Nanosized magnetofluorescent Fe3O4–curcumin conjugate for multimodal monitoring and drug targeting

doi:10.1016/j.colsurfa.2010.09.011

Colloids and Surfaces A: Physicochemical and Engineering Aspects

Volume 371, Issues 1–3, 20 November 2010, Pages 104-112

The authors dedicate this publication to Prof. Acad. Nguyen Van Hieu, father of Vietnam Nanotechnology, in celebration of his 72nd birthday.

https://doi.org/10.1016/j.colsurfa.2010.09.011 Get rights and content

Abstract

Magnetic drug targeting, the targeting of a drug conjugated with a magnetic material under the action of external magnetic field constitutes an important drug delivery system. This paper describes the strategy to design a multifunctional, nanosized magnetofluorescent water-dispersible Fe₃O₄–curcumin conjugate and its multiple ability to label, target and treat the tumor cells. The conjugate possesses magnetic nano Fe₃O₄ core, chitosan (CS) or oleic acid (OL) as outer shell and entrapped curcumin (Cur), serving dual function of naturally autofluorescent dye as well as anti-tumor model drug, delivered to the cells with the help of macrophage (Cur possesses anti-oxidant, anti-inflammatory and anti-tumor ability). Fe₃O₄–Cur conjugate exhibited a high loading cellular uptake which was clearly visualized dually by Fluorescence Microscope, Laser scanning confocal microscope (LSCM) as well as magnetization measurement (Physical properties measurement systems, PPMS). Preliminary magnetic resonance imaging (MRI) study also showed a clear contrast enhancement by using Fe₃O₄–Cur conjugate.

Graphical abstract

Research highlights

▶ Simple chemical conjugation route to functionalize Fe₃O₄ surface by chitosan or oleic acid and incorporate natural fluorescent dye and anticancer drug of curcumin onto these magnetic nanoparticles was proposed. ▶ The conjugates showed to be a good candidate of multimodal nanoprobe for in situ fluorescent (LSCM) as well as magnetic (PPMS, MR) imaging. ▶ It may be the first study reported about the original characteristics and application of Curcumin in cellular imaging and drug targeting.

Introduction

Magnetic nanoparticles (MNPs) with an appropriate surface modification have been widely used for numerous biomedical applications [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. In nanomedicine, MNPs can be used either in diagnostic (magnetic resonance imaging contrast agents and magnetic enhanced enzyme-linked immunoassay) and in therapeutic (drug delivery and hyperthermia) applications, for which it is required that the MNPs have high magnetization value, small size, and special surface coating by a non-toxic, biocompatible layer.

Surface coatings provide a steric barrier to prevent nanoparticle agglomeration and avoid opsonization (the uptake by the reticuloendothelial system (RES), thus shortens circulation time in the blood and MNP's ability to target the drug to specific sites and reduce side effects). In addition, these coatings provide a means to tailor the surface properties of MNPs such as surface charge and chemical functionality. Some critical aspects with regard to polymeric coatings that may affect the performance of an MNP system include the nature of the chemical structure of the polymer (e.g. hydrophilicity/hydrophobicity, biodegradation), its molecular weight and conformation, the manner in which the polymer is anchored or attached (e.g. electrostatic, covalent bonding) and the degree of particle surface coverage. A variety of natural polymers/surfactants have been evaluated for this puropse. The most widely utilized and successful coatings, in terms of in vivo applications, are dextran, PEG, chitosan (CS) and oleic acid (OL) [16], [17], [18], [19].

Monocytes and macrophages are phagocytes, acting in both non-specific defense (innate immunity) as well as to help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. Their role is to phagocytise (engulf and then digest) cellular debris and pathogens either as stationary or as mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen [20]. Hence, they can be used as potential vehicles for transport of MNPs into the core of tumor cells.

In this study, we do not take upon ourselves to introduce novel coating materials but emphasize our efforts on designing stable conjugates for their application in vivo, namely for imaging and drug targeting. Because MNPs that have a highly hydrophilic surface resist well to opsonizations and therefore are cleared slowly, our choice was based on well known hydrophilic chitosan (CS) and oleic acid (OL), rationalizing on the fact that CS is an excellent biocompatible biodegradable polymer with a high content of amino groups (–NH₂) that makes possible complexation reaction with metal ions in solution and other chemical reactions with the purpose of improving polymeric surface modification and drug delivery. As for OL, a wide spread substance in nature, it is intensively investigated in different aspects of its biological actions owing to the absence of its chronic adverse health effects and toxicity.

The aim of this work is first to fabricate Fe₃O₄–Cur conjugates with diameter < 500 nm, coated by CS or OL, and then to use macrophage as a vehicle to carry these conjugates into tumor. Being non-toxic, autofluorescent and anti-cancerous, Cur would play a role of multifunctional probe in Fe₃O₄–Cur uptake visualization/monitoring by two complementary methods of fluorescent and magnetic imaging. To our best knowledge, it may be the first study reported about the original characteristics and application of Cur in cellular imaging and drug targeting.

Section snippets

Chemical and biochemical materials

All the chemicals were of reagent grade used without further purification. Ferric chloride hexa-hydrate (FeCl₃·6H₂O), ferrous chloride tetra-hydrate (FeCl₂·4H₂O), NaOH, NH₄OH (26% of ammonia), oleic acid (C₁₇H₃₃COOH) were purchased from Aldrich. Chitosan (MW = 400.000, DA = 70%) was purchased from Nha Trang Aquatic Institute (Vietnam) and re-characterized by viscometry and IR measurements at our laboratory. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione) was from Institute

Size and structural characterizations of conjugates

DLS and TEM/FE-SEM data indicated that hydrodynamic diameters of OLF; CSF; OLF–Cur and CSF–Cur are ca. 10 nm, 30 nm, 300 nm and 500 nm, respectively (Fig. 1). First, the significant increase in size of OLF–Cur and CSF–Cur, compared to those of OLF and CSF respectively can be associated with the core- shell expansion after Cur loading. Second, although being in satisfactory agreement, slight discrepancy of TEM/FE-SEM data compared to DLS result can be understood if taking into account the fact that

Conclusion

This paper presents a simple chemical conjugation route to functionalize Fe₃O₄ surface and incorporate Cur, a natural fluorescent dye and anti-cancer drug onto these magnetic nanoparticles, and its demonstration as a potentially multimodal probe for fluorescence as well as magnetic (PPMS, MR) observation. Ability of phagocytosis of the OLF–Cur and CSF–Cur by either human monocytes-derived or mouse primary peritoneal macrophages was clearly observed by magnetic and fluorescent methods. The

Acknowledgments

The authors are grateful for the financial support for this work by application oriented basic research project (2009–2012, code 01/09/HD-DTDL), Korean–Vietnamese joint research project (2010–2011, code 59/2615/2010/HD-NDT). The authors would like to acknowledge their indebtedness to Prof. Nguyen Quang Liem and all members of IMS-VAST key laboratory for providing lab's facilities; Dr. N.T.K.Thanh (Davy-Faraday Research Laboratory, U.K) for her reading to early version of this manuscript.

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¹: These authors equally contributed to this paper.

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Nanosized magnetofluorescent Fe3O4–curcumin conjugate for multimodal monitoring and drug targeting

Abstract

Graphical abstract

Research highlights

Introduction

Section snippets

Chemical and biochemical materials

Size and structural characterizations of conjugates

Conclusion

Acknowledgments

Biology and Medicine

Biology and Medicine

Acta Biomaterialia

International Journal of Pharmaceutics

Journal of Alloys and Compounds

Journal of Lipid Research

Materials Science and Engineering: C

Food Chemistry

Journal of Colloid and Interface Science

Magnetic nanoparticles: synthesis, protection, functionalization, and application

Angewandte Chemie International Edition