Introduction
Cancer has been identified as the second main cause of mortality worldwide , after heart diseases (Sant, Iyer, Gaharwar, Patel, & Khademhosseini, 2013). Chemotherapy is one of the most common treatment procedures for cancer therapy which is used after surgery and in a combination with radiotherapy (Cao et al., 2011; Lv et al., 2014; Zou et al., 2012). Although the chemotherapy has been proved to be useful in many cases, nonetheless, the severity of its side effects and also the drug resistance to these drugs lead to reducing the efficacy of chemotherapeutic agents (Eggenberger et al., 2010; Zintchenko, Philipp, Dehshahri, & Wagner, 2008). During the previous few decades, nanoparticles were employed to optimize the effect of drugs and genes, reduce their side effects and deliver the medicines in a targeted manner for efficient therapy (Hami, Amini, Ghazi-Khansari, Rezayat, & Gilani, 2014a). Folic acid (FA) is an essential nutrient for the human body which can enter cells through folate receptors (FRs) (Zwicke, Mansoori, & Jeffery, 2012). In the human body, folic acid is used in the synthesis of the DNA. Therefore, the expression level of folate receptor in cancer cells is higher compared to normal cells, due to theirs need to high level of folic acid (Alibolandi et al., 2016; Mojica Pisciotti et al., 2014). Glucose is another important nutrient in the human body which provides the energy that is needed in many metabolic functions and synthetic processes of different compounds in cells, serum and tissues (Chatterjee, 2013; Talpur, Echard, Ingram, Bagchi, & Preuss, 2005). So, glucose transporters (Gluts) are over-expressed on the cell membrane of many malignant cells (Smith, Volkert, & Hoffman, 2005; Qiang Wang et al., 2010). In 1927, Warburg et al. reported that glucose uptake was significantly enhanced in cancer tissues compared to those in normal tissues because of their high metabolic activity (Warburg, Wind, & Negelein, 1927). After that, glucose has been used to target cancer cells for different diagnostic and therapeutic applications (Li, Ma, Dang, Liang, & Chen, 2014; Mamaeva et al., 2016).
It is well known that the targeted endocytosis pathway of nanoparticles is based on the interaction between cell surface receptors and ligands (S. Wang et al., 2013; Xia et al., 2013). Therefore, the efficiency of drug delivery was limited up to saturation of cell surface receptors by specific ligands of nanoparticles. Therefore, it seems that specific targeting of tumor tissues could be improved through simultaneous incorporation of several ligands such as glucose and folic acid inside the structure of nanoparticles. So, in this study it was aimed to optimize the surface of nanoparticles with co-addition of folic acid and glucose.
In recent years, drug resistance was emerged as one of the biggest therapeutic challenges in cancer therapy and so it attracted many research attentions (Bentley-Goode, Newton, & Thompson, 2017; Marques et al., 2014). Simultaneous co-targeting of cancer cells using two or more drugs seems to be a novel and effective approach to overcome the problem of drug resistance (Camirand, Lu, & Pollak, 2002; Q. He, Liu, Sun, & Zhang, 2004; Mancini et al., 2014).
The use of siRNA to suppress expression of oncogenes has been considered as a promising solution for cancer treatment in recent years (Kumar, Yigit, Dai, Moore, & Medarova, 2010; Patil & Panyam, 2009). Although, this method can be helpful lonely, however, due to the complexity of human cancer, other complementary therapies may be needed to improve the efficacy of cancer therapy by siRNA (Peng, Hsu, Lin, Cheng, & Hsu, 2017; X. Z. Yang et al., 2011). Combination therapy of siRNA and chemotherapeutics such as paclitaxel has been considered as a useful strategy for increasing the effectiveness of cancer therapy (Kapse-Mistry, Govender, Srivastava, & Yergeri, 2014).
Various carriers were used to deliver genetic agents. Cationic polymers such as polyethyleneimine (PEI) are of the most common ones and have the ability to interact with RNA and DNA and form complexes with high transfection efficiency. However, studies showed that application of PEI is associated with critical cytotoxicity effects (Abebe et al., 2015b; Moret et al., 2001). In addition, hydrophilic polymers such as PEI have low capacity to use as a nano-vector for delivering hydrophobic and neutral drugs such as PTX into cancer cells.
Several methods have been developed to transfer different compounds using nanoparticles to cancer cells (Amani, Zare, Asadi, & Asghari-Zakaria, 2018; Kircheis et al., 1999). Synthesis of copolymers by binding of hydrophobic polymers such as PLA to cationic hydrophilic polymers allows simultaneous co-delivery of siRNA and PTX to cancer cells.
Biodegradable polymers such as polylactide (PLA), poly(D,L-lactide-co-glycolide) (PLGA), and polyglycolide (PGA) have great application potential as drug carriers due to their good biocompatibility and biodegradability (Lu et al., 2014; Perez et al., 2001a; J. Wang, Xu, Liu, Sun, & Yang, 2016).
Researchers have developed tri-block copolymers using PLA, PEI, and PEG such as tri-block PEI-PLA-PEG copolymers, as potential gene delivery nano-vectors (Abebe et al., 2015a, 2015b; Sim et al., 2017). The hydrophobic PLA segment affords a degree of biodegradability to nanoparticles. It also increases the stability of nano-carrier through charge shielding effects. In recent decades, much study has been done on multifunctional nanoparticle. Multifunctional nanoparticles are attractive for cancer treatment due to high potential to overcome the barriers in various extracellular and intracellular conditions (Chen et al., 2015; Liu et al., 2016; Yan, Li, Li, Zhu, Shen, Yi, Wu, Yeung, Xu, Xu, & Chu, 2014). This study presents multifunctional biodegradable magnetic nanoparticles including PLA, PEG, PEI, FeCo nanoparticles, folic acid and glucose for co-delivery and targeting of siRNA and PTX.