Biohydrogels with magnetic nanoparticles as crosslinker: Characteristics and potential use for controlled antitumor drug-delivery

Abstract

Hybrid magnetic hydrogels are of interest for applications in biomedical science as controlled drug-delivery systems. We have developed a strategy to obtain novel hybrid hydrogels with magnetic nanoparticles (NPs) of CoFe₂O₃ and Fe₃O₄ as crosslinker agents of carboxymethylcellulose (CMC) or hyaluronic acid (HYAL) polymers and we have tested these systems for controlled doxorubicin release. The magnetic NPs are functionalized with (3-aminopropyl)trimethoxysilane (APTMS) in order to introduce amino groups on the surface. The amino coating is determined and quantified by standard Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy methods, and by cyclic voltammetry, a novel approach that permits us to look at the solution properties of the functionalized NPs. The gel formation involves the creation of an amide bond between the carboxylic groups of CMC or HYAL and the amine groups of functionalized NPs, which work as crosslinking agents of the polymer chains. The hybrid hydrogels are chemically and morphologically characterized. The rheological and the water uptake properties of the hydrogels are also investigated. Under the application of an alternating magnetic field, the CMC–HYAL hybrid hydrogel previously loaded with doxorubicin shows a drug release greater than that showed by the CMC–HYAL hydrogel crosslinked with 1,3-diaminopropane. In conclusion, the presence of magnetic NPs makes the synthesized hybrid hydrogels suitable for application as a drug-delivery system by means of alternating magnetic fields.

Introduction

Nanobiotechnology offers great opportunities for discovering new biomaterials and new applications in biomedicine. For instance, nanoscale magnetic materials have been used for the treatment of malignant tumors. When exposed to a high-frequency magnetic field, magnetic nanoparticles (NPs) generate heat through the oscillation of their magnetic moments, inducing tumor regression [1], [2], [3].

A recent new approach consists of combining magnetic NPs with drugs in order to produce a single entity conferring multiple functions, which hopefully will improve the efficacy and reduce the side effects of chemotherapy. Once at the target site the drug is released from the carrier, creating a local concentration in the tumor tissue [4], [5].

Nevertheless, due to the low quantity of drug that can be coated on the surface of the magnetic NPs it is necessary to inject a high concentration of NPs for treatment, with a potential systemic toxic effect [6].

Recently NPs of magnetic metal oxides have been incorporated into hydrogel matrix by mixing the NPs with a preformed hydrogel or by adding the NPs during the gel formation process [7], [8]. In this way the hybrid hydrogel can be manipulated by an external magnetic force and deliver a large quantity of the drug. This strategy of incorporation has the limitation that the NPs are only physically incorporated within the hydrogel. The consequence of such physical incorporation is that a continuous release of the NPs from the hydrogel matrix to the human environment may occur, thus providing the same potential effects of accumulation and perhaps toxicity in the tissue to which the hydrogel is applied [6].

In order to overcome these problems we have developed hybrid magnetic NP hydrogels that represent an effective matrix for the transport and the controlled release of a large amount of active ingredients without displaying any dispersion of potentially toxic inorganic magnetic NPs into the human environment. The magnetic NPs are used as agents for crosslinking the polymer chains, and therefore bind to the latter by covalent bonds, thus creating a three-dimensional structure, i.e. a gel [9], [10]. The amount of NP can be varied to tune the physicochemical and mechanical properties of the hydrogel. The presence of a polysaccharide as the organic component of the hybrid material makes the hydrogel injectable near the target, reducing drug wastage to a minimum. One of the main advantages of this nanocomposite hydrogel consists in the higher drug dose that can be delivered to the target by a lower amount of NPs. The hydrogels will be loaded with antitumor drugs and the kinetics of drug release will be determined under the effect of an alternating magnetic field [11].

An advantage of the magnetic properties of the hydrogel lies in the possibility of guiding the hydrogel loaded with the drug to a specific therapeutic site by applying an external static magnetic field, thus ensuring a level of drug that prevents the absorption thereof by tissues that are not involved in its action.