Effects of the Molecular Weight of Hyaluronic Acid in a Carbon Nanotube Drug Delivery Conjugate

Silvia Arpicco,Alessandro Barge,Paola Milla,Franco Dosio,Daniele Zonari,Loredana Serpe,Silvia Giordani,Michał Bartkowski,Barbara Stella

doi:10.3389/fchem.2020.578008

Silvia Arpicco, Alessandro Barge + Show 7 more

Open Access

https://doi.org/10.3389/fchem.2020.578008

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Abstract

Hyaluronic acid (HA) is a ubiquitous biopolymer involved in many pathophysiological roles. One HA receptor, the cluster of differentiation CD44 protein, is often overexpressed in tumor cells. As such, HA has attracted considerable interest in the development of drug delivery formulations, given its intrinsic targetability toward CD44 overexpressing cells. The present study is focused on examining the correlation of HA molecular weight with its targetability properties. A library of conjugates obtained by linking the amino group of the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) to the carboxylic residues of HA of different molecular weight (6.4, 17, 51, 200, and 1,500 kDa) were synthesized and fully characterized. The HA-DMPE conjugates were then used to non-covalently functionalize the highly hydrophobic single-walled carbon nanotubes (CNT), and further encapsulate the anticancer drug doxorubicin (DOX). Our results show that the complexes DOX/CNT/HA-DMPE maintain very good and stable dispersibility. Drug release studies indicated a pH-responsive release of the drug from the nanocarrier. Cell viability tests demonstrated that all HA modified CNTs have good biocompatibility, and specific targeting toward cells overexpressing the CD44 receptor. Among all the molecular weights tested, the 200 kDa HA showed the highest increase in cellular uptake and cytotoxic activity. All these promising attributes make CNT/HA200-DMPE a “smart” platform for tumor-targeted delivery of anticancer agents.

Highlights

Hyaluronic acid (HA) is a linear polysaccharide consisting of repeating β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine disaccharide units
The linkage between phospholipids and HA was obtained through amide formation mediated by the water-soluble carbodiimide derivative EDAC (Figure 1)
The phospholipid amino group is randomly linked to the carboxylic residues of HA, as previously reported (Surace et al, 2009; Cosco et al, 2017)

Summary

Introduction

Hyaluronic acid (HA) is a linear polysaccharide consisting of repeating β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine disaccharide units. The disaccharide unit can repeat thousands of times, achieving high molecular weights (MW) of over 5,000 kDa. HA represents the main component of the extracellular matrix and is ubiquitously distributed in vertebrate tissues. Predominantly in the skin, the total HA is about 15 g, with a rapid daily turnover achieved through the activity of hyaluronidases (Stern, 2004). A large amount of HA in the extracellular matrix of the central nervous system contributes to brain hydration (Perkins et al, 2017). In the lungs, it contributes to the mechanical

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