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.