Elsevier

Biomaterials

Volume 33, Issue 5, February 2012, Pages 1682-1687
Biomaterials

A magnetically guided anti-cancer drug delivery system using porous FePt capsules

https://doi.org/10.1016/j.biomaterials.2011.11.016Get rights and content

Abstract

Magnetic carriers with efficient loading, delivery, and release of drugs are required for magnetically guided drug delivery system (DDS) as the potential cancer therapy. The present article describes the fabrication of porous FePt capsules approximately 340 nm in diameter with large pores of 20 nm in an ultrathin shell of 10 nm and demonstrates their application to a magnetically guided DDS in vitro. An aqueous anti-cancer drug is easily introduced in the hollow space of the capsules without external stimuli and released to cancer cells on cue through the magnetic shell composed of an ordered-alloy FePt network structure, which exhibits superparamagnetic features at approximately body temperature. The drug-loaded magnetic capsules coated with a lipid membrane are efficiently guided to the cancer cells within 15 min using a NdFeB magnet (0.2 T), and more than 70% of the cancer cells are destroyed.

Introduction

A drug delivery system (DDS) has been developed which affords control over the accumulation of drugs at target lesions. In particular, for the treatment of cancer, the increment of the antitumor agent’s concentration in the tumor tissues along with a non-accumulation in normal tissues is important. However, it is difficult to control the delivery and release of drugs at tumor sites by conventional passively targeted DDS. Active-targeted DDS has the potential to effectively exert therapeutic effects on tumors with both pinpoint precision and minimal invasion. Among such systems, the use of magnetic materials as the drug carrier is one of the most promising approaches, because magnetic drug carriers can be attracted and manipulated by the gradient of an external magnetic field [1], [2], [3]

There are two types of magnetic carriers. These are: 1) porous magnetic capsules filled with a drug and 2) magnetic particle(s) adsorbing the drug on the outside of the structure [4]. The former method is superior to the latter as a method in terms of easy drug release along with the avoidance of any loss by elution in the bloodstream. This property is advantageous for the design of a DDS, because the majority of intravenously injectable medicines are hydrophilic. Moreover, while it is relatively easy to encapsulate water-soluble drugs in the hollow magnetic capsule through its porous wall, the latter method requires a surface modification of the magnetic particles in order to adsorb water-soluble drugs, because their surfaces are hydrophobic.

Therefore, hollow magnetic capsules are more widely applicable as a magnetic carrier of therapeutic agents, compared with solid magnetic particles. In terms of such magnetic capsules, hollow microspheres with a Fe3O4 shell have been already reported [5], [6], [7], [8], [9], [10], [11], [12], [13]. This shell was too thick (>20 nm) to afford sufficient internal space, and the pore size was also too small to either fill or release drugs. Therefore, it is anticipated that the Fe3O4 hollow microspheres are of little practical use for magnetically guided DDS. Alternatively, a sophisticated hollow microsphere no larger than 400 nm [14], [15], which is composed of a magnetic shell thinner than 10 nm with nanopores suitable for drug release, is needed to increase the drug loading capability and to decrease the amount of magnetic components which is required.

In our previous paper, we demonstrated that ferromagnetic inorganic-organic composite capsules were successfully fabricated by growing the ordered-alloy FePt nanoparticles on silica template particles with an anionic surface that had been modified with a cationic polymer poly(diaryldimethylammonium chloride) (PDDA) and sequentially dissolving the silica template particles from the FePt-nanoparticles/PDDA/silica composite particles in a NaOH aqueous solution [16]. The FePt-nanoparticles/PDDA magnetic capsule has great potential as a magnetic drug carrier, because the magnetic capsule has a nanometer-thick shell of approximately 5 nm. However, it is difficult to encapsulate drugs with a molecular size larger than the pore size (5 nm) in the magnetic capsules. The pore size is determined by the gaps among the FePt nanoparticles. Although we made an attempt to increase the pore size by decreasing FePt nanoparticle amount growing on the template particles in order to load drugs of larger molecular size, the FePt-nanoparticles/PDDA composites collapsed upon the removal of the template particles. The decrease of the FePt nanoparticles resulted in a decrease of the mechanical strength of the magnetic capsules, because the strength of their three-dimensional structure depended on the binding force between PDDA and the FePt nanoparticles; thus, magnetic capsules with a pore larger than 5 nm could not be obtained. For these reasons, we decided to fabricate mechanically stronger FePt hollow capsules by fusion of the FePt nanoparticles.

In the present article, we demonstrate the fabrication of porous FePt network magnetic capsules and their applicability to magnetically guided DDS. The porous FePt network capsules were obtained by hydrothermal treatment of the FePt-nanoparticles/PDDA/silica composite particles that we previously reported. Hydrothermal treatments are typically used for nanoparticle synthesis, especially the crystallization of metal particles and increasing the particle size [17], [18]. In our hydrothermal process, we obtained a three-dimensional capsule-structure by thermal fusion of FePt nanoparticles on silica templates by using a method of aqueous dispersion of the composite particles. The hydrothermal treatment effectively worked, not only on a thermal fusion of the FePt nanoparticles, but also on dissolving the silica template particles, resulting in the formation of magnetic hollow capsules composed of a FePt network shell with an approximate pore size of 20 nm. We then further investigated the magnetically guided antitumor effects of drug-containing FePt network capsules on lung and gastric cancer cells.

FePt network hollow capsules with a porous nanometer-thick shell and lipid-coated magnetic capsules containing an aqueous anti-cancer drug were fabricated as shown in Fig. 1. First, negatively charged silica template particles were modified with a cationic polymer PDDA in deionized water. FePt nanoparticles of approximately 10 nm in diameter were selectively grown on the surface of the PDDA-modified silica particles by a polyol-reduction method, resulting in the formation of FePt-nanoparticles/PDDA/silica composite particles [16]. The composite particles were subjected to annealing in supercritical water [18]. The porous magnetic capsules with a FePt network shell were then obtained by thermal fusion of the FePt nanoparticles and removal of the silica template particles during the hydrothermal treatment. The hollow internal spaces were filled with the aqueous anti-cancer drug and the surface of the drug-loaded magnetic capsules was sealed with lipid membrane to avoid any leakage of the agents. The capsular size and morphology is readily adjusted by changing the size of the silica template particles.

Section snippets

Synthesis of FePt-nanoparticles/PDDA/silica composite particles

FePt-nanoparticles/PDDA/silica composite particles were synthesized the following method [16]. PDDA-modified silica particles were fabricated by mixing an aqueous dispersion of amorphous silica particles (Nippon Shokubai, KE-P30, average diameter: 320 nm) with an aqueous solution of PDDA (Sigma-Aldrich, weight-average molecular weight (Mw): <100 kg/mol). The PDDA-modified silica particles were dispersed in tetraethylene glycol (TEG). Then FePt nanoparticles were synthesized in the presence of

Morphology of FePt-nanoparticles/PDDA/silica composite particles

FePt nanoparticles were synthesized at a temperature of 503 K in the presence of PDDA-modified silica particles. Fig. 2(a) shows a transmission electron microscope (TEM) image of the FePt-nanoparticles/PDDA/silica composite particles. FePt nanoparticles of 10 nm or less in size were grown on PDDA-modified silica template particles, and in the process the coverage of the silica template particles can be controlled by the amount of the precursors and the concentration of PDDA [16]

Formation, morphology, structure and magnetic property of FePt network capsule

Hollow capsules

Conclusions

We report the fabrication of magnetic capsules of approximately 340 nm in diameter which have an ultrathin shell and large pores of 20 nm, and have demonstrated their utility in magnetically guided DDS. The 10 nm-thick magnetic shell is composed of an ordered-alloy FePt network structure. The FePt network capsules were fabricated through thermal fusion of the FePt nanoparticles and dissolution of silica template particles by hydrothermal treatment of the FePt-nanoparticles/PDDA/silica composite

References (24)

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This work was supported by an Industrial Technology Research Grant, Program 08C46049a from the New Energy and Industrial Technology Development Organization (NEDO) of Japan, by Grant-in Aid for Scientific Research #20310077 from Japan Society for the Promotion of Science (JSPS) and by a Funding Program for Next Generation World-Leading Researchers LS114 from JSPS.

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