MNPs will be used to disrupt brain cancer cell pathways that are overactive and contribute to the resistance of malignant brain tumors to various therapies

MNPs will be used to disrupt brain cancer cell pathways that are overactive and contribute to the resistance of malignant brain tumors to various therapies. in progress to understand the promising impact of MNPs in the treatment of AMG517 AMG517 malignant brain tumors. in the past (Figure 3) [70,71]. The influence of surface functionalization has recently been shown to enhance the internalization of MNPs in cancer Rabbit Polyclonal to MEF2C (phospho-Ser396) cells [72]. Functional modifications of MNPs, involving surface binding of molecules specific for malignant brain tumors, has been increasingly used in order to more specifically target MNPs [42]. Targeted MNPs can be concentrated in tumors, providing sensitive tumor imaging as well as targeted therapy of tumors [73,74]. Antibodies, peptides (including toxins), cytokines and chemotherapeutic agents have been reported as possible MNP-targeting options [75]. We have recently utilized a GBM-specific antibody bioconjugated to iron oxide-based MNPs for the targeted imaging and therapy of GBM. Amphiphilic triblock copolymer IONPs were conjugated with a purified antibody that selectively binds to the EGFR deletion mutant, EGFRvIII, which is solely expressed by GBM tumors [1]. MRI contrast enhancement of EGFRvIII-expressing GBM cells occurred after treatment with the EGFRvIII-IONPs. Treatment of patient-derived GBM neurospheres containing GSCs with the EGFRvIII-IONPs resulted in tumor cell apoptosis. GBM cell treatment also resulted in disruption of EGFR cell signaling and decreased phosphorylation of the EGFR tyrosine kinase. A significant increase in overall animal survival resulted after local intratumoral convection-enhanced delivery (CED). Conjugation of MNPs with peptides that target receptors on the tumor cell surface can enable internalization of the NPCpeptide conjugate via receptor-mediated endocytosis. Examples of two peptides for targeting NPs to GBM cells include chlorotoxin and F3. Chlorotoxin is derived from scorpion venom and specifically binds to matrix metalloproteinase-2, which is overexpressed on the surface of GBM cells and other cancer cells [76,77]. matrix metalloproteinase-2 accounts for degradation of the extracellular matrix during tumor invasion and therefore chlorotoxin results in inhibition of GBM cell invasion [78,79]. Chlorotoxin conjugated to MNPs can act as an MRI contrast agent as well as an intra operative optical dye [67,68,80]. F3 is a small peptide that specifically binds to nucleolin overexpressed on proliferating endothelial cells of tumor cells and the associated vasculature [81]. Multifunctional NPs conjugated with F3 peptides have been used to deliver encapsulated MRI contrast enhancers and photosensitizers to malignant brain tumors implanted in rats. These F3-coated IONPs can provide significant MRI contrast enhancement of intracranial rat-implanted tumors, compared with non-coated F3 NPs, when administered intravenously [82]. Conjugation with chemotherapeutic drugs is an alternative method that has been used for targeting of MNP-based MRI contrast agents to brain tumors. Polyethylene glycol-coated IONPs have been conjugated with the chemotherapeutic agent methotrexate for tumor targeting [83]. Such drug-loaded MNPs can result in targeted tumor therapy, as well as facilitating monitoring of the delivered drug load via MRI imaging [84]. These multifunctional NPs have increased uptake by tumor cells, resulting in increased accumulation and cytotoxicity of tumor cells [85]. MNPs for stem cell tracking The remarkable feature of MNPs to act as MRI contrast agents has also been used in tracking stem cell tropism to malignant brain tumors by MRI, due to the intrinsic magnetic properties of MNPs that enable them to be used as MRI contrast agents [138]. Convection-enhanced delivery A novel approach for efficient drug delivery into brain tumors is CED. CED has been designed to infuse agents directly into the brain parenchyma, bypassing the BBB and avoiding nonspecific uptake [139]. CED involves continuous delivery of an agent with a specific infusion rate and volume through one or more infusion catheters that have been stereotactically placed directly within and around brain tumors. A pump is connected to each infusion catheter in order to ensure a positive pressure gradient during delivery. The positive pressure gradient during infusion establishes fluid convection, which supplements simple diffusion. Simple diffusion alone governs local intracerebral delivery achieved by stereotactically guided injections. The additive effect of convection to simple diffusion through CED enhances the distribution of small AMG517 and large molecules into the brain and increases the locoregional concentration of the infused compound [140]. Agent surface properties (cationic charge), large hydrodynamic size ( 100 nm), catheter positioning and high interstitial tumor pressures can compromise agent distribution [16,140C144]. CED of therapeutic agents has been used in multiple human GBM clinical trials to determine efficacy [145,146]. Imaging CED in the brain for agent distribution and tumor targeting is the single largest impediment to this delivery strategy. Visualizing the distribution of infused agents is necessary to ensure accurate delivery into target sites and provides feedback on catheter placement and.