Introduction: Aggressive pediatric brain tumors are terminal upon diagnosis, yet no new therapeutic protocols have been developed in over 30 years. Glioblastoma multiforme is considered recalcitrant to current surgical and local radiotherapeutic approaches, while systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. However, these invasive brain tumors upregulate the avβ3 integrin at tumor vasculature to promote angiogenesis, which differ from the surrounding tissue. Thus, the avβ3 integrin provides a unique opportunity for vascular targeting of a nanoparticte imaging agent to glioma sites. We fabricated an integrin-targeted nanoparticle composed of multiple iron oxide (IO) nanospheres chemically assembled into a linear nanochain . Compared to small molecules or spherical nanoparticles, we show that the flexible, oblate shape of the integrin-targeted nanochains can facilitate superior and accurate targeting of the brain tumor's vascular bed due to geometrically enhanced mullivalent docking onto blood vessels associated with brain tumors. Materials and Methods: Using well-established methods, nanochains were synthesized and a cyclic RGO peptide was attached for targeting. In vivo efficacy studies were conducted in mouse orthotopic models of pediatric glioblastoma. Brain tumors were induced by intracranial injection of two GFP-expressing cell lines (SJ-GBM2 and CHLA200) into antithymic mice. Following intravenous injection of nanochains, in vivo fluorescent imaging was performed to non-invasively and quantitatively monitor the time-course of tumor deposition of the particles. Initially, we compared the targeted nanochains to targeted nanospheres and their non-targeting variants in their ability to target pediatric brain tumors. To confirm the findings of in vivo imaging, post mortem histological analyses were performed. Results and Discussion: The shape and prolonged blood residence time of the nanochain resulted in increased interactions with the vascular bed of the primary site of brain tumors as well as their infiltrating edges. As expected, the non-targeted spheres or nanochains slowly accumulate into the tumor via the EPR effect. However, targeted nanochains displayed at least 5-fold higher tumor deposition than their non-targeting variant. Compared to spherical nanoparticles, chain-like particles resulted in superior targeting of avβ3 integrins due to geometrically enhanced multivalent docking. Vascular targeting via the RGD peptide resulted in ＞4% of the administered nanochains attached to the tumor within -30 min after injection. Using a fluorescence imaging system, ex vivo imaging confirmed nanoparticle accumulation at the glioma sites. Similar to optical imaging, MR imaging accurately detected the cancer. Conclusions: Our data indicate that a vascular targeting strategy can selectively target the nanochain particles to pediatric glioblastoma multiforme resulting in tumor detection by optical imaging or MRI.
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