Doxorubicin-conjugated core–shell magnetite nanoparticles as dual-targeting carriers for anticancer drug delivery
Graphical abstract
Introduction
In recent years, there has been an increasing impetus for targeting therapeutic agents to specific cells of the diseased site with the aim to improve their efficiency and/or minimize the undesirable side effects [1]. Among the numerous approaches used for this purpose, targeting based on magnetic properties using magnetic nanoparticles, mainly magnetite (Fe3O4)-based nanoparticles, is widely considered as a promising targeted delivery system due to its distinct advantages, mainly including a well-documented biosafety, ease of preparation and handling, the possibility of controlling the characteristics of the nanocarriers, availability, affordability of the materials needed for this procedure, and more importantly, possibility of targeting the drug(s) of interest to the desired location within the host body by using an external magnetic field. Furthermore, core–shell magnetic nanoparticles have attracted much attention due to their multifunctional properties such as small size, superparamagnetism and low toxicity [2], [3]. Silica-coated Fe3O4–nanoparticles are one of the most extensively used Fe3O4–nanoparticles which possess very high specific surface with abundant Si–OH or Si–NH2 groups with ability to react with proper functional groups [4], [5].
Besides the above mentioned advantages, there are a number of drawbacks against the widespread use of Fe3O4 nanoparticles for targeted drug delivery systems. Firstly, due to the high surface-area-to-volume ratio characteristic of such nanoparticles, they tend to aggregate and form clusters with low magnetization properties. Secondly, it is shown that a major part of the naked Fe3O4 nanoparticles are rapidly cleared from blood circulation by the reticular endothelial system (RES) before they could be able to reach the intended target site, thereby being localized in the RES organs, mainly liver [5], [1]. To address these issues, one approach is to encapsulate Fe3O4 nanoparticles within biodegradable and/or biocompatible polymers [6]. Additionally, polymer-encapsulated Fe3O4 nanoparticles can be designed in order to provide further diverse and desirable functionality to enable conjugation to the drug of interest [7]. It is believed that the use of a trigger alone as a targeting function cannot ensure complete localization of drug at the site of interest. Therefore, to enhance targeting characteristic of a carrier, it represents a well-established approach to use more than one trigger to direct carrier to the specific site. Such carriers are generally referred to as dual targeting drug delivery systems [8]. Zhang and Misra [7] synthesized a novel dual targeted magnetic carrier consisting of magnetic nanoparticles encapsulated within dextran-g-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) co-polymer as a smart thermo-sensitive polymer showing high drug release rate for longer durations specially in acidic pH.
Chitosan, a naturally-derived co-polymer of N-acetyglucosamine and d-glucosamine, has been extensively studied as a biodegradable and biocompatible polymer in drug delivery systems, gene therapy, and membranes for ultrafiltration [9], [10]. It seems that chitosan-encapsulated Fe3O4 nanoparticles would most likely improve magnetite nanoparticles characteristics in terms of biocompatibity and long circulation time. The amino groups on the chitosan structure can also be used for further functionalization with specific components, such as various drugs, targeting agents, or other functional groups. Thus, it seems to be a suitable polymer to modify the Fe3O4 nanoparticles [11]. Feng et al. [12] synthesized monodisperse chitosan/polyacrylic acid/Fe3O4 nanoparticles which could be used for magnetic resonance imaging (MRI). Donadel et al. [13] prepared iron oxide magnetic particles coated with chitosan intended for hyperthermia.
Recently, Shen et al. [14] prepared dual-drug delivery system in which doxorubicin and verapamil were physically loaded into chitosan coated magnetite nanoparticles. The resultant nanoparticles were entrapped into the poly (lactic acid-coglycolicacid) (PLGA) nanoparticles and used as near infrared (NIR) trigger drug delivery system. The anthracycline antibiotic doxorubicin is a widely used anticancer drug in clinical practice for the treatment of a variety of cancers like leukemia, ovarian, prostate, brain cancers, especially late stage breast cancer [15]. Although doxorubicin is one of the most widely used anticancer agents, its application is still limited by its deleterious side effects, including myelosuppression, gastrointestinal toxicity and, more importantly, cardiotoxicity. Drug targeting, therefore, represents an interesting incentive to prevent side effects and increase cytotoxicity of doxorubicin [15], [16]. A number of approaches including chemical conjugation and/or physical entrapment have been employed to target doxorubicin using different carriers such as dendrimers, polymeric nanoparticles, polymer–drug conjugates and micelles [17], [18], [19], [20], [16]. Herein we report the synthesis and in vitro characterization of a dual targeted drug delivery system using a core–shell magnetite nanoparticulate system conjugated with doxorubicin via acid-cleavable imine linkage. To enhance the biocompatibility of the prepared dual targeted carrier and minimize undesirable side effects of doxorubicin and Fe3O4 nanoparticles, conjugated magnetite core–shell nanoparticles were encapsulated within chitosan.
Section snippets
Materials and methods
Ferric chloride hexahydrate (FeCl3·6H2O), ferrous chloride tetrahydrate (FeCl2·4H2O), tetraethylorthosilicate (TEOS), (3-aminopropyl)triethoxysilane(APTES) all were purchased locally from Merck and used as received. Chitosan of molecular weight in the range of 105–3 × 105 g/mol and degree of deacetylation ≥75% was provided from Sigma. Solvents of the highest grade commercially available (Merck) were purchased locally and used without further purification. Doxorubicin hydrochloride was purchased
Results and discussion
In order to enhance the therapeutic efficacy of doxorubicin, while minimizing its life-threatening side effects, a dual targeting drug delivery system was designed and prepared. The carrier composed of magnetite nanoparticles in order to direct the drug toward tumor sites with the aid of an external magnetic field. On the other hand, the drug was conjugated via acid-cleavable linker to the nanostructures with the ability to release the conjugated drug in the low-physiologic pH environments (pH
Conclusion
Synthesis of dual-targeting core–shell nanostructures composed of magnetite (Fe3O4) nanoparticles conjugated with doxorubicin via pH sensitive linkage with characteristics of substantially longer drug release time in circulation compared to the similar physically-entrapped drug, as well as capability to deliver the drug specifically to the tumor-bearing tissues based on both the external magnetic localization and pH-sensitive drug cleavage from the nanoparticles was achieved in this study. To
Acknowledgments
We are most grateful for the continuing financial support of this research project by Zanjan University of Medical Sciences and University of Zanjan.
References (29)
- et al.
Acta Biomater.
(2008) - et al.
Pharmacol. Res.
(2010) - et al.
Nano Today
(2007) - et al.
Carbohydr. Polym.
(2011) - et al.
Acta Biomater.
(2007) - et al.
J. Control. Release
(2001) - et al.
Colloids Surf. B
(2012) - et al.
Adv. Powder Technol.
(2010) - et al.
J. Alloy Compd.
(2009) - et al.
Mater. Sci. Eng. C
(2008)