Multi-stimuli responsive mesoporous silica-coated carbon nanoparticles for chemo-photothermal therapy of tumor
Graphical abstract
Introduction
Currently, chemotherapy remains one of the most common ways to treat cancer. However, the application of chemotherapy was impeded thanks to the side effects to normal tissues, inadequate dosage and multidrug resistance to tumor sites [1,2]. Photothermal therapy (PTT), as a promising cancer therapy method, has caused widespread attention due to the high lethality to tumors and harmlessness to human body [3,4]. Local hyperthermia generated by NIR resonant materials via converting light into heat can not only directly kill tumor cells and promote drug release, but also enhance the sensitivity of chemotherapy and cellular uptake of drugs by changing the permeability of cell membrane to improve treatment efficacy [5,6]. However, it has been reported that utilization of PTT alone has no obvious tumor ablating effects due to the inadequate penetration depth of light [7]. To satisfy the treatment demands that individual chemotherapy or PTT alone cannot meet, combination therapy has been exploited to overcome the embarrassment. Under such circumstances, multifunctional chemo-photothermal synergistic treatment nanosized drug delivery platforms have attracted universally focus owing to the advantages of increasing drug accumulation at tumor sites, improving the antitumor effect and minimizing the invasive damage to healthy tissues [[8], [9], [10]].
To better treat tumors, various approaches have been reported in recent years [11,12]. Mesoporous nanomaterials were widely employed in drug delivery due to their unique ascendancies, such as large specific surface area and pore volume, adjustable aperture and size and high drug loading [13]. In our previous work, we have constructed a visible nanoplatform by grafting carbon dots (CDPEI) on the hollow mesoporous carbon (HMC) nanoparticles to realize the aim of chemo-photothermal synergistic therapy against tumors. However, the fluorescence of the CDPEI is quenched when being attached to the HMC, while it is visible only when the CDPEI breaking away from HMC, it is not good for observing the entire drug delivery process. A strategy was proposed to solve the florescence quenching problem caused by mesoporous carbon nanoparticles (MCN) in vitro by coating polymers on MCN to shield the π-π stacking interactions between carriers and quantum dots, however, the payload of drug was reduced after coating of polymers [13]. Thus, it is necessary to further explore a new strategy to address the florescence quenching problem and remain the high drug loading simultaneously.
Inspired by the intrinsic biocompatibility [14] and easily modified surface property [15] of mesoporous silica nanoparticles (MSN) and its application in cancer chemo-photothermal combination therapy by encapsulating NIR absorbing materials (e.g., gold nanorods [16,17], grapheme nanosheets [1], Pd@Ag [18], copper chalcogenides [19] and carbon materials [8,20,21]). Integrating the merits of both mesoporous silica and carbon as drug delivery vehicles to fabricate a nanocomposite via coating mesoporous silica on mesoporous carbon (MCN@Si) was proposed [22]. We suppose that the florescence quenching problem resulted by MCN could be solved after coating silica layer and the payload of drug could increase. Besides, MCN@Si nanocomposite possesses some unique advantages as the drug carrier: (1) higher hydrophilicity, dispersity and biocompatibility, (2) higher drug loading or co-delivery due to the dual-pore structure, (3) easily functionalized surface, (4) being able to realize track, and (5) outstanding photothermal conversion ability. In light of the mentioned virtues, MCN@Si could be utilized to construct an intelligent nanoplatform for chemo-photothermal synergistic treatment of tumors.
Preventing premature drug release is the key to improve therapy efficacy and reduce system toxicity. Plenty of gatekeepers, such as polymers [[23], [24], [25]], metal materials [26,27], biomacromolecules [28], inorganic nanoparticles [29] and quantum dots (QDs) [30,31], have been conjugated or coated on inorganic carriers. Among them, carbon dots (CDs) as a gatekeeper to inhibit drug leakage have received great attention by virtue of their superior feature, for instance, appropriate and controllable diameter, good water solubility and biocompatibility [32]. In addition, CDs have been applied in bio-imaging due to their fabulous luminescent property and photo-stability [[33], [34], [35]]. Therefore, CDs could be used as a cap to block drug and a fluorescent probe to monitor the drug delivery and release process in vitro. Certainly, drug release at tumor sites is also essential for therapy. The glutathione (GSH) concentration of tumor cells cytoplasm is at least 4 times than that of normal cells which provides a design idea to make drug precisely release at tumor sites [36,37]. Thus, redox-sensitive disulfide bonds, which can be cleaved under high GSH concentration [[38], [39], [40]], were selected to link carriers and CDs to make sure drugs could be released at the tumor site.
Herein, we proposed to address the fluorescence quenching problem caused by MCN via wrapping mesoporous silica on MCN, and fabricated a novel dual-porous MCN@Si with high drug loading and excellent photothermal conversion ability as drug carrier. Antitumor drug DOX was selected as a model drug to be encapsulated in the channels of carriers. DOX could rapidly release from carriers after arriving in tumor sites since the protonation effect of DOX in low pH environment. Therefore, a rational redox-, NIR- and pH- stimuli-responsive controlled-release nanodelivey system (DOX/MCN@Si-CDs) with ability to monitor system delivery process in vitro was established for the chemo-photothermal synergistic treatment of tumors (Scheme 1). After the nanoparticles reach in tumor by EPR-mediated targeting effect and are internalized by tumor cells, disulfide bonds are quickly broken and then gatekeepers CDs fall off the surface of the carrier to allow drug release. Moreover, acid environment and NIR irradiation also help drug release to produce synergistic effects. All the results indicated that DOX/MCN@Si-CDs is a promising visible nanoplatform and possesses excellent chemo-photothermal therapy synergistic therapy in vitro and in vivo with low system toxicity.
Section snippets
Experimental reagents
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 98 %), N-hydroxysuccinimide (NHS, 98 %), 3-Aminopropyltriethoxysilane (APTES), doxorubicin hydrochloride (DOX, 98 %), glutathione (GSH, 98 %), tetraethoxysilane (TEOS), cetyltrimethylammonium bromide (CTAB), polyethyleneimine (PEI), 3-mercaptopropyltrimethoxysilane (MPTMS, 95 %), 3-mercaptopropionic acid (98 %), 5, 5′-Dithiobis-(2-nitrobenzoic acid) (DTNB) and 2, 2′-Dithiodipyridine (Py-SS-Py, 98 %) were provided by Aladdin
Preparation and characterization of MCN-COOH and MCN@Si
The MCN were prepared according to the previous study [42]. In order to obtain a carrier with hydrophilic and easily functionalized surface, the wet oxidation method was adopted to prepare MCN-COOH. The morphology of MCN-COOH was characterized by TEM. As shown in Fig. 1A, MCN-COOH with an average diameter of 95 nm had a mesoporous structure and exhibited a uniform and monodispersed spherical morphology. To synthesize a vector with more easy surface modification, favorable biocompatibility, high
Conclusion
In a word, considering the merits of both mesoporous carbon and mesoporous silica, a novel mesoporous silica-coated mesoporous carbon nanocomposite (MCN@Si) was fabricated to build a drug delivery system (DOX/MCN@Si-CDs) with multi-stimuli responsive controlled release and thermal-chemotherapy for tumor treatment. Compared with MCN-COOH, MCN@Si possesses high loading capacity and high photothermal conversion capacity (η = 30.5 %) which could be used as an excellent drug carrier and photothermal
Declaration of Competing Interest
The authors declared that there is no conflict of interest.
Acknowledgement
This work was supported by National Natural Science Foundation of China Nos. 81603058 and81473165).
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