سنتز، شناسایی و سمیت کنترل شده یک ماده ترکیبی جدید بر مبنای سیس پلاتین و دوستاکسل Synthesis, characterization and controlled toxicity of a novel hybrid material based on cisplatin and docetaxel

۱٫ Introduction Breast cancer seems to be the most common cancer in women all over the world in the last decade [1]. Being so agressive for both incidence and mortality, research concerning breast cancer therapy has been widely developed in the last decade [1,2]. The research was focused mainly on the common types of treatment for different forms of cancer, such as surgery, radiotherapy and chemotherapy, but has also involved less common therapies, such as thermotherapy, immunotherapy, and targeted therapy [3]. The treatment modalities were able to partially alleviate the burden of this terible disease, but much more needs to be done in complementary fields, including materials as therapeutic agents, new systems for drug delievery, etc. [4,5] and this fact enhances research in the field. The therapeutic agents can be divided into various categories: alkylating agents, antibiotics which attack nucleic acids, platinum derivative agents as cisplatin, carboplatin or oxiplatin, mitotic inhibitors, antimetabolites, camptothecin type agents, and biological response modifiers. In this idea targeting specific carriers [6] to achieve higher therapeutic efficacy is gaining more importance in the pharmaceutical field and specifically, the nanohybrid compounds with potential sinergetic effects is posed to edge over chemotherapy [7]. An important part of efficacy agents such as the alkylating agents, the tumor targeting antibiotics, and the platinum compounds, is that they act by generating cellular damage by initiating free radical formation, the altered redox status and the presence of reactive oxygen species (ROS) being common biochemical aspects in cancer cells [8]. Oxidative stress is generated by an imbalance favouring prooxidants and/or disfavouring antioxidants, potentially leading to cellular damage and its presence in cancer cells could have important treatment implications [2,9] and allow the development of novel therapeutic strategies [10]. In recent years, lots of nanomaterials were developed and some of the most promising and exciting applications involve their use in cancer therapy. The nanoscale systems have proved to be efficient carriers for drugs to specific tissues or cell populations due to decreased deleterious side effects. In this context, carbon nanotubes (CNTs) are considered possible components of delivery systems [4,11], due to their transporting capabilities and their physicochemical properties. Over the past decade, such properties resulted in the use of CNTs in many other important bioapplications, such as antibacterial studies [12] and biosensors [13]. CNTs are formed by thin sheets of benzene ring carbons rolled up into the shape of a seamless tubular structure. They belong to the family of fullerenes, the third allotropic form of carbon, along with graphite and diamond [14] and present properties such as ultralight weight, high mechanical strength, as well as high electrical and thermal conductivity [15]. According to their structure, CNTs can be single-walled (SWCNTs) and multi-walled (MWCNTs). The appropriate functionalization of SWCNTs and MWCNTs allows a better biocompatibility and dispersability [8,16]. There are two main ways to increase their water miscibility; covalent and noncovalent functionalizations. In the search for new cancer drugs, both approaches have been widely used, and functionalized nanotubes have been loaded with various molecules to generate new hybrid materials as drug delivery systems [11,17]. Double functionalization via oxidation and introduction of an anticancer agent was firstly tested in nanotube cancer therapy with cisplatin [12], but soon after, carboplatin and doxorubicin were also investigated [13,14]. In our previous paper [18], our goal was to introduce docetaxel in SWCNTs and MWCNTs, and to estimate encapsulation efficiency, which was better for MWCNT-COOH. According to known data, both types of CNTs had positive impacts on cell proliferation and differentiation [2,3,19]. It has been shown that two therapeutic compounds, cisplatin and docetaxel, carried by MWCNT-COOH, had positive impacts on cell proliferation and differentiation [2]. However, their effect on cell death and potential usage in cancer treatment are still absent. The present paper is focused on the synthesis, characterization and controlled toxicity of such a drug delivery system simultaneously containing cisplatin and docetaxel loaded on functionalized carbon nanotubes (MWCNTCOOH). The aim of this paper was to investigate the in vitro response of a cancer breast cell line, MDA-MB 231, to exposure to functionalized CNTs and citostatic dopped functionalized CNTs. ۲٫ Experimental procedure ۲٫۱٫ Synthesis Multi-walled Carbon Nanotubes (MWCNTs) were purchased from Sigma Aldrich having more than 90% carbon basis and D×L 10-15 nm × ۰٫۱-۱۰ μm, produced by Catalytic Chemical Vapor Deposition (CCVD). Functionalization via oxidation was achieved by their dispersing (3.0 g) in 8% sulfuric acid and ultrasonication at 50°C for 48 hours, to afford MWCNT-COOH [20]. The drugs (cisplatin and docetaxel) and 7% NaCl solution were purchased from the pharmaceutical markets. Cisplatin (CDDP, 20 mg) was dispersed in saline solution (5 mL) and then MWCNT-COOH (0.5 mg) was added. Docetaxel (DOX, 20 mg) was dispersed in saline solution (10 mL) and then MWCNT-COOH (0.5 mg) was added. Subsequently, both suspensions were ultrasonicated for 48 hours at 50°C and filtered.