Tumor-Targeted Drug Delivery and MRI Contrast Enhancement by Chlorotoxin-Conjugated Iron Oxide Nanoparticles

Abstract

Aims-This study examines the capabilities of an actively targeting superparamagnetic nanoparticle to specifically deliver therapeutic and magnetic resonance imaging contrast agents to cancer cells. Materials & methods-Ironoxide nanoparticles were synthesized and conjugated to both a chemotherapeutic agent, methotrexate, and a targeting ligand, chlorotoxin, through a poly(ethylene glycol) linker. Cytotoxicity of this nanoparticle conjugate was evaluated by Alamar Blue cell viability assays, while tumor cell specificity was examined in vitro and in vivo by magnetic resonance imaging.Results & discussion-Characterization of these multifunctional nanoparticles confirms the successful attachment of both drug and targeting ligands. The targeting nanoparticle demonstrated preferential accumulation and increased cytotoxicity in tumor cells. Furthermore, prolonged retention of these nanoparticles was observed within tumors in vivo.Conclusion-The improved specificity, extended particle retention, and increased cytotoxicity toward tumor cells demonstrated by this multifunctional nanoparticle system suggest that it possesses potential for applications in cancer diagnosis and treatment.Keywords iron oxide; nanoparticle; chlorotoxin; methotrexate; tumor; drug delivery; magnetic resonance imaging The development of tumor specific multifunctional nanoparticles is currently an area of intense research with the potential to revolutionize the diagnosis and treatment of cancer. These particle systems, also referred to as nanovectors, have been envisioned as novel contrast agents for non-invasive molecular imaging and targeted carriers for drug delivery [1,2]. As a major class of these materials, superparamagnetic iron oxide nanoparticles have been examined extensively for applications in cancer diagnosis and therapeutics due to their biocompatibility and magnetic properties [3,4]. Early forms of these nanoparticles, which exploit the body's natural clearance pathways (e.g. reticuloendothelial system (RES)-mediated passive targeting), * Author for correspondence: Department of Materials Science & Engineering, 302L Roberts Hall, University of Washington, Seattle, WA 98195-2120, Tel: (206) 616 9356, Fax: (206) 543 3100, mzhang@u.washington.edu. NIH Public AccessAuthor Manuscript Nanomedicine (Lond) In addition, the magnetic properties of these iron oxide nanoparticles have also been examined as a means of remotely directing therapeutic agents specifically to a disease site [7]. Nanoparticles possess a high surface area-to-volume ratio allowing them to be loaded with large amounts of a therapeutic or cytotoxic drug. As with other drug delivery systems, specific accumulation in malignant tissues results in reduced dosages necessary for a therapeutic effect and less deleterious side-effects associated with non-specific uptake of cytotoxic drugs by healthy tissue. Additional advantages of drug carrier systems over traditional systemic chemotherapy include the ability to improve the solubility of hydrophobic drugs, stabilizatio...

Purificación parcial de péptidos y actividad citotóxica del veneno T. macrochirus

“…Según lo descrito por otros investigadores, esta es una característica general de diferentes venenos de escorpión: por ejemplo, se ha determinado que el veneno de Rhopalurus junceus es selectivo frente a células cancerosas de pulmón (40); la clorotoxina, purificada del veneno de Leiurus quinquestriatus (41), es específica para células de glioma (42) y se la ha propuesto como una alternativa para el reconocimiento de otro tipo de células cancerosas con base en ensayos con nanopartículas que permitieron reconocer ganglios positivos para linfoma de cáncer de mama, próstata y testículo (43,44); el veneno de Androctonus crassiacauda, por su parte, resultó selectivo para la línea celular BC3H1 (45) (13,(17)(18)(19)(20)(21)(22)(23)29,45). …”

“…Con base en los resultados descritos, es posible concluir que el componente peptídico del veneno de T. macrochirus tuvo actividad citotóxica en las líneas celulares evaluadas, lo cual se ha observado también en péptidos purificados y sintetizados a partir de otros venenos de escorpión, por lo cual se han empezado a considerar como una alternativa para el diseño y la elaboración de nuevos agentes terapéuticos (13,16,18,(43)(44)(45)(46)(47)(48)(49)(50)(51). De ahí la necesidad de separar completamente algunos de los péptidos de este veneno y evaluar el efecto que cada uno de ellos produce en las diferentes líneas celulares evaluadas para determinar plenamente el responsable de cada uno de los efectos observados.…”

Multifunctional Magnetic Hybrid Nanoparticles as a Nanomedical Platform for Cancer-Targeted Imaging and Therapy

“…In vivo, these MNPs demonstrated therapeutic efficacy against target tissue, as determined by real time PCR and histological evaluation, while simultaneously demonstrating image contrast in both MR and optical imaging. In a study by Sun et al (2008a) active cell targeting was shown by PEG-coated MNPs to which the chemotherapeutic, methotrexate, and targeting molecule, chlorotoxin, were attached. The selective contrast enhancement of the 9L brain tumor by these MNPs indicates preferential accumulation compared with the same MNP construct without the chlorotoxin peptide in a 3-day study.…”

Multimeric, Multifunctional Derivatives of Poly(ethylene glycol)

“…In order to investigate the capabilities of an actively targeting superparamagnetic nanoparticle to specifically deliver drug and MRI contrast agents to cancer cells, iron oxide nanoparticles were also synthesized and conjugated to both a chemotherapeutic agent, methotrexate, and a targeting ligand, chlorotoxin, through a poly(ethylene glycol) linker [53]. The targeting nanoparticle demonstrated preferential accumulation and increased cytotoxicity in tumor cells.…”