent than in the hormone-dependent tumors, but there were a number of hormone-independent tumors with higher receptor levels than some of the hormone-dependent tumors had. A better correlation of tumor response to endocrine ablation resulted from a combination of the 2 receptor levels than from either receptor concentration alone. These results suggest that there is a complex relationship between mammary tumor response to endocrine ablatin and levels of estrogen and prolactin receptors and that some tumors may be dependent upon 1 or both of these hormones for growth.

9,10-Dimethyl-1,2-benzanthracene

Engineered MXene-based nanozyme platform: NIR-II photothermal and dual enzyme-mimetic potentiated chemodynamic synergy for precision tumor eradication.

The antioxidant defense barrier in the tumor microenvironment, particularly glutathione (GSH), considerably restricts the therapeutic efficacy of chemodynamic therapy (CDT). Moreover, CDT generally exhibits relatively mild therapeutic efficacy owing to its intrinsic reaction kinetics, making it difficult to achieve complete tumor eradication within a short time. To address these issues, we construct a functionalized nanotherapeutic platform, Nb2CTx@Ru-PEG2000-FA (NCRPF), for tumor photothermal ablation and enhanced CDT resulting from GSH depletion. NCRPF possesses three key advantages: 1. Efficient near-infrared II photothermal conversion (η = 42.08%), raising the tumor temperature above 45 °C within 90 s for rapid ablation; 2. Dual peroxidase-like and glutathione peroxidase-like activities, simultaneously depleting GSH and generating a burst of ·OH to eliminate residual tumors; 3. Targeted tumor accumulation with 2.9-fold higher efficiency than passive diffusion. Both in vitro and in vivo results confirm that this combined strategy achieves complete tumor eradication with favorable biosafety. Collectively, the NCRPF nanotherapeutic system provides a powerful new paradigm with high translational potential for the complete eradication of breast cancer.

Animals

Detection of cancer-associated antigen(s) in urine of sarcoma patients.

Tumor-associated antigens were demonstrated in concentrated and dialyzed urine of several sarcoma patients with large tumor burden. The antigens were detected by complement fixation using autologous and allogeneic sera from sarcoma patients. The antigenic activity in three patients who were studied sequentially disappeared after surgical ablation of tumor. In two of these three patients, the antigenic activity reappeared before tumor recurrence. The reactivity of the sarcoma sera to the urine could be abolished by absorption of the sera with human sarcoma cells but not by normal human liver cells, which indicates that the same antigen was present in the urine and on biopsy-obtained sarcoma cells. Urine from cancer patients with high tumor burden may be useful as a source of tumor-associated antigen. Further studies on the presence of these antigens in urine of sarcoma patients may lead to a method for detecting subclinical tumor recurrence.

Adult