Regular ArticleFluorescent carbon dot modified mesoporous silica nanocarriers for redox-responsive controlled drug delivery and bioimaging
Graphical abstract
Introduction
Cancer has been a major public health problem worldwide for centuries and cancer-related mortality is increasing dramatically [1], [2], [3]. Current cancer treatments such as chemotherapy affect many parts of the body, leading to severe side-effects due to nonspecific interactions and premature leakage of chemotherapeutic drugs [4], [5], [6]. In order to reduce these side-effects and improve the therapeutic efficacy, the use of targeted drug delivery systems (DDSs) have received considerable attention for cancer treatment in the past few decades. However, targeted DDSs still have some limitations owing to the premature leaking of therapeutic drugs prior to reaching their specific target site. Therefore, there is a pressing need to develop an ideal DDS to deliver cytotoxic drugs to tumor cells without premature leakage and release therapeutic drugs rapidly after being taken up by tumor cells [7]. Recently, stimuli-responsive drug delivery systems (DDSs) have attracted increasing attention since they can encapsulate drugs effectively and avoid unwanted drug leakage during the drug delivery process.
Among the various nanocarriers explored, mesoporous silica nanoparticles (MSNs) with a pore diameter of 2–50 nm have unique advantages as drug carriers for stimuli-responsive DDS, such as a high surface area and large pore volume, a well-defined pore structure, an adjustable pore size, good biocompatibility and an easily functionalized surface [8]. In this regard, various MSNs based stimuli-responsive DDS involve various gatekeepers, such as biomacromolecules [9], polymers [10], macrocyclic compounds [11] and inorganic nanoparticles [12] with diverse stimuli, including pH-, redox potential-, temperature- and enzyme-responsiveness [9]. Among the various stimuli-responsive DDS, redox-responsive systems have received a great deal of attention, especially for cancer therapy. In addition, the redox potential has become a popular stimulus due to the marked difference in the concentration of glutathione (GSH) between the extracellular fluids (10 μM) and intracellular fluids (1–10 mM) [13], [14]. Moreover, the cytosolic GSH concentration in many tumor cells is at least 3-fold higher than those in normal cells [15]. Hence, we have developed a redox-responsive MSNs to achieve site-specific drug delivery.
As a new kind of fluorescent nanomaterial, carbon dots (CDs) have attracted a great deal of attention recently due to their great potential in biological imaging/labeling and sensor design [16]. Compared with traditional heavy-metal based quantum dots, these functional CDs exhibit excellent photo-stability, good water solubility and excellent biocompatibility [17]. Moreover, CDs can be anchored to the entrance of MSNs to control the on-demand drug release since their diameter size ranges from 2 nm to 10 nm. Positively charged MSNs can aggregate markedly and be eliminated rapidly from the circulation owing to the strong interactions with serum components while, negatively charged nanoparticles have the capacity to prolong the blood circulation time during biomedical applications [18], [19].
Based on the above theories, poly(acrylic acid) (PAA), a polyanion polymer, was used as the carbon source to prepare carboxyl-abundant CDPAA by the hydrothermal method. The negatively charged CDPAA were anchored to the openings of the terminal amino group of MSNs containing the disulfide bonds through an amidation reaction and were used as gatekeepers for trapping the drugs within the pores. When a high concentration of GSH was added to the release medium, the disulfide bonds between the CDPAA and MSNs carriers were cleaved, separating the gatekeepers from the MSNs. Carboxyl-abundant CDPAA was chosen for three reasons: (1) CDPAA is biocompatible and its size below 6 nm allows it to block the outlets of MSNs; (2) fluorescent CDPAA could serve as an imaging agent during the transport process; (3) the negatively charged CDPAA has the ability to prolong the circulation time and increase the biocompatibility and physiological stability of MSNs when administered intravenously [17].
In the present work, carboxyl-abundant carbon dots (CDPAA) with a diameter of 3 nm were prepared by hydrothermal polymerization method. MSNs-SS-CDPAA nanocarriers were developed and found to have great potential for redox-responsive drug release at tumor sites and real-time imaging to monitor the cellular behavior during cancer treatment, where the CDPAA was grafted onto the surface of MSNs via disulfide bonds as described in Scheme 1. Doxorubicin (DOX) was used as a model drug to evaluate the redox-responsive drug release of MSNs-SS-CDPAA. Also, the redox-responsive release mechanism was studied by measuring the Zeta change of MSNs-SS-CDPAA and the supernatant fluorescence intensity in the presence or absence of GSH. Stability and hemolytic assays were used to evaluate the biocompatibility of MSNs-SS-CDPAA. CLSM was used to evaluate the fluorescence and location of the nanocomposites with regard to A549 cells. Furthermore, MTT assay was used to estimate the therapeutic effect of DOX-loaded MSNs-SS-CDPAA. In a word, this MSNs-SS-CDPAA not only served as a drug delivery system to realize controlled drug delivery but is also promising for monitoring the cellular real-time imaging of carriers during cancer treatment.
Section snippets
Materials
Tetraethoxysilane (TEOS), 3-mercaptopropyltrimethoxysilane (MPTMS, 95%), cetyltrimethylammoniumbromide (CTAB), cysteamine hydrochloride, 2,2′-dipyridyl disulfide, poly(acrylic acid) (PAA, Mw = 2000), glutathione (GSH), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) and doxorubicin hydrochloride (DOX) were obtained from Aladdin Chemical Inc. (Shanghai, China). Cell culture medium dulbecco’s modified eagle medium (DMEM), trypsin-EDTA solution (0.25%),
Preparation and characterization of CDPAA
The synthetic procedure for CDPAA is illustrated in Scheme 2. The PAA solution was first pretreated with 1 M APS for 1 h to obtain oxygen-rich material. Then the starting solution obtained was transferred to a hydrothermal autoclave and heated at 180 °C for 10 h. Finally, the larger carbon particles were removed by centrifugation and the supernatant was dialyzed against deionized water and freeze-dried to obtain fluorescent CDPAA. As can been seen from Fig. 1, the CDPAA without the addition of APS
Conclusions
In summary, carboxyl-abundant carbon dots (CDPAA) with a diameter of 3 nm were prepared by a hydrothermal polymerizing method. The carboxyl-abundant CDPAA were attached to the outlet of the MSNs by disulfide bonds and served as the gatekeepers to entrap drug molecules within the mesopores and the fluorescent marker tracked the carrier behavior during cancer treatment. The DOX loaded MSNs-SS-CDPAA/DOX had a relatively high drug loading up to 13.1%. The in vitro release results indicated that the
Disclosures
We have no conflicts of interest.
Acknowledgements
This work was supported by National Basic Research Program of China (973 Program) (No. 2015CB932100), National Natural Science Foundation of China (No. 81473165) and the Liaoning Provincial Key Laboratory of Drug Preparation Design & Evaluation of Liaoning Provincial Education Department (No. LZ2015068).
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2021, Chemical Engineering JournalCitation Excerpt :In addition, methods such as impregnation method [103] and ultrasonic method [104] have also been proven to introduce CDs into the pore channels of mesoporous SiO2. In the design of drug delivery nanocarriers, CDs can be grafted to the pore openings of mesoporous silica via chemical bonds or electrostatic interactions to serve as gatekeeper to prevent premature drug release [105–107]. Much work is devoted to coupling CDs with porous metallic compounds, hoping to show better performance or expand other applications based on the original through synergistic effects.