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Over the last decades, when analysing the main causes of human mortality, we are faced with the determining role that cancer plays, being only surpassed by cardiovascular pathologies. Homologous, the statistics provided by the World Cancer Report 2018 [1], estimate that 18.1 million new cases of cancer have been diagnosed and, simultaneously, 9.6 million people have succumbed due to the same pathology. This worrying mortality rate is a consequence of the limitations of conventional therapeutic approaches, namely the low solubility of drugs, their poor pharmacokinetic profile, non-specificity, and brutal side effects, which currently define the majority of contemporary treatments such as radiotherapy, chemotherapy or surgical intervention. Therefore, the present problem gives meaning to the investigation of new and better treatments that maximize the life expectancy and quality of the global population.
The term nanotechnology was first introduced by physicist Richard Feynman, in the famous lecture he conducted in 1959, entitled ‘There´s plenty of room at the bottom’. In this work, Richard Feynman explores the vast potential, both in terms of properties and applications, which could arise from the atomic manipulation of materials. The continuous research and development of this area has been increasingly attracting interest from the scientific community, showing great relevance in future therapeutics.
In this sense and within the scope of this article, nanomaterials, and more specifically carbon nanotubes, appear as therapeutic alternatives, which stand out for their distinct properties, such as the ultra-high aspect ratio, high cargo loading, chemical stability and intracellular bioavailability [2]. These same assets enable the introduction of a new revolutionary methodology, Controlled Drug Delivery, which minimizes premature drug degradation and, simultaneously, sustains drug concentrations within the therapeutic window, culminating in a higher percentage of absorbed active principle and treatment effectiveness.
Structure and Production
Carbon nanotubes (CNTs) were firstly introduced by Lijima and colleagues in 1990, during the process of developing C60 carbon molecules. Regarding the structure of CNTs, these consist of rolled graphene sheets, which acquire a cylindrical configuration, with the ends having an arrangement suchlike the aforementioned C60 molecules [3]. On the other hand, CNTs can be subdivided into two distinct categories, Single-walled CNTs (SWCNTs), which comprise a single sheet of graphene, while Multi-walled CNTs (MWCNTs) are defined by the presence of multiple embedded graphene cylinders, with a spacing of approximately 0.34 nm. Therefore, due to the characteristics of its structures, SWCNTs have a smaller diameter and greater flexibility, whereas MWCNTs exhibit a greater surface area and, consequently, a higher drug loading capacity. As for their dimensions, CNTs have a diameter between 0.4-100 nm and a length that can reach several micrometres. When it comes to chirality, this nanomaterial can present different forms such as zigzag, armchair and chiral [3].
The production of carbon nanotubes can be carried out according to three main techniques, namely arc-discharge, laser ablation and chemical vapor deposition, originating CNTs with different features. The analysis of the literature makes it evident that the CVD method is the most promising due to its simplicity, low cost, process control, energy efficiency, raw materials used, as well as the ability to obtain CNTs with a high degree of precision (diameter, length) and yield. Finally, CNTs must undergo a purification and functionalization process to ensure their suitability for clinical use.
Applications in Cancer therapy: Delivery of anticancer agents
The presented methodology is extremely versatile, where different types of biomolecules have been associated with CNTs, with diverse principles of operation associated (Tumour Cell Vaccines, Gene Therapy), such as peptides, proteins, plasmid DNA, small interference RNA, among others [2].
In the present article, the strategies for therapeutic delivery of anticancer drugs will be discussed, in which a multitude of drugs can be associated with CNTs, such as Carboplatin, Oxaliplatin, Doxorubicin, among others. More specifically, the association of the drug gemcitabine (GEM) is explored, which operates by inhibiting DNA replication to trigger apoptosis of cancer cells. Despite this drug being applied in a wide range of oncological diseases, it presents major limitations due to its rapid metabolism and reduced half-life (17 min), leading to the necessity of implementing a prolonged drug delivery methodology with CNTs. Therefore, SWCNTs were initially purified by acid refluxing with hydrochloric acid and then functionalized through carboxylation, acylation, amination, PEGylation and conjugation with the desired GEM, in order to adapt the nanomaterial to biomedical use. The connection of the GEM to the CNTs was performed according to an ester bond that presents a high degree of sensitivity to changes in pH, in other words, in the presence of a pH below 7.4, the drug will tend to free itself from the respective nanostructure. Considering that the healthy tissue has a pH value of 7.4, while tumour regions have values below 6.8, this justifies the principle of operation of the therapy under study. In addition, these targeted delivery mechanisms will be completed by the Enhanced Permeability Effect, which involves the preferred displacement of nanomaterials to tumour regions, due to the superior dimensions of the blood and lymph vessels in these regions. Finally, in in vitro tests with human lung cancer cell lines (A549) and human pancreatic cancer (MIA PaCa-2), the potential for continued drug release was demonstrated, as shown in Figure 1. Subsequently, in in vivo tests with nude rats, the suppression of significant tumour growth was observed, which then culminated in an increase in average life expectancy of 23 days, with one subject showing complete remission of the tumour, as illustrated in figure 1 [4].
Figure 1 – Tumour volume (on the left) and drug concentration (on the right) across time for CNTs based methodologies and conventional therapeutic approaches [4].
Bibliography:
[1] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA. Cancer J. Clin., vol. 68, no. 6, pp. 394–424, 2018, doi: 10.3322/caac.21492.
[2] A. V. V. V. Ravi Kiran, G. Kusuma Kumari, and P. T. Krishnamurthy, “Carbon nanotubes in drug delivery: Focus on anticancer therapies,” J. Drug Deliv. Sci. Technol., vol. 59, no. June, p. 101892, 2020, doi: 10.1016/j.jddst.2020.101892.
[3] R. Jha, A. Singh, P. K. Sharma, and N. K. Fuloria, “Smart carbon nanotubes for drug delivery system: A comprehensive study,” J. Drug Deliv. Sci. Technol., vol. 58, no. February, p. 101811, 2020, doi: 10.1016/j.jddst.2020.101811.
[4] A. Razzazan, F. Atyabi, B. Kazemi, and R. Dinarvand, “In vivo drug delivery of gemcitabine with PEGylated single-walled carbon nanotubes,” Mater. Sci. Eng. C, vol. 62, pp. 614–625, 2016, doi: 10.1016/j.msec.2016.01.076.
