Review articleAnticancer DOX delivery system based on CNTs: Functionalization, targeting and novel technologies
Graphical abstract
Introduction
Since their discovery in 1991 [1], carbon nanotubes (CNTs) have become one of the most amazing materials of modern science with optical, thermal, mechanical and electrical properties arising from the electronic structure of their surface. These nanomaterials are graphene layers rolled up into seamless cylinders, which are divided into two classes based on the number of layers used: Single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT) (Fig. 1) [[2], [3], [4]].
CNTs have a diameter about 0.4–2 nm for SWCNT and 2–100 nm for MWCNT and their length varies from a few hundred nanometers to several microns [[4], [5], [6]]. CNTs can be produced by electric arc discharge and laser ablation method using the vaporization of graphite targets [7,8]. In addition, they are synthesized using a more applied method of chemical vapor deposition (CVD) by passing a carbon-containing vapor over metal catalysts in a furnace [[9], [10], [11]].
CNTs have versatile and abundant applications due to their extraordinary physical and chemical properties. For example, CNTs have a tensile strength higher than 100 GPa (MWCNT type) and a Young's modulus over 1 TPa (SWCNT and MWCNT type) [[12], [13], [14]], making them as one of the strongest known materials [15,16].
The electrical conductivity of CNTs (106 to 107 Sm−1 for pure CNTs) is in the overall range of metals conductivity (105 to 107 Sm−1), which can be enhanced by increasing the purity of the nanotubes [17,18]. In addition, a thermal conductivity of about 3500 Wm−1 K−1 has been reported for a SWCNT with a length of 2.6 μm and a diameter of 1.7 nm at room temperature [19]. These conductivity features of nanotubes make them suitable for smart electronics [18]. CNTs have a string-like structure (known as a needle-like structure) due to their ultrahigh length-to-diameter ratio. This structure facilitates translocation of CNTs over the plasma membrane into the cytoplasm through an endocytosis-independent mechanism [20].
CNTs have many applications in various industrial and science areas such as materials science, sensors, nanocomposite, as battery electrodes, supercapacitors, microelectronics, energy storage devices, nanoprobes, microelectronics, energy storage devices, etc. [[21], [22], [23], [24], [25], [26], [27], [28]]. In the field of biomedical applications, CNTs have attracted extensive attention with many applications [[29], [30], [31], [32]]. They have been used as biosensors [[33], [34], [35]], substrates for growth of neurons [[36], [37], [38]], in bone tissue engineering [39,40] and tissue engineering [41], gene delivery systems [42,43], targeted cancer therapy [44,45], cancer photothermal therapy [[46], [47], [48], [49]] and drug delivery systems(DDSs) [[50], [51], [52], [53], [54], [55]]
DDSs are designed to modify the pharmacokinetics and biodistribution of their active cargo. In addition, they protect the active drug from degradation and also promote its sustained release within cell by acting as a drug reservoir [56].CNTs have been widely studied as nanocarriers for delivery of drugs and therapeutic agents [2,51,[57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67]]. Two key factors make CNTs suitable candidates as nanocarriers for drug delivery applications. Firstly, the high surface area allows them to attach large amounts of drug and therapeutic molecules onto their surfaces [[67], [68], [69]] and secondly, their high length-to-diameter ratio enables them to penetrate biological membranes and accumulation into intracellular spaces with the enhanced permeation and retention (EPR) effect [[70], [71], [72], [73]]. The production of strong Raman signals [74] and the absorption of the near-infrared(NIR) wavelength are other intrinsic abilities of CNTs, which are significantly important in diagnostic and therapeutic techniques based on CNT-based DDS and targeting systems [47,48]. CNTs exhibit strong resonance Raman scattering due to their unique electronic structure, which makes it possible to detect long-term accumulation of CNT carriers injected into animals in vivo for clinical purposes [75,76]. Alternatively, the heat generated by the absorption of NIR radiation (photothermal effect), which is dependent on the π-conjugated structure of CNTs, can both destroy cancer cells and weaken the π- π interactions between CNT carriers and drugs with aromatic section such as DOX [47,48,77,78]. Moreover, because of their particular physicochemical properties, CNTs have proved safe and efficacious carriers for drug targeting and delivery systems, leading to an increase in the design of the CNT-based delivery systems [54]. There are many reports showing that CNTs are efficient nanocarriers with reduced toxicity, for the delivery of therapeutic agents and drugs, including antimicrobials [79], chemotherapeutic drugs [52,53,68,80], anti-inflammatory agents [81] vaccines [82], small interference ribonucleic acids (siRNA) [83,84] and plasmid DNA gene [42].
This study presents recent progress in the use of CNTs as nanocarriers in DDSs for the delivery of anticancer drug doxorubicin (DOX), highlighting particularly various methods for the functionalization and targeting of CNT-based DDSs loaded with DOX. Moreover, new techniques and technologies in the field of CNT-based DDSs for controlled and targeted DOX delivery to the target sites in vitro and in vivo are reviewed.
Section snippets
Anticancer DOX delivery based on CNTs
Owing to its unique conjugated structure, CNT as a versatile nanocarrier is able to form strong π-π stacking interactions with many drugs and therapeutic agents that have aromatic rings in their structure [52,68,85]. Therefore, π-π stacking interaction is a key parameter in the design of CNT based DDSs [86,87].This drug-loaded CNT can pass through biological barriers and release the drug to the target sites. DOX is a potent anticancer, chemotherapy drug that is extensively used to treat various
Functionalization of CNTs for DOX delivery
It is imperative to be carried out the purification of as-synthesized CNTs. As-synthesized CNTs are usually accompanied by some impurities such as amorphous carbon, metal catalyst particles, fullerenes, and other carbon nanoparticles. Another reason for purification of synthesized CNTs lies in the fact that biological applications like drug delivery require high purity of the materials [101]. CNTs for DOX delivery systems are generally purified in a concentrated H2SO4/HNO3 mixture under
DOX loading and unloading on CNT-based DDSs
CNTs are able to load a large amount of DOX drug on their surface due to high surface area, while maintaining stability of the DOX-CNTs complex and the activity of the DOX in various biological media [92]. DOX with aromatic moieties can be attached to the graphitic sidewalls of CNTs via π-stacking. This physical adhesive does not damage the structure of DOX or CNTs [77]. The strength of the non-covalent binding between DOX and CNT is dependent on the environment pH. At a low pH, the amino group
Targeting and imaging agents
Attaching a targeting agent on the surface of CNTs can result in a selective release of DOX to the target site with a much higher efficacy than free DOX [56,67,92]. In addition, targeted CNTs loaded with drug due to their sustained release can reduce drug-related side effects in animal models and clinical studies [92]. Also, the use of targeting agents in the design of CNT-based DDSs reduces DOX amount for use in cancer treatment compared to non-targeted CNT based carriers because of the high
Novel techniques and technologies in CNT-based DOX delivery systems
Given that research on the DOX release from the DOX loaded CNT-based DDSs to target cancer depends on living systems, issues such as the systemic toxicity of DOX drug and its carrier as well as the efficacy of drug on target sites, are of particular importance. DOX delivery efficiency and DOX release control will also be addressed in the next step. Therefore, in order to employ the DOX loaded CNT-based DDSs for clinical purposes in the treatment of many cancers, various methods and techniques
CNT cellular uptake
One of the most important advantages of CNTs is their ability to translocate through plasma membrane, allowing their use as nanocarrier for the delivery of various therapeutic agents into different cell types. The needle-like shape and high aspect ratio of the nanotubes make it possible for them to penetrate the plasma membrane and enter the cytoplasm. However, the data obtained to date indicate that a single mechanism alone cannot be responsible for the internalization and cellular uptake of
Challenges
Despite the promising reports above related to excellent performance of CNTs as the core of a CNT-based DDS for in vitro and in vivo DOX release, the toxicity issue of CNTs in the biological systems remains unresolved to this date.
The production of CNTs with current technologies is associated with various metallic and carbonaceous impurities. The distribution of these impurities into biological systems causes significant toxicity to tissues and cells. Although the current methods are able to
Conclusions and perspectives
The rich surface chemistry of CNTs allows many functions, including functionalizing agents, targeting molecules, imaging agents, drugs, and other therapeutic agents to be introduced on the same nanotube. In addition, drugs with conjugated aromatic ring systems, for instance DOX, can physically be adsorbed onto the surface of CNTs via non-covalent π stacking interactions, which makes CNT-DOX construct as the basis of CNT-based DDSs. CNT carriers loaded with DOX can pass through the cell membrane
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
This work supported by the “Iran National Science Foundation: INSF” and the” University of Zanjan. Also, the present work has been done in line with Alireza Yaghoubi PhD thesis.
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