Photodynamic Therapy Activity of New Porphyrin-Xylan-Coated Silica Nanoparticles in Human Colorectal Cancer.

Ludovic Bretin,David Yannick Leger,Vincent Chaleix,Claire Carrion,Aline Pinon,Alain Chaunavel,Bertrand Liagre,Frédérique Bregier,Catherine Ouk,Laurence Richard,Vincent Sol,Soukaina Bouramtane,Marie-Laure Perrin,Marie-Laure Perrin

doi:10.3390/cancers11101474

Abstract

Photodynamic therapy (PDT) using porphyrins has been approved for treatment of several solid tumors due to the generation of cytotoxic reactive oxygen species (ROS). However, low physiological solubility and lack of selectivity towards tumor sites are the main limitations of their clinical use. Nanoparticles are able to spontaneously accumulate in solid tumors through an enhanced permeability and retention (EPR) effect due to leaky vasculature, poor lymphatic drainage, and increased vessel permeability. Herein, we proved the added value of nanoparticle vectorization on anticancer efficacy and tumor-targeting by 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (TPPOH). Using 80 nm silica nanoparticles (SNPs) coated with xylan-TPPOH conjugate (TPPOH-X), we first showed very significant phototoxic effects of TPPOH-X SNPs mediated by post-PDT ROS generation and stronger cell uptake in human colorectal cancer cell lines compared to free TPPOH. Additionally, we demonstrated apoptotic cell death induced by TPPOH-X SNPs-PDT and the interest of autophagy inhibition to increase anticancer efficacy. Finally, we highlighted in vivo, without toxicity, elevated anticancer efficacy of TPPOH-X SNPs through improvement of tumor-targeting compared to a free TPPOH protocol. Our work demonstrated for the first time the strong anticancer efficacy of TPPOH in vitro and in vivo and the merit of SNPs vectorization.

Highlights

In 2018, colorectal cancer (CRC) was the third most common cancer with 1.8 million cases globally, and the second leading cause of death for oncological reasons with 862,000 deaths [1].The conventional treatment options for patients with CRC are surgery, chemotherapy, and/orCancers 2019, 11, 1474; doi:10.3390/cancers11101474 www.mdpi.com/journal/cancersCancers 2019, 11, 1474 radiotherapy, which has many side effects and long recovery periods
Human CRC cell lines submitted to TPPOH-X silica nanoparticles (SNPs)-Photodynamic therapy (PDT) showed a complete breakdown of intracellular structures. These cells exhibited morphological features such as cell membrane shrinkage, nuclear condensation and formation of phagocytic vesicles, or apoptotic bodies, which are hallmarks of apoptosis. These results demonstrated that TPPOH-X SNPs-PDT induced death of human CRC cell lines through apoptosis
We demonstrated that TPPOH-X SNPs-PDT induced in vitro and in vivo cell death through the apoptosis pathway due to reactive oxygen species (ROS) generation in CRC cell lines

Summary

Introduction

In 2018, colorectal cancer (CRC) was the third most common cancer with 1.8 million cases globally, and the second leading cause of death for oncological reasons with 862,000 deaths [1].The conventional treatment options for patients with CRC are surgery, chemotherapy, and/orCancers 2019, 11, 1474; doi:10.3390/cancers11101474 www.mdpi.com/journal/cancersCancers 2019, 11, 1474 radiotherapy, which has many side effects and long recovery periods. The conventional treatment options for patients with CRC are surgery, chemotherapy, and/or. The increasing resistance of tumor cells toward these novel drugs and persistent side effects due to toxicity on healthy tissues make it imperative to find other methods of CRC therapy [2,3,4,5,6]. Photodynamic therapy (PDT), an alternative cancer treatment, appears to be a promising option [7]. PDT has several advantages including non-invasive therapy, non-cytotoxic molecules without light activation, and site-specific light treatment which decreases the side effects, accelerating the healing process [8,9]. The PS is activated from a ground to an excited state.

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