Michael Faraday first described the generation of colloidal gold nanoparticles in 1857 and since then, it has been used to meet a variety of needs in science and even in medicine.
Recently, gold nanoparticles have emerged as attractive candidate for delivery of various therapeutic molecules into their targets due to their unique chemical and physical properties.
Colloidal gold particles are relatively inert and biologically compatible non-toxic carriers. It can be synthesized easily with sizes ranging from 1 nm to 150 nm and functionalized with organic monolayer to provide required functionality (Grabar et al., 1995). Studies across the world have shown that different types of therapeutics such as small drug molecules, proteins, DNA and RNA can be delivered through colloidal gold nanoparticles (Ghosh et al., 2008). Small molecule drugs such as methotrexate, kahalalide F etc. were conjugated over the gold NP surface through electrostatic interaction or thiol functionalization and shown to act as drug carrier (Chen et al., 2007; Hosta et al., 2009). Paciotti et al., (2004) carried out in vivo study to investigate the therapeutic effect of PEGylated gold colloids with adsorbed tumor necrosis factor (cAu-PEG-TNF). When cAu-PEG-TNF was injected intravenously into mice, they were largely accumulated in MC-38 colon carcinoma tumors compared to liver, spleen, or other healthy organs. TNF provided both targeting and therapeutic action via killing the targeted cells. Importantly, the particles were more effective at diminishing tumor mass than free TNF. Recent studies by this group have demonstrated enhanced tumor therapy by grafting paclitaxel, an anticancer drug, onto cAu-PEG-TNF. In another approach to generate a multifunctional gold nanoparticle, a vector named CYT-21001, is designed to target the delivery of both TNF and paclitaxel to solid tumors (Paciotti et al., 2006). Gold NPs can also be modified and conjugated with suitable proteins/peptides to be target the cell
nucleus. Tkachenko et al (2004) combined a cell-targeting peptide and a nucleus-targeting peptide from adenovirus into a long peptide and loaded them onto gold NPs which were already modified with a shell of BSA and used for target the nucleus of human hepatocarcinoma HepG2 cells. The resulting cellular trajectories indicated that the NP uptake and nucleus translocation strongly depends on the peptide sequence and cell type. In addition to the surface chemistry of gold NPs, their physical properties can be exploited for cancer treatment. Gold NPs cause local heating when they are irradiated with light in the
“water window” (800 nm – 1200 nm). Huang et al. (2007) have reported about potential use of gold NPs in photothermal destruction of tumors.
1.4.2 Magnetic Nanoparticle
Magnetic NPs have been investigated for biomedical applications for more than 30 years.
Up to now, magnetic NPs have been used in medicine as contrast agents in magnetic resonance imaging (MRI), for local hyperthermia and as targetable carriers for drug delivery systems. The concept of using magnetic micro and nanoparticles for drug delivery was originally proposed by Widder, Senyi and colleagues (Senyi et al., 1978; Widder et al., 1979) and in recent years it has gained prominence for targeted delivery of therapeutics in cancer chemotherapy (Gupta and Gupta, 2005; Dobson 2006). In these systems, therapeutic compounds are attached to biocompatible magnetic nanoparticles and magnetic fields generated outside the body are focused on specific targets in vivo. The fields capture the particle complex resulting in enhanced delivery to the target site.
There are many magnetic materials available with a wide range of magnetic properties.
However, many of these materials, such as cobalt and chromium are not suitable for the use as biomedical agents in vivo due to their high toxic nature. The iron oxide based
nanoparticles such as magnetite (Fe3O4) and maghemite (J-Fe2O3) are relatively safe and the most commonly used materials suitable for drug targeting in vivo. They are commonly prepared by co-precipitation of Fe2+ and Fe3+ aqueous salt solutions by addition of a base.
The overall chemical reaction of Fe3O4 precipitation can be given as (Lu et al., 2007a):
Fe2+ + 2 Fe3+ + 8 OH- = Fe3O4 + 4 H2O
The control of size, shape and composition of nanoparticles depends on the type of salts used (e.g. chlorides, sulphates, nitrates, perchlorates, etc.), Fe2+ and Fe3+ ratio, pH and ionic strength of the media (Lu et al., 2007a). The other established method of magnetic NP synthesis includes thermal decomposition and microemulsion (Lu et al., 2007a).
Biocompatible magnetic particles are prepared by coating the magnetic cores with a metal or polymer (Mandal et al., 2005; Gupta and Gupta, 2005). By functionalizing the polymer or metal coating it is possible to attach or encapsulate the anticancer agents for targeted cancer chemotherapy. This coating also prevents the leaching of potentially toxic components into the body during in vivo applications. After encapsulating or attaching the drug molecules into the particle, the complex is injected into the blood stream, often using a catheter to position the injection site near the target. High magnetic fields are focused over the target tumor site which forces the injected particles to extravasate into the tumor tissue. While this may be effective for the tumors close to the body’s surface, as the magnetic field strength falls off rapidly with distance, tumors deeper into the body become more difficult to target.
The key parameters in the behavior of magnetic NPs are related to surface chemistry, size (magnetic core, hydrodynamic volume, and size distribution), and magnetic properties (magnetic moment, remanence, coercivity). The surface chemistry is especially important to avoid the action of the reticuloendothelial system (RES) to increase the half-life in the blood stream. Coating the NPs with a neutral and hydrophilic polymer i.e. polyethylene glycol
(PEG), polysaccharides, serum albumin etc. increases the circulatory half-life from minutes to hours or days. The main advantages of magnetic (organic or inorganic) NPs are that they can be: (i) visualized (superparamagnetic NPs are used in MRI), (ii) guided or held in place by means of a magnetic field and (iii) heated in a magnetic field to trigger drug release or to produce hyperthermia/ablation of tissue. Magnetic particles were first applied by Widder et al (1983) to deliver cytotoxic drugs into sarcoma tumors implanted in rat tail and directed by an external magnetic field. Their results showed a total remission of the sarcomas. In contrast, there was no remission in the control group without magnetic directing even with 10 times higher dose of the drug. Alexiou et al (2000) have used mitoxantrone (MTX) bound to starch stabilized magnetic ferrofluids (FFs) for the treatment of locoregional cancer. Mitoxantrone bound to magnetic ferrofluids (FF-MTX) was injected intraarterially (femoral artery) into the New Zealand white rabbits, previously implanted with VX-2 squamous cell carcinoma. Targeting of MTX-FF into the tumor site with an external magnetic field resulted in significant remission of the tumor compared with the control group (no treatment) without systemic toxicity. A preclinical study in Sprague-Dawley rats with anticancer drug attached magnetic NPs showed no intolerance and good efficiency in tumor regression (Lubbe et al., 1996a). The first phase I clinical trial of magnetically targeted drug delivery in human patients with advanced solid tumors was performed by Lubbe et al (1996b). In that study, epirubicine was complexed to magnetic NPs on the basis of electrostatic interactions between phosphate group bound to the surface of the particle and amino sugar present within the drug. Out of 14 patients studied, epirubicin was effectively targeted to the tumor site in 6 patients. A second clinical trial was performed by Koda et al (2002) on 32 patients with hepatocellular carcinoma, in which doxorubicin hydrochloride was coupled to magnetic particles and delivered by sub selective hepatic artery
catheterization. The particle-drug complex was targeted to the tumor site using an external magnetic field and particle localization examined with MRI. The results showed that out of 32 patients studied, tumors were targeted effectively in the 30 patients. Although progress in clinical applications of magnetically targeted carriers has been slow but the results have been promising and with further development it may provide another tool for the effective treatment of cancers.