• angiogenesis
• apoptosis
• autophagy
• bleomycin
• hesperidin
• lung cancer

• UV light
• aggregation
• bleomycin
• monoclonal antibody
• sodium hypochlorite

• Trastuzumab/chemistry
• Trastuzumab/metabolism
• Hydrogen Peroxide/chemistry
• Oxidative Stress
• Ultraviolet Rays
• Humans
• Protein Aggregates
• Drug Stability
• Ferrous Compounds/chemistry
• Antineoplastic Agents, Immunological/chemistry

• BT/COE/34/ SP15097/2015 Department of Biotechnology

• Humans
• RNA Stability
• RNA/metabolism
• RNA/chemistry
• RNA Interference
• CRISPR-Cas Systems

• Bleomycin
• Calcium
• Cell viability
• Electroporation
• Sonoporation
• Ultrasound

• Calcium/metabolism
• Electroporation/methods
• Bleomycin/pharmacology
• Humans
• Cell Survival/drug effects
• Drug Delivery Systems/methods
• Cell Line, Tumor

• bone disease
• electrochemotherapy
• metastasis
• spine tumor

• Anticuerpo monoclonal
• Chemotherapy
• Efecto secundario
• Monoclonal antibody
• Pequeñas moléculas
• Quimioterapia
• Side effect
• Small molecules
• Targeted therapy
• Terapia dirigida

• Humans
• Quality of Life
• Eye
• Face
• Ophthalmologists

• ECT
• EGT
• cancer
• dog
• electrogene transfer
• electroporation
• immune response
• immunotherapy

• BA- MED-123 Instituto Universitario de Ciencias de la Salud Fundación HA Barceló
• PIP 379/2012/2016 National Scientific and Technical Research Council
• STAN 534/12 National Scientific and Technical Research Council
• PICT 2017-3802 Agencia Nacional de Promoción Científica y Tecnológica
• DSB.AD007.257 National Research Council
• UBACyT 2014/2017 University of Buenos Aires

• Adenocarcinoma
• Balb/C
• Bleomycin
• Chemotherapy
• In Vivo
• Magnetic Fields
• Permeabilization

• Low-electric field (LEF) monopolar pulses
• MCF-7 cells
• bleomycin (BLM)
• cloning efficacy test
• nanosecond pulsed electric fields (nsPEF)

Electroporation-based therapies (reversible electroporation, irreversible electroporation, electrochemotherapy) are used for the selective treatment of deep-seated tumors. The combination of the structural modifications of the lipid bilayer of cell membranes, due to the application of electrical pulses in the targeted tissue, with the concomitant systemic (intravenous) administration of drugs can be considered as a sort of bridge between local-regional and systemic treatments. A possible further application of these techniques can be envisaged in their use as enhancers of the so-called “enhanced permeability and retention” effect. The intratumoral uptake of drug-loaded nanocarriers concomitant with the application of electric pulses in the target tumor is a new scenario worthy of attention and can represent a potential new frontier for drug delivery in oncology.

Surgical resection is the gold standard for the treatment of many kinds of tumor, but its success depends on the early diagnosis and the absence of metastases. However, many deep-seated tumors (liver, pancreas, for example) are often unresectable at the time of diagnosis. Chemotherapies and radiotherapies are a second line for cancer treatment. The “enhanced permeability and retention” (EPR) effect is believed to play a fundamental role in the passive uptake of drug-loaded nanocarriers, for example polymeric nanoparticles, in deep-seated tumors. However, criticisms of the EPR effect were recently raised, particularly in advanced human cancers: obstructed blood vessels and suppressed blood flow determine a heterogeneity of the EPR effect, with negative consequences on nanocarrier accumulation, retention, and intratumoral distribution. Therefore, to improve the nanomedicine uptake, there is a strong need for “EPR enhancers”. Electrochemotherapy represents an important tool for the treatment of deep-seated tumors, usually combined with the systemic (intravenous) administration of anticancer drugs, such as bleomycin or cisplatin. A possible new strategy, worthy of investigation, could be the use of this technique as an “EPR enhancer” of a target tumor, combined with the intratumoral administration of drug-loaded nanoparticles. This is a general overview of the rational basis for which EP could be envisaged as an “EPR enhancer” in nanomedicine.

• EPR effect
• EPR enhancer
• bleomycin
• cancer nanomedicine
• cisplatin
• deep-seated tumors
• electrochemotherapy
• electroporation

• bleomycin
• electrochemotherapy
• electroporation
• gene electrotransfer
• vaccines

• 15/26580-9 Fundação de Amparo à Pesquisa do Estado de São Paulo

In the first studies of electrochemotherapy (ECT), small cutaneous metastases were treated and only mild or moderate pain was observed; therefore, pain was not considered a significant issue. As the procedure began to be applied to larger cutaneous metastases, pain was reported more frequently. For that reason, reduction of both muscle contractions and pain have been investigated over the years.

To present an overview of different protocols described in literature that aim to reduce muscle contractions and pain caused by the electroporation (EP) effect in both ECT and irreversible EP treatments.

Thirty-three studies published between January 1999 and November 2020 were included. Different protocol designs and electrode geometries that reduce patient pain and the number of muscle contractions and their intensity were analysed.

The analysis showed that both high frequency and bipolar/biphasic pulses can be used to reduce pain and muscle contractions in patients who undergo EP treatments. Moreover, adequate electrode design can decrease EP-related morbidity. Particularly, needle length, diameter and configuration of the distance between the needles can be optimised so that the muscle volume crossed by the current is reduced as much as possible. Bipolar/biphasic pulses with an inadequate pulse length seem to have a less evident effect on the membrane permeability compared with the standard pulse protocol. For that reason, the number of pulses and the voltage amplitude, as well as the pulse duration and frequency, must be chosen so that the dose of delivered energy guarantees EP efficacy.

Pain reduction in EP-based treatments can be achieved by appropriately defining the protocol parameters and electrode design. Most results can be achieved with high frequency and/or bipolar/biphasic pulses. However, the efficacy of these alternative protocols remains a crucial point to be assessed further.

• Electrochemotherapy
• Irreversible electroporation
• Pain
• Muscle contraction
• Monopolar or monophasic pulses
• Bipolar or biphasic pulses

• electromagnetic stimuli
• electrospinning
• hyperthermia
• nanocomposite membrane
• nanoparticle
• pulsed electric field
• stimuli-responsive
• tunable properties

• cholangiocarcinoma
• debulking
• electrochemotherapy
• heated intraperitoneal chemotherapy
• peritoneal metastases

• Electrochemotherapy
• immune system
• radiofrequency
• tumor hypoxia

• Electromagnetic Fields
• Animals
• Electrochemotherapy/methods
• Mice
• Cell Line, Tumor
• Cell Survival/drug effects
• Cell Survival/radiation effects
• Tumor Hypoxia/drug effects
• Tumor Hypoxia/radiation effects
• Female
• Interferon-gamma/metabolism
• Mice, Inbred BALB C

• ablation treatment
• computed tomography
• functional imaging
• magnetic resonance imaging
• pancreatic cancer

• Antibiotics
• Anticancer
• Antitumor bacteria
• Bacteriocins
• Cytotoxic
• Non-ribosomal peptides

• electrochemotherapy
• human oncology
• preclinical studies
• veterinary oncology

In electrochemotherapy (ECT), chemotherapeutics are first administered, followed by short 100 μs monopolar pulses. However, these pulses cause pain and muscle contractions. It is thus necessary to administer muscle relaxants, general anesthesia and synchronize pulses with the heart rhythm of the patient, which makes the treatment more complex. It was suggested in ablation with irreversible electroporation, that bursts of short high-frequency bipolar pulses could alleviate these problems. Therefore, we designed our study to verify if it is possible to use high-frequency bipolar pulses (HF-EP pulses) in electrochemotherapy.

We performed in vitro experiments on mouse skin melanoma (B16-F1) cells by adding 1–330 μM cisplatin and delivering either (a) eight 100 μs long monopolar pulses, 0.4–1.2 kV/cm, 1 Hz (ECT pulses) or (b) eight bursts at 1 Hz, consisting of 50 bipolar pulses. One bipolar pulse consisted of a series of 1 μs long positive and 1 μs long negative pulse (0.5–5 kV/cm) with a 1 μs delay in-between.

With both types of pulses, the combination of electric pulses and cisplatin was more efficient in killing cells than cisplatin or electric pulses only. However, we needed to apply a higher electric field in HF-EP (3 kV/cm) than in ECT (1.2 kV/cm) to obtain comparable cytotoxicity.

It is possible to use HF-EP in electrochemotherapy; however, at the expense of applying higher electric fields than in classical ECT. The results obtained, nevertheless, offer an evidence that HF-EP could be used in electrochemotherapy with potentially alleviated muscle contractions and pain.

• cell survival
• cisplatin
• drug uptake
• electrochemotherapy
• electroporation
• high-frequency bipolar pulses

• Bleomycin
• Breast cancer
• Electrochemotherapy
• Head and neck cancer
• Melanoma
• Skin cancer

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• Cell Hypoxia
• Drug Delivery Systems/methods
• Drug Design
• Drug Liberation
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Neoplasms/diagnosis
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Prodrugs/therapeutic use
• Tumor Microenvironment

• R01 CA068682 NCI NIH HHS
• R15 CA232765 NCI NIH HHS

• King Abdulaziz University
• Jadavpur University

Three new iron(iii) complexes were prepared, and complex 3 exhibited a 14-fold higher selectivity index for HeLa vs. LO2 normal cells than cisplatin.

• calcium electroporation
• cell microenvironment
• chemical enhancement
• cytotoxic drugs
• irreversible electroporation
• surfactants

• Algorithms
• Animals
• Antineoplastic Agents/pharmacology
• Calcium/pharmacology
• Cell Survival/drug effects
• Cellular Microenvironment/drug effects
• Electroporation/methods
• Electroporation/standards
• Humans
• Models, Theoretical
• Surface-Active Agents/pharmacology

• National Natural Science Foundation of China

• bleomycin
• electrochemotherapy
• electroporation
• head and neck cancer
• quality-of-life

Calcium electroporation is a potential novel anticancer treatment, where high concentrations of calcium are introduced into the cell cytosol by electroporation. This is a method where short, high-voltage pulses induce a transient permeabilization of the cell membrane and thereby allow influx and efflux of ions and molecules. Electroporation is used in combination with chemotherapeutic drugs (electrochemotherapy) as a standard treatment for cutaneous metastases, and electroporation using a higher electric field and number of pulses (irreversible electroporation) is increasingly being used as an anticancer treatment. In this review, calcium electroporation is described with emphasis on the investigations of differences in the effect on normal and malignant cells and tissues in vitro and in vivo. Calcium electroporation has been shown to induce cell death in vitro and tumor necrosis in vivo with a difference in sensitivity between different tumor types. Normal cells treated in vitro are significantly less affected than cancer cells, and a similar trend is shown in vivo where muscle and skin tissue surrounding a treated tumor as well as muscle and skin directly treated with calcium electroporation were less affected than tumors. The mechanism behind this difference in sensitivity is not fully understood but might be affected by differences in electric impedance, membrane repair, and expression of plasma membrane calcium ATPases in normal and malignant cells. The research on calcium electroporation shows a potential novel anticancer treatment with significant effect on cancer cells and tissues while normal cells and tissues are clearly less affected.

• calcium electroporation
• in vitro
• in vivo
• malignant
• normal

• electrochemotherapy
• electroporation
• head and neck cancer
• immune response
• skin metastasis

Electrochemotherapy is a new therapeutic option for patients with locally spread melanoma. It is based on the phenomenon of reversible electroporation, i.e. a transient increase in permeability of cell membranes under the influence of an appropriately modulated electric field. This allows multiplication of toxicity of a cytostatic agent entering the tumour cell. It is highly effective, especially in the palliative treatment of cancers located in the integument of the human body (skin and subcutaneous tissue). Available literature provides a mandate both for the application of this method in the aforementioned cases as well as for further work on its development.

This paper focuses on reviewing the literature concerning the use of electrochemotherapy in the treatment of melanoma.

• bleomycin
• electrochemotherapy
• mel-anoma

Cancer chemotherapeutic systems with high antitumor effects and less adverse effects are eagerly desired. Here, a pH-sensitive delivery system for bleomycin (BLM) was developed using egg yolk phosphatidylcholine liposomes modified with poly(ethylene glycol)-lipid (PEG-PE) for long circulation in the bloodstream and 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidylethanolamine (CHexPG-PE) for pH sensitization. The PEG-PE/CHexPG-PE-introduced liposomes showed content release responding to pH decrease and were taken up by tumor cells at a rate 2.5 times higher than that of liposomes without CHexPG-PE. BLM-loaded PEG-PE/CHexPG-PE-introduced liposomes exhibited comparable cytotoxicity with that of the free drug. Intravenous administration of these liposomes suppressed tumor growth more effectively in tumor-bearing mice than did the free drug and liposomes without CHexPG-PE. However, at a high dosage of BLM, these liposomes showed severe toxicity to the spleen, liver, and lungs, indicating the trapping of liposomes by mononuclear phagocyte systems, probably because of recognition of the carboxylates on the liposomes. An increase in PEG molecular weight on the liposome surface significantly decreased toxicity to the liver and spleen, although toxicity to the lungs remained. Further improvements such as the optimization of PEG density and lipid composition and the introduction of targeting ligands to the liposomes are required to increase therapeutic effects and to reduce adverse effects.

• bleomycin
• cancer
• pH-sensitive liposome
• poly(ethylene glycol)
• polyglycidol
• polymer–lipid

Electroporation-based treatments and other therapies that permeabilize the plasma membrane have been shown to be more devastating to malignant cells than to normal cells. In this study, we asked if a difference in repair capacity could explain this observed difference in sensitivity. Membrane repair was investigated by disrupting the plasma membrane using laser followed by monitoring fluorescent dye entry over time in seven cancer cell lines, an immortalized cell line, and a normal primary cell line. The kinetics of repair in living cells can be directly recorded using this technique, providing a sensitive index of repair capacity. The normal primary cell line of all tested cell lines exhibited the slowest rate of dye entry after laser disruption and lowest level of dye uptake. Significantly, more rapid dye uptake and a higher total level of dye uptake occurred in six of the seven tested cancer cell lines (p < 0.05) as well as the immortalized cell line (p < 0.001). This difference in sensitivity was also observed when a viability assay was performed one day after plasma membrane permeabilization by electroporation. Viability in the primary normal cell line (98 % viable cells) was higher than in the three tested cancer cell lines (81–88 % viable cells). These data suggest more effective membrane repair in normal, primary cells and supplement previous explanations why electroporation-based therapies and other therapies permeabilizing the plasma membrane are more effective on malignant cells compared to normal cells in cancer treatment.

• Cancer
• Electroporation
• In vitro
• Membrane repair
• Normal

• Electrochemotherapy
• Electroporation
• Fluorescence guided surgery
• Optical imaging
• Peritoneal metastases
• Tumor targeting

Local progression of papillary thyroid carcinoma (PTC) after failure of standard therapies may cause pain, ulceration, and bleeding. As patients are fully aware of the tumor growth, they might suffer high grade anxiety. Electrochemotherapy (ECT) is a new local palliative treatment for skin metastases of malignant melanoma or other tumors, including squamous head e neck cancer patients.

To evaluate the impact of ECT in patients with local progression of PTC.

Four patients with local progression of PTC were treated with ECT based on Bleomycin, and evaluated according to tumor response, local pain and side effects.

In all cases, some grade of tumor response was observed, lasting 6, 7, 12 and 8 months, respectively. Also, reduction of local pain and anxiety was registered in all patients. Tumor infiltrated skin necrosis was the only collateral effect of the treatment. ECT induced a tumor response in all PTC patients with improvement of symptoms.

ECT may be an option for local palliative treatment in PTC patients with local tumor progression.

The iron complexes discussed in this review highlight their promising future as anticancer agents.