Elsevier

Journal of Controlled Release

Volume 327, 10 November 2020, Pages 198-224
Journal of Controlled Release

Review article
Anticancer DOX delivery system based on CNTs: Functionalization, targeting and novel technologies

https://doi.org/10.1016/j.jconrel.2020.08.001Get rights and content

Highlights

  • Functionalizing and targeting CNTs for designing DOX loaded CNT-based DDSs

  • In vitro and in vivo studies on DOX delivery with CNT-based DDSs for cancer therapy

  • Novel techniques and technologies for delivery of DOX using CNT-based DDSs

  • Current challenges and future perspectives on CNT-based DDSs

Abstract

Carbon nanotubes (CNTs) have attracted significant attention as promising nanocarriers in the field of drug delivery, due to their properties such as ultrahigh length-to-diameter ratio and excellent cellular uptake. The unique conjugated structure of CNTs suits their surface for π-π stacking interactions with many drugs and therapeutic molecules with aromatic rings, including anthracyclines. Doxorubicin(DOX), as an anthracycline anticancer drug, can be easily adsorbed onto the surface of CNTs via π-π stacking, making the CNTs-DOX conjugation, as the basis of CNT-based drug delivery systems(DDSs) for the delivery of DOX to cancer cells. In this review article, the delivery of DOX using various CNT-based DDSs is presented. In addition, the current progress of in vitro and in vivo research on the design of DOX loaded CNT-based DDSs, including the functionalization and targeting of CNTs, has been reviewed, focusing particularly on emerging technologies and techniques to date for DOX delivery by CNT-based DDSs.

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.

References (173)

  • L. Meng et al.

    Single walled carbon nanotubes as drug delivery vehicles: targeting doxorubicin to tumors

    Biomaterials

    (2012)
  • M. Habibizadeh et al.

    Preparation and characterization of PEGylated multiwall carbon nanotubes as covalently conjugated and non-covalent drug carrier: a comparative study

    Mater. Sci. Eng. C

    (2017)
  • Z. Ji et al.

    Targeted therapy of SMMC-7721 liver cancer invitro and invivo with carbon nanotubes based drug delivery system

    J. Colloid Interface Sci.

    (2012)
  • S. Boncel et al.

    Liberation of drugs from multi-wall carbon nanotube carriers

    J. Control. Release

    (2013)
  • P.M. Costa et al.

    Functionalised carbon nanotubes: from intracellular uptake and cell-related toxicity to systemic brain delivery

    J. Control. Release

    (2016)
  • M. Foldvari et al.

    Carbon nanotubes as functional excipients for nanomedicines: II. Drug delivery and biocompatibility issues

    Nanomedicine

    (2008)
  • C. Klumpp et al.

    Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics

    Biochim. Biophys. Acta

    (2006)
  • S. Merum et al.

    Functionalized carbon nanotubes in bio-world: applications, limitations and future directions

    Mater. Sci. Eng. B

    (2017)
  • S. Peretz et al.

    Carbon nanotubes as nanocarriers in medicine

    Curr. Opin. Colloid Interface Sci.

    (2012)
  • S.K. Vashist et al.

    Delivery of drugs and biomolecules using carbon nanotubes

    Carbon

    (2011)
  • B.S. Wong et al.

    Carbon nanotubes for delivery of small molecule drugs

    Adv. Drug Deliv. Rev.

    (2013)
  • S. Mahajan et al.

    Functionalized carbon nanotubes as emerging delivery system for the treatment of cancer

    Int. J. Pharm.

    (2018)
  • X. Zhang et al.

    Targeted delivery and controlled release of doxorubicin to cancer cells using modified single wall carbon nanotubes

    Biomaterials

    (2009)
  • M.S. Dresselhaus et al.

    Raman spectroscopy of carbon nanotubes

    Phys. Rep.

    (2005)
  • S.-T. Yang et al.

    Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice

    Toxicol. Lett.

    (2008)
  • X. Dong et al.

    Thermosensitive hydrogel loaded with chitosan-carbon nanotubes for near infrared light triggered drug delivery

    Colloids Surf. B: Biointerfaces

    (2017)
  • X. Dong et al.

    An innovative MWCNTs/DOX/TC nanosystem for chemo-photothermal combination therapy of cancer

    Nanomedicine: Nanotechnology, Biology and Medicine

    (2017)
  • X. Luo et al.

    Carbon nanotube nanoreservior for controlled release of anti-inflammatory dexamethasone

    Biomaterials

    (2011)
  • N. Nakashima

    Solubilization of single-walled carbon nanotubes with condensed aromatic compounds

    Sci. Technol. Adv. Mater.

    (2006)
  • W.-R. Zhuang et al.

    Applications of π-π stacking interactions in the design of drug-delivery systems

    J. Control. Release

    (2019)
  • N. Fattahi et al.

    Emerging insights on drug delivery by fatty acid mediated synthesis of lipophilic prodrugs as novel nanomedicines

    J. Control. Release

    (2020)
  • A. Gabizon et al.

    Development of liposomal anthracyclines: from basics to clinical applications

    J. Control. Release

    (1998)
  • E. Heister et al.

    Drug loading, dispersion stability, and therapeutic efficacy in targeted drug delivery with carbon nanotubes

    Carbon

    (2012)
  • S. Tang et al.

    Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer

    Biomaterials

    (2014)
  • J. Ren et al.

    The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2

    Biomaterials

    (2012)
  • S. Iijima

    Helical microtubules of graphitic carbon

    Nature

    (1991)
  • N. Sinha et al.

    Carbon nanotubes for biomedical applications

    IEEE Trans. NanoBiosci.

    (2005)
  • S. Iijima et al.

    Single-shell carbon nanotubes of 1-nm diameter

    Nature

    (1993)
  • H.-C. Wu et al.

    Chemistry of carbon nanotubes in biomedical applications

    J. Mater. Chem.

    (2010)
  • C. Journet et al.

    Large-scale production of single-walled carbon nanotubes by the electric-arc technique

    Nature

    (1997)
  • C.D. Scott et al.

    Growth mechanisms for single-wall carbon nanotubes in a laser-ablation process

    Appl. Phys. A

    (2001)
  • H. Dai

    Carbon nanotubes: synthesis, integration, and properties

    Acc. Chem. Res.

    (2002)
  • Z. Huang et al.

    Growth of highly oriented carbon nanotubes by plasma-enhanced hot filament chemical vapor deposition

    Appl. Phys. Lett.

    (1998)
  • W. Li et al.

    Large-scale synthesis of aligned carbon nanotubes

    Science

    (1996)
  • Q. Zhao et al.

    Ultimate strength of carbon nanotubes: a theoretical study

    Phys. Rev. B

    (2002)
  • D. Zhao et al.

    Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity

    Clin. Cancer Res.

    (2011)
  • B. Peng et al.

    Measurements of near-ultimate strength for multiwalled carbon nanotubes and irradiation-induced crosslinking improvements

    Nat. Nanotechnol.

    (2008)
  • R. Zhang et al.

    Controlled synthesis of ultralong carbon nanotubes with perfect structures and extraordinary properties

    Acc. Chem. Res.

    (2017)
  • Y. Bai et al.

    Carbon nanotube bundles with tensile strength over 80 GPa

    Nat. Nanotechnol.

    (2018)
  • A. Lekawa-Raus et al.

    Electrical properties of carbon nanotube based fibers and their future use in electrical wiring

    Adv. Funct. Mater.

    (2014)
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