Glycyrrhetinic Acid-Functionalized Mesoporous Silica Nanoparticles for the Co-Delivery of DOX/CPT-PEG for Targeting HepG2 Cells.

Gabriel Martínez-Edo,David Sánchez-García,Salvador Borrós,Cristina Fornaguera

doi:10.3390/pharmaceutics12111048

Gabriel Martínez-Edo, David Sánchez-García + Show 2 more

Open Access

https://doi.org/10.3390/pharmaceutics12111048

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Abstract

A pH-triggered mesoporous silica nanoparticle (MSN)-based nano-vehicle for the dual delivery of doxorubicin (DOX)/camptothecin-PEG (CPT-PEG) has been prepared. To enhance its selectivity, the nanoparticles were decorated with glycyrrhetinic acid (GA) to target HepG2 cells. The highly insoluble CPT was derivatized with a reductive-cleavable PEG chain to improve its loading within the MSN. The preparation of these particles consisted of four steps. First, CPT-PEG was loaded within the pores of the MSN. Then, dihydrazide polyethylene glycol chains were introduced onto the surface of an aldehyde-functionalized MSN by means of a hydrazone bond. Afterwards, DOX was covalently attached to the other end of the dihydrazide polyethylene glycol chains. Finally, the resulting nanoparticles were decorated with GA by formation of an imine bond between the amino group of DOX and a benzaldehyde-GA derivative. The system was stable at physiological conditions and the release of both drugs was negligible. However, at acidic pH, a burst release of DOX and a gradual release of CPT-PEG takes place. GA-decorated drug delivery systems (DDS) selectively internalizes into HepG2. In vitro tests demonstrated that this system shows a great cytotoxicity towards HepG2 cells. Furthermore, glutathione cleavage of CPT prodrug assures the formation of free CPT leading to a synergistic effect in combination with DOX.

Highlights

Hepatocellular carcinoma has become one of the world’s most devastating diseases because of its high morbidity and high mortality [1]
The nanoparticles were decorated with glycyrrhetinic acid (GA) to target HepG2 cells
The major issue associated with the administration of chemotherapeutics is their high toxicity and lack of selectivity leading to systemic toxicity that can be detrimental for the patient quality of life [4]

Summary

Introduction

Hepatocellular carcinoma has become one of the world’s most devastating diseases because of its high morbidity and high mortality [1]. In the last years, mesoporous silica nanoparticles (MSN) have emerged as effective platforms to prepare smart nano-carriers to ferry drugs with precision to the tumors owing to its outstanding properties such as good biocompatibility, easy chemical modification, and high encapsulation capacity [5,6,7,8,9,10,11,12,13,14,15,16] These DDSs accumulate selectively into the tumors thanks to the so-called enhanced permeability retention effect (EPR effect) [13,17]. This feature has been capitalized on the design of selective DDSs and the surface of nanoparticles has been decorated with these ligands to enhance the concentration of the nanocarrier in the tumoral tissue [4,20,21,22]

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