Full Length Articleβ-Cyclodextrin grafted polypyrrole magnetic nanocomposites toward the targeted delivery and controlled release of doxorubicin
Graphical abstract
Introduction
Currently, chemotherapy is an effective tool in cancer treatment. However, the therapeutic efficiency of traditional chemotherapy drugs, like doxorubicin and paclitaxel, is always restricted, due to nonspecific absorption and premature degradation [1]. To avoid the side effect of anti-cancer drugs, the novel targeted drug delivery systems (DDS) with high drug efficacy, desired stimuli-responsive controlled release and marked biocompatibility are of the important concern.
In recent years, various carrier materials such as mesoporous silica [2], carbon nanotubes [3], magnetic nanoparticles (MNPs) [4] etc., have been introduced for intracellular delivery of chemotherapeutics. Among them, Fe3O4 magnetic nanoparticles (Fe3O4 NPs) have attracted considerable attention because of their larger magnetic moments, excellent superparamagnetism, and biological degradability. And more importantly, they could target drug at tumor sites with external magnetic field under physiological conditions. However, Fe3O4 NPs get agglomerated easily and can be oxidized in biological media due to their high surface area and magnetic dipole interaction [5], which limits their further application. The chemical modification is an effective method for the improvement of the stability of Fe3O4 NPs. Very commonly used modifiers involve polymer [6], micelle [7], organic molecules[8] etc. With the development of research, attractive drug delivery systems have the tendency toward dual-targeting function based on immobilization of targeting molecule on magnetic nanoparticles [9]. To date, including but not limited to antibodies [10], aptamers [11], and various ligands [12] have been used as targeting molecules. One favorable candidate with targeting function is hyaluronan (HA) which is able to bind cluster of differentiation 44 (CD44) receptors with high affinity. CD44 receptors are over expressed in lymphoma, colorectal, melanoma, breast and lung tumor cells [13].
To realize controllable drug release, choosing suitable modifying materials is essential. Polypyrrole (PPy), an NIR-light-absorbing polymer, has been used to modify Fe3O4 NPs for NIR-triggered drug release with enhanced antitumor efficacy in vivo. In particular, PPy is also applied in photothermal therapy (PTT) due to its strong NIR absorbance, good biocompatibility and outstanding stability [13], [14], [15]. Wang et al. [14] showed that DOX release from the Fe3O4@PPy-PEG-DOX nanocomposites could be triggered by an external NIR laser. Subsequently, DOX-loaded monodispersed spindle-like polypyrrole hollow nanocapsules was developed by Wang et al. for pH-sensitive and NIR light-enhanced release of DOX under acidic pH [16].
β-Cyclodextrin (β-CD) as the modifying agent with a hydrophilic exterior and a hydrophobic interior is able to form inclusion complexes with size suitable molecules. Magnetic nanoparticles-graft-β-CD NPs for drug loading of 5-fluorouracil [17], curcumin [18], docetaxel [19], ketoprofen [20] and doxorubicin [8] have been reported involving in effective drug encapsulation and controlled release. These findings trigger our research interests to engineer PPy-based nanocarriers for simultaneous photothermal therapy and controlled drug delivery in one.
In the present work, we designed a novel combination strategy for the fabrication of PPy-coated magnetic nanocomposites modified with β-CD and HA (Fe3O4@PPy-HA-CD). As illustrated by Scheme 1, the drug carrier is composed of two steps. First, HA-conjugated Fe3O4@PPy NPs were prepared using a facile surfactant-directed chemical polymerization method and then ethylenediamine derivative of β-CD (en-β-CD) was grafted onto the surface of Fe3O4@PPy-HA via an amidation reaction. Afterward, a common anticancer drug doxorubicin was loaded into the cavity of en-β-CD by host-guest interaction. The DOX-loaded Fe3O4@PPy-HA-CD NPs exhibited both NIR-triggered sustainable release in the acid environment of tumors, as will be demonstrated in detail below. Moreover, the cell uptake and cytotoxicity were investigated on Hep-G2 cells to confirm the HA mediated targeted therapeutic efficacy of Fe3O4@PPy-HA-CD/DOX complexes in vitro.
Section snippets
Materials
FeCl3·6H2O (AR) and FeCl2·4H2O (AR) were procured from Tianjin Reagent Factory. Ammonia (25–28% NH3 in water solution), N-hydroxysuccinimide (NHS), pyrrole (98%), hyaluronic acid sodium salt (95%), 3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC), and sodium dodecyl sulfate (SDS, ACS) were purchased from Aladdin Chemical Reagent Co. Ltd. China. β-CD was from Guangdong Reagent Factory and re-crystallized twice from water and dried in vacuum prior to use. Doxorubicin hydrochloride (DOX)
Characterization of Fe3O4@PPy-HA-CD nanocomposites
The whole fabrication process of Fe3O4@PPy-HA-CD was illustrated in Scheme 1. Bare Fe3O4 NPs were prepared by a chemical coprecipitation method. Subsequently, the as-prepared Fe3O4 NPs were encapsulated with PPy layer, polymerized from pyrrole monomers through oxidative polymerization using Fe3+ as the catalyst and HA as the stabilizer. Meanwhile, due to charge–charge interactions between negatively charged carboxyl groups of HA molecules and positively charged polypyrroles, HA was incorporated
Conclusions
In summary, a novel multifunctional drug delivery platform based on Fe3O4@PPy core-shell structured nanocomposites was facilely constructed and exhibited satisfactory properties such as high drug loading content, good biocompatibility, NIR-triggered drug release behavior from in vitro experiments. HA modification of the shell provided the molecule targeting, and the iron oxide nanoparticles core can also be utilized to magnetic-guided drug delivery. Both MTT assay and cellular uptake assays
Acknowledgements
This work was supported by the National Natural Science Foundation of China (21475080 and 21575084) and the Shanxi Province Hundred Talents Project.
References (33)
- et al.
Targeted therapy of SMMC-7721 liver cancer in vitro and in vivo with carbon nanotubes based drug delivery system
J. Colloid Interface Sci.
(2012) - et al.
Magnetite-loaded fluorine-containing polymeric micelles for magnetic resonance imaging and drug delivery
Biomaterials
(2012) - et al.
Targeted delivery and pH-responsive release of stereoisomeric anti-cancer drugs using β-cyclodextrin assemblied Fe3O4 nanoparticles
Appl. Surf. Sci.
(2015) - et al.
Magnetic core-shell hybrid nanoparticles for receptor targeted anti-cancer therapy and magnetic resonance imaging
J. Colloid Interface Sci.
(2017) - et al.
Epirubicin loaded super paramagnetic iron oxide nanoparticle-aptamer bioconjugate for combined colon cancer therapy and imaging in vivo
Eur. J. Pharm. Sci.
(2013) - et al.
Folate-mediated delivery of macromolecular anticancer therapeutic agents
Adv. Drug Deliv. Rev.
(2002) - et al.
Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation
J. Controlled Release
(2016) - et al.
Conjugation of methotrexate onto dedoped Fe3O4/PPy nanospheres to produce magnetic targeting drug with controlled drug release and targeting specificity for HeLa cells
Synth. Met.
(2015) - et al.
Characterization and evaluation of a folic acid receptor-targeted cyclodextrin complex as an anticancer drug delivery system
Eur. J. Pharm. Sci.
(2016) - et al.
Synthesis and characterization of novel drug delivery system using modified chitosan based hydrogel grafted with cyclodextrin
Chem. Eng. J.
(2016)
Magnetic properties of novel superparamagnetic iron oxidenanoclusters and their peculiarity under annealing treatment
Appl. Surf. Sci.
Core-shell superparamagnetic iron oxide nanoparticle (SPION) clusters: TEM micrograph analysis, particle design and shape analysis
Ceram. Int.
Diffusion coefficient of paracetamol in achitosan hydrogel
Mater. Lett.
Development of next generation macromolecular drugs based on the EPR effect: challenges and pitfalls
Expert Opin. Drug Deliv.
Charge-reversal APTES-modified mesoporous silica nanoparticles with high drug loading and release controllability
ACS Appl. Mater. Interfaces
Targeted drug delivery with polymers and magnetic nanoparticles: covalent and noncovalent approaches, release control, and clinical studies
Chem. Rev.
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