Document Type : Review Paper
1 Department of Medical Genetic, Faculty of Medicine, Mashhad University, Mashhad, Iran
2 Department of Medical physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4 Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
5 Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, UK.
Colorectal cancer (CRC) is the third leading cause of cancer death the U.S. and additionally the third widely diagnosed cancer in the world . CRC survival is greatly dependent on the stage of the disease and usually ranges from a 90% 5-year survival rate for cancers detected at the localized stage to 10% of people diagnosed for distant metastatic cancer. The earlier the stage of diagnosis, the higher the chance of survival . Currently there are many various therapies for CRC which include surgery, chemotherapy, and radiation therapy. However, these procedures are not very efficient as the drug reaches the target site in non-effective concentrations. However, higher dose may lead to adverse effects . Nanoparticles, of which at least one dimension is smaller than 100 nm , have a great potential in drug delivery and clinical therapeutics and are important for applications in cancer drug delivery [4-6]. There are key advantages of nanoparticle drug delivery including longer circulation half-lives, improved pharmacokinetics, being capable of carrying a large amount of drugs, decreasing side effects and targeting the drug to a specific location in the body (Table 1)[7, 8]. This article briefly reviews the nanoparticle-assisted co-delivery of drugs for CRC therapy.
DRUG DELIVERY SYSTEM WITH NANOPARTICLES
Nanoparticle drug delivery platforms have been in center of focus of researchers. Many solid tumors such as breast, lung, prostate, and colon cancers have unique structural features including the hyper permeable vasculature and impaired lymphatic drainage, hence, tumor tissues are quite permeable to macromolecules and nanocarriers [23, 24]. There are two major mechanisms for cell-specific targeting with nanocarriers: active and passive. The first strategy depends on the interaction between the nanocarriers and receptors on the target cell. Passive targeting involves mechanisms to increase vascular permeability and also to retain long-circulating nanocarriers at tumor sites in their flow to impaired lymphatic system . Enhanced permeability and retention (EPR) effect, nanoparticle clearance by the mononuclear phagocyte system (MPS), and desirable nanoparticle characteristics for cancer applications are important concepts in nanoparticle drug delivery. The EPR effect has a critical role in determining the efficacy of the nanoparticle-based drug delivery system . There is however, a common problem among nanoparticles where they are quickly absorbed by macrophages, so-called MPS. The MPS (also known as the Reticulo Endothelial System (RES)) is mostly responsible for clearing macromolecules from circulation . One of the major programs to prevent the rapid RES uptake is coating of the particles with surfactants or covalent linkage of polyoxyethylene [27, 28]. There are different characteristics for delivering conventional therapeutics to solid tumors; life-size (less than 200nm), spherical shape and a smooth texture. Although particles larger than 500 nm are rapidly eliminated from the circulation .
In 1961, Bangham described liposomes as the first nanoparticle platform applied in medicine . Liposomes were the first drug-delivery system approved for clinical purposes. One of the most used delivery systems for small molecules, peptides, small and long nucleic acids, and proteins are liposomes and particularly nanoliposomes . Liposomes are small, spherical artificial carriers with an aqueous core and are naturally non-toxic . Due to their phospholipid bilayer, their size and their ability to incorporate various substances liposomes are the most effective drug delivery systems into cells with slow-releasing and targeting characteristics and the ability to decrease side effects [33, 34].
Liposomes according to their different properties are divided into 3 groups:
1) Long-circulating liposomes (stealth liposomes): The conventional liposome surface is strongly affected by opsonization and the opsonized liposomes are subjected to uptake by MPS and subsequent clearance. Phospholipid bilayer structure of the liposome is modified by adding gangliosides or a polyethylene glycol (PEG) which tends to avoid blood plasma opsonins binding to the liposome surface. Subsequently, PEG causes a decrease in recognition of liposomes by the mononuclear phagocyte system and enables liposomes to stay stable in the circulation and maintain a prolonged half-life [35-37];
2) Active targeting liposomes: Liposomes targeting antibodies, glycoside residues, receptors, hormones and peptides;
3) Liposomes with special properties include thermo-sensitive, pH-sensitive, magnetic and positive;
Liposome formulation carrying the chemotherapeutic drug such as Doxorubicin (Doxil®) and daunorubicin (DaunoXome®) has been approved by FDA since the mid-1990s . Doxil is approximately 100 nm and has much less cardiac and gastrointestinal toxicity although many side effects such as: redness, tenderness, and peeling of the skin which can be painful  can still be seen. The most recent liposomal drug, which has been approved by FDA since 2012, is Marqibo® (Fig. 1) [40-42]. Marqibo is about 100 nm and cell cycle-dependent anticancer drug. There have been some efforts to fight drug resistance such as the results obtained when administrating liposome-based like Doxorubicin. Li et al. have determined that when administering high dosages of a carrier for the antitumor drug Doxorubicin (DOX); such as L33, an aptamer-based drug delivery system, has the conceivability to conduct high dosages of the drug towards the target cells (Fig. 2) . Thermodox® (also known as thermo-sensitive liposome Doxorubicin) is another example which is in Phase II trials for colorectal liver metastases in combination with RFA (radiofrequency ablation). It is a liposomal Doxorubicin formulation that releases the drug in response to a mild hyperthermic trigger (Fig. 3) . Thermodox has been shown to deliver 25 fold more Doxorubicin into tumors than IV Doxorubicin does and fivefold more Doxorubicin than standard liposomal formulations of the drug in animal models (Table 2).
Polymeric nanoparticles (PNPs) or synthetic polymers are structures with a diameter between 10 to 100 nm. The PNPs are mostly covered with nonionic surfactants to decrease immunological interactions (e.g. opsonization) [48, 49]. Poly lacticco-glycolic acid (PLGA) and polycaprolactone (PCL) are two main examples of PNPs which have been approved by the US FDA . 5 fluorouracil (5-FU) is the first-line therapy for CRC, however in practice, the healthy cells are also affected when administered and on the other hand, the drug availability is not great in the colon region. Subudhi et al. have chosen citrus pectin and Eudragit S100 (pH-responsive enteric polymer) to use as nanoparticle drug delivery systems for site-specific delivery of 5-FU for the effective treatment of CRC . They concluded that Pectin was a good carrier material in the colon-specific drug delivery systems. Safety and effectiveness of Eudragit S100 coated CPNs (E-CPNs) to deliver 5-FU in CRC both in vitro and in vivo studies have also been shown[51, 52]. Eudragit S-100 is used for coating solid dosage and does not degrade below pH 7. The main purpose of using Eudragit S-100 was to prevent quick drug release in GI system rather than the target site (colon) [53, 54]. Citrus pectin is over-expressed acts as a ligand for galectin-3 receptors on CRC cells (Table 3) .