Functionalized organic nanotubes with highly tunable crosslinking site density for mechanical enhancement and pH-controlled drug release of nanocomposite hydrogels [original]

Dongwei Wu, Wuxiao Ding, Naohiro Kameta

Functionalized organic nanotubes with highly

tunable crosslinking site density for mechanical

enhancement and pH-controlled drug release of

nanocomposite hydrogels

Open Access via institutional repository of Technische Universität Berlin

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Journal article | Accepted version

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publication; also known as: Author’s Accepted Manuscript (AAM), Final Draft, Postprint)

This version is available at

https://doi.org/10.14279/depositonce-21399

Citation details

Wu, D., Ding, W., & Kameta, N. (2021). Functionalized organic nanotubes with highly tunable crosslinking site

density for mechanical enhancement and pH-controlled drug release of nanocomposite hydrogels. In Polymer

Journal (Vol. 54, Issue 1, pp. 67–78). Springer Science and Business Media LLC.

https://doi.org/10.1038/s41428-021-00556-1.

This work is protected by copyright and/or related rights. You are free to use this work in any way permitted by

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Functionalized organic nanotubes with highly tunable

crosslinking site density for mechanical enhancement and

pH-controlled drug release of nanocomposite hydrogels

Dongwei Wu,a,b,c Wuxiao Ding,a,* Naohiro Kametaa

a Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology,

Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan

b Department of Applied Biochemistry, Institute of Biotechnology, 4/3-2, Technische Universität

Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany

c Department of Materials Science and Engineering, Jinan University, Guangzhou 510632, China

Abstract:

Organic nanotubes (ONTs) have attracted growing attention in biomedical

applications because of their unique inner and outer nanospaces. Here, ONTs were

functionalized and hybridized with poly(ethylene glycol) (PEG) to construct

nanocomposite hydrogels, with the aim of enhancing their mechanical strength and

controlling their release properties. These nanoengineered hydrogels have 4-fold

greater mechanical stiffness than unreinforced hydrogels and show a more stable

network. The effects of ONT concentration and crosslinkable site density on the

hydrogel mechanical properties were systematically assessed. Moreover, the

incorporation of ONTs enabled simple and effective post-loading of the model drug, as

well as a sustained drug release profile from the hydrogels. These results provide a

novel method to generate mechanically enhanced nanocomposite hydrogels with

improved drug delivery in an easy, efficient and tunable manner, and the obtained

nanocomposite hydrogels may have potential applications in drug delivery and other

related bioapplications.

Keywords:

Drug delivery / Nanocomposite / Organic nanotubes / Reinforced hydrogels

1. Introduction

Hydrogels are interpenetrating three-dimensional polymeric networks with a high

water content that can closely mimic native tissue microenvironments1, 2. They have

found significant applications, such as in drug delivery and regenerative medicine, in

recent decades3, 4. However, the use of hydrogels in biomedical fields remain severely

hampered due to their limited mechanical properties and trade-off between drug loading

capacity and sustained release 5-7. Therefore, numerous efforts have been made to

improve the mechanical performances of hydrogels, such as with double-network

hydrogels8, topological hydrogels9 and nanocomposite hydrogels10-12. Notably,

nanocomposite hydrogels incorporating different types of nanostructures have attracted

increasing attention in biomedical fields 13.

Among the various types of nanostructures used in nanocomposite hydrogels,

tubular nanostructures have been demonstrated to address the shortcomings of

conventional hydrogels, as incorporated nanotubes that are either covalently or

noncovalently bound to the hydrogel network can not only mechanically reinforce the

matrix but also lead to improved drug loading and release behaviors. Moreover,

nanotubes, owing to their high aspect ratio and one-dimensional nanospace as a drug

reservoir, endow composite hydrogels with a favorable drug-loading capacity and

stability to effectively control drug release14, 15. For example, it was reported that a

nanohybrid silk hydrogel with single-walled carbon nanotubes showed significantly

enhanced mechanical strength and sustained doxorubicin release16. Ribeiro et al. used

halloysite aluminosilicate nanotubes and gelatin methacryloyl to formulate composite

hydrogels as an injectable drug delivery system for dental infection ablation17. Many

studies have been carried out to investigate the mechanical reinforcement and drug

delivery enhancement properties of nanotube composite hydrogels. However,

controlling the mechanical properties is desirable so that the hydrogel can match the

properties of the target tissue. To this end, currently, most nanocomposite hydrogels

require changing the polymer concentration or quantity of incorporated nanoparticles

that adjust the crosslinking density and mechanical behaviors. Nevertheless, these

changes will also influence the microstructure, drug loading capacity and release

behavior of the composite hydrogels.

In addition to inorganic nanotubes, organic nanotubes (ONTs) commonly self-

assemble from polymers and small amphiphilic molecules, providing an attractive

platform for diverse biomedical applications by utilizing their unique one-dimensional

nanospace and exterior outer surfaces18-22. To explore their biomedical applications,

ONTs have been further fabricated into hydrogels as platforms for DNA delivery and

protein refolding23, 24, utilizing noncovalent bonding with the hydrogel. Herein, we

propose a simple and efficient way to produce crosslinkable ONTs with variable

numbers of crosslinkable sites on the surface, which were further incorporated into

poly(ethylene glycol) dimethylacrylate (PEGDMA) to generate nanocomposite

hydrogels (Fig. 1). It is expected that the mechanical performance of these

nanoengineered hydrogels can be easily tailored by manipulating the crosslinkable site

density on the nanotube surface as well as the concentration of reinforcing nanotubes.

We also predict that the introduction of ONTs can affect the physical stability of the

hybrid hydrogels and drug encapsulation/release profiles. Highly adjustable ONTs can

be used to tune the mechanical properties and drug loading and release capacities of

hydrogels, particularly to decouple their direct association. The method in this study

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