PEGylated Chitosan Nanoparticles Encapsulating Ascorbic Acid and Oxaliplatin Exhibit Dramatic Apoptotic Effects against Breast Cancer Cells.

Sherif Ashraf Fahmy,Hassan Mohamed El-Said Azzazy,Asmaa A Mandour,Asmaa Ramzy,Udo Bakowsky,Soad Nasr,Anwar Abdelnaser

doi:10.3390/pharmaceutics14020407

Sherif Ashraf Fahmy, Hassan Mohamed El-Said Azzazy + Show 5 more

Open Access

https://doi.org/10.3390/pharmaceutics14020407

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Abstract

This study aims to design a pH-responsive dual-loaded nanosystem based on PEGylated chitosan nanoparticles loaded with ascorbic acid (AA) and oxaliplatin (OX) for the effective treatment of breast cancer. In this regard, non-PEGylated and PEGylated chitosan nanoparticles (CS NPs) loaded with either ascorbic acid (AA), oxaliplatin (OX), or dual-loaded with AA-OX were fabricated using the ionotropic gelation method. The hydrodynamic diameters of the fabricated AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs were 157.20 ± 2.40, 188.10 ± 9.70, and 261.10 ± 9.19 nm, respectively. While the hydrodynamic diameters of the designed AA/PEG-CS NPs, OX/PEG-CS NPs, and AA-OX/PEG-CS NPs were 152.20 ± 2.40, 156.60 ± 4.82, and 176.00 ± 4.21 nm, respectively. The ζ-potential of the prepared nanoparticles demonstrated high positive surface charges of +22.02 ± 1.50, +22.58 ± 1.85 and +40.4 ± 2.71 mV for AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs, respectively. The ζ-potential of the PEGylated CS NPs was reduced owing to the shielding of the positive charges by the PEG chains. Additionally, all the prepared nanoparticles exhibited high entrapment efficiencies (EE%) and spherical-shaped morphology. The chemical features of the prepared nanoparticles were investigated using Fourier transform infrared (FTIR) spectroscopy. Release studies showed the capability of the prepared non-PEGylated and PEGylated chitosan NPs to release their cargo in the acidic environment of cancer tissue (pH 5.5). Furthermore, the AA/CS NPs, AA/PEG-CS NPs, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs and AA-OX/PEG-CS NPs exhibited remarkable cytotoxic activities against breast adenocarcinoma (MCF-7) cells with IC50 values of 44.87 ± 11.49, 23.3 ± 3.73, 23.88 ± 6.29, 17.98 ± 3.99, 18.69 ± 2.22, and 7.5 ± 0.69 µg/mL, respectively; as compared to free AA and OX (IC50 of 150.80 ± 26.50 and 147.70 ± 63.91 µg/mL, respectively). Additionally, treatment of MCF-7 cells with IC50 concentrations of AA, AA/CS NPs, AA/PEG-CS NPs, OX, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs or AA-OX/PEG-CS NPs increased the percentages of early apoptotic cells to 5.28%, 9.53%, 11.20%, 5.27%, 13.80%, 8.43%, 2.32%, and 10.10%, respectively, and increased the percentages of late apoptotic cells to 0.98%, 0.37%, 2.41%, 2.06%, 0.97%, 9.66%, 56%, and 81.50%, respectively. These results clearly indicate that PEGylation enhances the apoptotic effect of AA and OX alone, in addition to potentiating the apoptotic effect of AA and OX when combined on MCF-7 cells. In conclusion, PEGylated chitosan nanoparticles encapsulating AA, OX, or AA and OX represent an effective formula for induction of apoptosis in MCF-7 cells.

Highlights

Breast cancer is the most common cancer among newly diagnosed cancers worldwide and ranks second in cancer-related deaths among women [1]
The diameters of all prepared nanoparticles were found to lie in the range between 150−300 nm previously reported for different nanosystems encapsulating anticancer drugs
Our results demonstrated that none of the tested concentrations of the blank NPs had any significant effect on MCF-7 cellular viability, eliminating the possibility that the effect of encapsulated ascorbic acid (AA) or OX is due to the cytotoxic effects of the blank NPs alone on MCF-7 cells (Figure 5I,J)

Summary

Introduction

Breast cancer is the most common cancer among newly diagnosed cancers worldwide and ranks second in cancer-related deaths among women [1]. Several anticancer drugs have been introduced, breast cancer remains one of the leading causes of cancerrelated deaths [1]. Platinum-based anticancer drugs (PBDs) are powerful broad-spectrum antitumor treatments effective against many solid tumors, including breast cancer. Cisplatin [cisdiammine-(dichloro)platinum(II)] is a first-generation platinum-based complex that was granted the US Food and Drug Administration (FDA) approval in the late ’70s. Hundreds of PBDs have been synthesized and entered clinical trials to enhance the anticancer activities and minimize toxic effects (including nephrotoxicity, ematogenesis, and resistance) compared to cisplatin. From these developed PBDs, only carboplatin and oxaliplatin have been approved by FDA for cancer treatment [2–5]

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