Bottom-up synthesis of carbon nanoparticles with higher doxorubicin efficacy
Graphical abstract
Introduction
Nanoparticle technology is an attractive field at the forefront of research and plays important roles in medicine, agriculture and electronics. Nanoparticles have wide applications in medicinal fields as nanocarriers for drug delivery and agents for multifunctional diagnosis, for example [1], [2]. Recently, a new class of carbon nanomaterials, including nanodiamonds [3] and fluorescent carbon nanoparticles (CNPs) [4], have been widely investigated due to their high hydrophilicity, excellent biocompatibility, good cell permeability, high photostability and flexibility in surface modification as a result of the presence of different functional groups (carboxyl, hydroxyl and amino groups), allowing the covalent conjugation of chemotherapeutic and targeting agents [5]. Particularly, fluorescent CNPs have wide applications in areas such as bioimaging, drug delivery [6], [7], [8], [9], [10], sensors [11], [12], [13], [14], optoelectronics [15] and photocatalysis [16]. CNPs are comparable to quantum dots (QDs) and organic dyes [17]. QDs are semiconductor nanostructures with unique optical and electrical properties and great flexibility in their bright and tunable photoluminescence. The blinking effect is a problem with QDs that can be overcome by surface passivation or core-shell formation [18]. QDs are composed of heavy metal precursors such as selenium (Se) and cadmium (Cd), which are toxic at low concentrations in the human body and environment [17], [19]. The use of CNPs in place of QDs might overcome the above mentioned problems. Notably, CNPs have attracted considerable interest, as they offer potential advantages over the other carbon nanomaterials such as carbon nanotubes [20], [21], [22] and Halloysite nanotubes [23], [24] including their small size, simple and inexpensive synthetic routes, high aqueous solubility, their fluorescence property which make them useful for cell imaging and their high cargo loading.
In recent years, much progress has been made in terms of the synthesis, properties and applications of CNPs [17], [25]. The synthesis of CNPs can be classified in two groups: chemical and physical methods. Chemical methods include electrochemical synthesis [26], acidic oxidation [4], [6], [27], thermal/hydrothermal synthesis [28], [29], [30], [31] and microwave/ultrasonic synthesis [12], [17], [28], [32]. Physical methods include arc discharge [33], laser ablation [34] and plasma treatment [35]. Chemical oxidation was commonly used to prepare fluorescent CNPs, which almost always originate from carbon-based nanomaterials. This method is easier, avoids multi-step synthesis and introduces carboxyl and hydroxyl groups on the CNP surface, making the particles negatively charged and hydrophilic. As a result, a variety of fluorescent CNPs have been prepared using food waste [36], carbon nanotubes [37], candle soot [4], carbohydrates (sucrose, glucose) [30], [38], active carbon [32], orange juice, polyphenol [39], [40] and honey [41]. Although numerous synthetic approaches have been developed, those that are eco-friendly and inexpensive are in demand. Furthermore, large-scale synthesis and size-controlled CNPs remain unmet technological needs.
In the field of drug delivery, carbon nanomaterials have gained considerable attention as nano-carriers due to their high surface area, enhanced cellular uptake and easy conjugation with therapeutics [42], [43], [44], [45]. CNPs are spherical and composed of an sp2 carbon core, which can be conjugated with chemotherapeutic drugs and biomolecules through covalent or noncovalent interactions (π–π stacking or electrostatic interactions) and used for in vitro and in vivo drug delivery applications [43], [46]. However, most of the published papers to date on this topic have focused on the optical properties and in vitro biocompatibility of CNPs [47], [48], [49], [50], and few have studied CNPs as delivery agents in depth [9], [51], [52]. Therefore, clinical application remains a challenge.
In this report, we present a green source, “black tea”, as a suitable precursor for the synthesis of CNPs by nitric acid (HNO3) oxidation. This synthesis is simple and economical because of the selection of an inexpensive carbon source. These CNPs are non-toxic; easily synthetized in large-scale production with tunable optical properties up to red spectra, which can be utilized for multiplexing applications; and can efficiently deliver doxorubicin (doxo). The biodistribution, pharmacokinetics (PK) profiles and kinetics of release suggest that CNPs-doxorubicin (Cdoxo) is an optimal drug delivery vector for cancer therapy.
Section snippets
Reagents
Commercially available Brooke Bond Taaza tea was utilized. HNO3 (70%) and sodium hydroxide (NaOH) were purchased from Sigma Aldrich (St. Louis, Missouri, US), doxo was obtained from Accord Healthcare Ltd. (Durham, NC, US) and daunorubicin was purchased from Teva Pharmaceutical Industries Ltd. (Petah Tikva, Israel). All reagents were used as received without further purification. Minisart® syringe filters with a pore size of 0.2 μm were from Sartorius Stedim Biotech (Concord, CA, US), and a
Characterization of CNPs prepared from black tea
The CNPs were prepared from tea by HNO3 oxidation and characterized by UV–Vis absorption spectroscopy, fluorescence spectroscopy, powder XRD, FT-IR spectroscopy and TEM. The zeta potential of the CNPs was also measured at − 16.6 mV, indicating a negative charge on the CNP surface due to the presence of carboxylic groups.
Fig. S1 shows the UV–Vis absorption and fluorescence spectra of CNPs excited at 360 nm. The UV–Vis absorption spectrum contained two distinct peaks: one at 300 nm that could be
Conclusions
In this study, we prepared a new nanovector that can be used to image subcellular compartments such as exosomes with excellent properties for drug delivery [82]. These CNPs can be efficiently loaded with doxo, a widely used chemotherapeutic drug, and exhibit controlled release under acidic conditions, as in the tumour microenvironment. Cdoxo was more effective in vivo than free doxo due to a different PK profile. Hence, a simple and green synthesis starting from tea could produce a tunable and
Funding sources
My First AIRC (No. 1569)
AIRC Special Program Molecular Clinical Oncology, 5 × 1000, (No. 12214)
Italian Ministry of Education MIUR (FIRB prot. RBAP11ETKA)
Competing interests
The authors declare no competing interests.
Acknowledgements
The authors are thankful to My First AIRC (No. 1569); AIRC Special Program Molecular Clinical Oncology, 5 × 1000, (No. 12214); and Italian Ministry of Education MIUR (FIRB prot. RBAP11ETKA) for funding.
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