Pore forming channels as a drug delivery system for photodynamic therapy in cancer associated with nanoscintillators

Abstract

According to the World Health Organization (WHO), cancer is one of main causes of death worldwide, with 8.2 million people dying from this disease in 2012. Because of this, new forms of treatments or improvement of current treatments are crucial. In this regard, Photodynamic therapy (PDT) has been used to successfully treat cancers that can be easily accessed externally or by fibre-optic endoscopes, such as skin, bladder and esophagus cancers. In addition, this therapy can used alongside radiotherapy and chemotherapy in order to kill cancer cells. The main problem in implementing PDT is penetration of visible light deeper than 10 mm in tissues, due to scattering and absorption by tissue chromophores. Unfortunately, this excludes several internal organs affected by cancer. Another issue in this regard is the use of a selective cancer cell-photosensitizing compound. Nevertheless, several groups have recently developed scintillation nanoparticles, which can be stimulated by X-rays, thereby making this a possible solution for light production in deeper tissues. Alternative approaches have also been developed, such as photosensitizer structure modifications and cell membrane permeabilizing agents. In this context, certain channels lead to transitory plasma membrane permeability changes, such as pannexin, connexin hemmichannels, TRPV1-4 and P2×7, which allow for the non-selective passage of molecules up to 1,000 Da. Herein, we discuss the particular case of the P2×7 receptor-associated pore as a drug delivery system for hydrophilic substances to be applied in PDT, which could also be carried out with other channels. Methylene blue (MB) is a low cost dye used as a prototype photosensitizer, approved for clinical use in several other clinical conditions, as well as photodynamic therapy for fungi infections.

Differential sensitivity of acute myeloid leukemia cells to daunorubicin depends on P2X7A versus P2X7B receptor expression

“…Formation of the macropore is dependent upon the presence of the long intracellular carboxyl tail as its deletion prevents pore formation while leaving unaltered the ion channel activity 14 , 16 . P2X7R activated macropore opening was also shown to enhance the intracellular uptake of drugs including chemotherapeutics such as doxorubicin 17 and was therefore proposed as tumor cell-specific drug delivery system 18 , 19 . The structure of P2X7R C terminal was recently reported 20 and it was speculated that this region was acquired by genomic rearrangement from a P2X4R like-gene in ancient jawed vertebrates generating the actual mammalian P2X7R 21 .…”

Real-time Live-cell Flow Cytometry to Investigate Calcium Influx, Pore Formation, and Phagocytosis by P2X7 Receptors in Adult Neural Progenitor Cells

“…Interest in P2X7 receptors as a drug target 21,22 or even as a drug delivery route 23,24 is growing rapidly, and so methods to study this enigmatic receptor must be continuously adapted and improved upon to facilitate these studies. This protocol outlines methodologies that may be used to explore P2X7 function in adult neural progenitor cells, and it is hoped that achieving a greater understanding of P2X7 receptors in the neurogenic niches may lead to advancements in the treatment of stroke and other ischemic injuries.…”

<p>Smart Targeting To Improve Cancer Therapeutics</p>

“…[186][187][188] To overcome this, the PS is conjugated to a DDS to increase the selectivity for tumor tissues over healthy tissues. [189][190][191] Positive effects include accumulation of the PS in the tumor by the EPR effect and reduction of unwanted radical formation by the PS due to self-quenching prior to DDS disintegration. 192,193 Internal and external stimuli can be combined within a single system to reduce self-quenching of the drug and produce the therapeutic effect preferentially at the tumor site.…”