Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors
Introduction
Malignant gliomas are one of the most debilitating and lethal forms of cancer. Despite advancement in treatments, the survival and quality of life for high-grade, malignant brain tumor patients remain poor [1]. Current treatment modalities include surgery, radiotherapy and chemotherapy [2]. Surgery and radiotherapy are hampered by the limited tumor accessibility to resection and the risk of damaging the surrounding normal tissue that may carry critical brain functions, whereas a major pitfall in chemotherapy is the failure to accumulate and retain a therapeutically relevant drug concentration at the tumor site [3]. Prolonged exposure of a tumor lesion to sufficiently high drug concentrations is a prerequisite for therapeutic efficacy [4]. However, passive biodistribution of a systemically administered drug, which is governed by the physicochemical properties (e.g. molecular weight, lipophilicity, etc.) of the compound, often results in subtherapeutic drug levels at the tumor site [5]. Exposure of the tumor to subtherapeutic drug concentration does not only fail to irradicate the lesion, but can even stimulate overgrowth of resistant malignant cells [6]. Moreover, most chemotherapeutic agents possess poor selectivity toward the target tissue and can harm normal cells as well as cancer cells. Thus, dose escalation in order to formulate an effective dosing regimen is limited by possible systemic toxicity [4].
The failure to achieve therapeutic drug concentrations in brain tumors has been traditionally attributed to the impermeable nature of the blood–brain barrier (BBB), composed of tight intercellular junctions and deficient in both pinocytotic vesicles and fenestrations [7]. Thus, strategies for circumvention or temporary disruption of the BBB, such as direct intracranial injection of chemotherapeutic drugs, e.g. methotrexate [8] and drug-loaded liposomes [9], tumor implantation of BCNU-loaded polymeric wafers [10], and osmotic disruption of the BBB with hypertonic solutions of mannitol [11], [12] have been attempted. However, it has been well established that glioma microvasculature exhibits physiological characteristics quite distinct from those of the intact cerebral BBB [13], [14], [15], [16]. Structural abnormalities of the endothelial lining, driven by an erratic angiogenesis, include open endothelial gaps (interendothelial junctions and transendothelial channels), cytoplasmic vesicles and fenestrations that contribute to leakiness and hyperpermeability of the tumor vasculature [17]. Circumvention of the BBB, although it increases drug concentrations in the tumor, also inevitably results in high concentrations of the cytotoxic drug in the normal brain—posing a threat of severe neurotoxicity [18]. Similarly, direct intervention into delicate brain structures often results in the loss of neurological and neurocognitive functions [19], [20], [21]. Therefore, a reasonable approach for the design of less invasive and more selective brain tumor drug delivery is to exploit the physiological differences in vascular permeability between the tumor and normal brain to achieve potential selectivity.
Colloidal systems, such as liposomes and nanoparticles, have shown promise as drug carriers to target brain tumors after minimally invasive intravenous administration [15], [22]. For example, systemic delivery of stealth liposomes loaded with the anti-cancer agent doxorubicin was found to significantly increase the extent and selectivity of drug accumulation in gliomas compared to administration of the free drug [23]. This advantage of colloidal carriers has been attributed to the so-called enhanced permeability and retention (EPR) effect [24], [25], whereby macromolecules and nanoparticles, even as large as 300 nm, are able to extravasate into the tumor interstitium through the hyperpermeable vasculature of most solid tumors [15], [26]. Moreover, deficient lymphatic drainage retards the tumor clearance of the macromolecular structures, rendering the use of nanoparticles a promising approach for “passive” tumor targeting.
Magnetic nanoparticles, composed of a magnetic (e.g. iron oxide/magnetite) core and a biocompatible polymeric shell (e.g. dextran, starch), offer a potential method for tumor drug delivery with benefits that extend beyond the EPR effect. These additional advantages come from such specific properties of magnetic nanoparticles as magnetic responsiveness and MRI visibility. Several investigators have previously shown that magnetic nanoparticles can be retained at tumor sites, after local administration combined with a locally applied external magnetic field, due to the “magnetic responsiveness” of the iron oxide core, thereby enabling magnetic targeting [27], [28], [29], [30]. Additionally, it has also been demonstrated that detectable amounts of magnetic nanoparticles are able to reach the tumor of 9L-glioma bearing rats after intravenous administration [31], [32].
While colloidal carriers have been shown to accumulate in brain tumors, the assessment of accumulation and retention is often hindered by a lack of non-invasive methods to monitor the time-course of nanoparticle distribution within the brain. Since iron oxide magnetic nanoparticles are known to be strong enhancers of proton spin–spin (T2/T2*) relaxation, MRI is a suitable modality for non-invasive detection of such nanoparticles [33]. The resulting reduction in signal intensity (negative contrast) at the spatial location of magnetic nanoparticles renders them visible on MR images collected in vivo.
In the present study, we examined the applicability of magnetic nanoparticles for both magnetically enhanced brain tumor accumulation and non-invasive MRI monitoring. We hypothesized that the fraction of magnetic nanoparticles passively reaching the brain tumor site after systemic administration would be actively retained by magnetic interaction with an externally applied magnetic field, thus prolonging tumor exposure to the drug carrier. We further hypothesized that the MRI visibility of magnetic nanoparticles could be utilized to achieve non-invasive monitoring of nanoparticle accumulation, as well as to evaluate the effect of magnetic targeting on the time-course of distribution and elimination of magnetic nanoparticles, in brain tumors.
Section snippets
In vitro characterization of magnetic nanoparticles
Magnetic nanoparticles (G100) were kindly provided by Chemicell® (Berlin, Germany). Total iron concentrations of nanoparticle preparations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-EOS) using an Optima 2000 DV spectrometer (Perkin-Elmer, Boston, MA). Samples were prepared by complete digestion of the colloidal nanoparticles in 12 m hydrochloric acid (HCl) at 70 °C for 2 h. Calibration curves were constructed using standard iron solutions. Light-scattering
In vitro characterization of magnetic nanoparticles
According to previous investigations [35], the success of magnetic targeting is generally contingent upon the magnetic properties and size distribution of the nanoparticles. In addition, the ability of the nanoparticles to enhance proton relaxation is a pre-requisite for their MRI visibility [36]. The G100 nanoparticles consisted of an iron oxide core and a starch coating (Fig. 1A), and exhibited a narrow distribution of the hydrodynamic diameter of 110±22 nm (mean±SD) (Fig. 1B). The iron oxide
Discussion
Established differences in the vascular architecture and permeability of brain tumors and uncompromised normal brain tissues offer an attractive physiological basis to achieve tumor-selective accumulation of drug carriers [15], [17]. In addition to selectivity, residence time of the carrier at the tumor site is of critical importance since it determines the total extent of exposure of the tumor mass to the potential drug. A major goal of the present study was to assess whether magnetic
Conclusions
Results presented reveal that continued development of magnetic nanoparticle based systems for the delivery of chemotherapeutic agents to brain tumors is warranted. Intravenous administration, along with magnetic targeting resulted in a 5-fold increase in the total glioma exposure to magnetic nanoparticles over non-targeted tumors and a 3.6-fold enhancement in the TSI of nanoparticle accumulation in glioma tissue over normal brain parenchyma. In addition, the ability to monitor magnetic
Acknowledgments
The authors would like to thank Dr. Kyle Kuszpit for his help with animal surgery. This study was partially supported by NIH Grants RO1 HL55461, RO1CA114612, R24 CA083099 and the Hartwell Foundation Biomedical Research Grant. Fred W. Lyons Jr. Fellowship and Rackham Predoctoral Award for Beata Chertok are gratefully acknowledged.
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