**5. Multimodal tumor imaging and therapy**

There has been moderate impact of targeted therapies in glioma. The therapies that have demonstrated a significant survival benefit for gliomas in Phase III clinical trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. An emerging field in glioblastoma nuclear medicine is use of radionanoparticles. These radioactive nanocarriers can be used passively as a simple tumor brachytherapy or can be actively used with a specific targeting to vectorize a large amount of radioactivity. The targeting is usually directed against a glioblastoma-specific antigen or receptor. Antigen targets, like epidermal growth factor receptor (EGFR), tenascin, or DNA histone H1 complex. Radiolabeled antibodies and peptides hold promise for molecular radiotherapy but are often limited by a low payload resulting in inadequate delivery of radioactivity to tumor tissue and, therefore, inadequate therapeutic effect and adverse effects due irradiation of normal tissues [24]. Song et al. developed a synthetic method of radiolabeling indium-111 (111In) to epidermal growth factor (EGF)-gold nanoparticles ( 111In-EGF-Au NP) with a high payload [25]. By using radiolabeled nanoparticles, comparatively higher payloads are obtained due to large surface area to volume ratio. This results in multivalent effect of nanoparticles, thus accommodating a large number of targeting ligands, such as antibodies, peptides or aptamers on a single nanoparticle. This facilitates maximal binding to the molecular target in vivo, thus enhancing delivery of radioactivity to target tissue with improved imaging and therapeutic efficacy. PEGylation of nanoparticles and alteration of their surface properties improves their stability and mean residence time in vivo [26]. It also permits loading a combination of imaging, radiotherapeutic and/or chemotherapeutic moieties for multimodal tumor imaging and therapy [27]. Antibodies, radiolabeled antibodies, antibody fragments or peptides because of their small size easily penetrate surrounding normal tissues. Loading onto nanoparticles limits their penetration through normal vasculature and capillaries, thus minimizing their side-effects [28].

Different nanocarriers such as metallofullerenes, liposomes, or lipid nanocapsules have been used to deliver radionanoparticle passively. A typical metallofullerene (177Lu-DOTA-f-Gd3N@C80) radionanoparticles when administered by convection-enhanced delivery (CED) in brain tumor model showed an improved

survival time of more than 2.5 times that of the control group [29]. Similarly liposomes loaded with beta-negative emitters such rhenium-186 and demonstrated promising results when administered by CED in an orthotopic glioblastoma rat model [30]. Lipid nanocapsules loaded with rhenium-188 in a rat orthotopic model showed a significant survival benefit after intratumoral stereotactic injection at day 6 and CED injection at day 12 [31].

A recent approach using radionanoparticles consists of an active targeting approach where the nanoparticles are functionalized and directed against a tumor target. The aim of this active targeting is to optimize the spatial localization of the radioactivity close to the tumor cells. As an example, lipid nanocapsules can be loaded with rhenium-188 and coupled to a monoclonal antibody directed against the CXCR4 antigen. These CXCR4-recognizing immune-nanoparticles irradiate the tumor cells and have been shown to increase efficacy in an orthotopic mouse model. Recurrence for the passive protocol was observed at 65 versus 100 days for the active targeting approach, and this appears to be the most effective therapy with the longest measured time to progression [32].
