Encapsulation of Nedaplatin in Novel PEGylated Liposomes Increases Its Cytotoxicity and Genotoxicity against A549 and U2OS Human Cancer Cells.

Salma El-Shafie,Nada Elzahed,Sherif Ashraf Fahmy,Laila Ziko,Andreas Kakarougkas,Tamer Shoeib

doi:10.3390/pharmaceutics12090863

Salma El-Shafie, Nada Elzahed + Show 4 more

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https://doi.org/10.3390/pharmaceutics12090863

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Journal: Pharmaceutics	Publication Date: Sep 10, 2020
Citations: 36	License type: CC BY 4.0

Affiliation: American University in Cairo

Abstract

Following the discovery of cisplatin over 50 years ago, platinum-based drugs have been a widely used and effective form of cancer therapy, primarily causing cell death by inducing DNA damage and triggering apoptosis. However, the dose-limiting toxicity of these drugs has led to the development of second and third generation platinum-based drugs that maintain the cytotoxicity of cisplatin but have a more acceptable side-effect profile. In addition to the creation of new analogs, tumor delivery systems such as liposome encapsulated platinum drugs have been developed and are currently in clinical trials. In this study, we have created the first PEGylated liposomal form of nedaplatin using thin film hydration. Nedaplatin, the main focus of this study, has been exclusively used in Japan for the treatment of non-small cell lung cancer, head and neck, esophageal, bladder, ovarian and cervical cancer. Here, we investigate the cytotoxic and genotoxic effects of free and liposomal nedaplatin on the human non-small cell lung cancer cell line A549 and human osteosarcoma cell line U2OS. We use a variety of assays including ICP MS and the highly sensitive histone H2AX assay to assess drug internalization and to quantify DNA damage induction. Strikingly, we show that by encapsulating nedaplatin in PEGylated liposomes, the platinum uptake cytotoxicity and genotoxicity of nedaplatin was significantly enhanced in both cancer cell lines. Moreover, the enhanced platinum uptake as well as the cytotoxic/antiproliferative effect of liposomal nedaplatin appears to be selective to cancer cells as it was not observed on two noncancer cell lines. This is the first study to develop PEGylated liposomal nedaplatin and to demonstrate the superior cell delivery potential of this product.

Highlights

It is over 50 years since the accidental discovery of cisplatin as an antitumor agent by the Rosenberg laboratory at Michigan State University
Some tumors are inherently resistant to cisplatin whilst others acquire resistance via mechanisms resulting in reduced DNA binding or via up regulation of the DNA damage responses leading to increased cell survival [6,7]
TThhee lliippoossoommaall ffoorrmmuullaattiioonn pprroodduucceedd wwaass sshhoowwnn ttoo hhaavvee 8899%% EEEE ooff NNDD, wwhhiillee zzeettaa ppootteennttiiaallss ooff −−3333..5500 mmvv aanndd−−4400.7.700mmvv((FFigiguurree11))wweerreeoobbttaaiinneeddffoorrtthheeLLNNDDaannddtthheevvooididlilpipoossoommeess,rreessppeeccttiivveellyy. These negative zeta potential values are favorable for increasing liposome stability through the reduction of particle aggregation

Summary

Introduction

It is over 50 years since the accidental discovery of cisplatin as an antitumor agent by the Rosenberg laboratory at Michigan State University. To this day, cisplatin and other platinum-based drugs form the backbone of cancer treatment, with more than 50% of cancer patients receiving chemotherapy using platinum drugs [1]. Platinum-based drugs exert their antitumor effect by binding to DNA and forming DNA adducts. Some tumors are inherently resistant to cisplatin whilst others acquire resistance via mechanisms resulting in reduced DNA binding or via up regulation of the DNA damage responses leading to increased cell survival [6,7]

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