Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible "EPR Effect Enhancer" to Improve Cancer Nanomedicine Efficacy.

Maria Cristina Bonferoni,Elisabetta Gavini,Milena Sorrenti,Paolo Giunchedi,Laura Catenacci,Marcello Maestri,Luca Ansaloni,Sara Perteghella,Giovanna Rassu,Maria Luisa Torre

doi:10.3390/cancers13174437

Abstract

Simple SummaryElectroporation-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.

Highlights

Cancer is the leading cause of death in advanced countries
Surgical treatment with tumor removal is the best approach, but its success depends on early diagnosis and the absence of metastases
Islam et al claimed that this blood flow suppression is a key feature of late-stage cancers and, Cancers 2021, 13, 4437 determines “little or no drug delivery and, a highly limited enhanced permeability and retention” (EPR) effect” after systemic administration of the nanomedicine [22]

Summary

Introduction

Cancer is the leading cause of death in advanced countries. Its incidence increases with the aging of the population, and it is considered the biggest limit to the expectancy of life duration in the 21st century, as globally, mortality rates determined by cancer are increasing [1].Surgical treatment with tumor removal is the best approach, but its success depends on early diagnosis and the absence of metastases. In 1986, Maeda and Matsumura discovered the enhanced permeability and retention (EPR) effect, and this was the starting point of many studies about the possible use of nanomedicines in cancer chemotherapy [3,4]. Islam et al claimed that this blood flow suppression is a key feature of late-stage cancers and, Cancers 2021, 13, 4437 determines “little or no drug delivery and, a highly limited EPR effect” after systemic administration of the nanomedicine [22].

Results

Conclusion