Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By two hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof of concept for a broadly improved method for glioblastoma treatment.

<p>Supplementary Fig. S1. Representative in vivo and ex vivo images using a Maestro FLEX In Vivo Imaging System. Supplementary Fig. S2. Effect of the RF field on the temperature of brain tissues. Supplementary Fig. S3. Bright field microscopy and fluorescence was performed on an entire histological section of the brain stained with Hematoxylin-Eosin (green: CNS-1 glioma cells (GFP)). The same histological section shown in Fig. 4A was used (left panel). Higher magnification of the same section shows the H&E stain of an invasive site (right panel). Supplementary Fig. S4. Cytotoxicity of nanochain particles on CNS-1 cells. Supplementary Fig. S5. Weight progression of animals bearing orthotopic (A) CNS-1 or (B) 9L glioma tumors after DOX treatments.</p>

<p>Supplementary Fig. S1. Representative in vivo and ex vivo images using a Maestro FLEX In Vivo Imaging System. Supplementary Fig. S2. Effect of the RF field on the temperature of brain tissues. Supplementary Fig. S3. Bright field microscopy and fluorescence was performed on an entire histological section of the brain stained with Hematoxylin-Eosin (green: CNS-1 glioma cells (GFP)). The same histological section shown in Fig. 4A was used (left panel). Higher magnification of the same section shows the H&E stain of an invasive site (right panel). Supplementary Fig. S4. Cytotoxicity of nanochain particles on CNS-1 cells. Supplementary Fig. S5. Weight progression of animals bearing orthotopic (A) CNS-1 or (B) 9L glioma tumors after DOX treatments.</p>

<div>Abstract<p>Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood–tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the α_vβ₃ integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. <i>In vivo</i> efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment. <i>Cancer Res; 75(7); 1356–65. ©2015 AACR</i>.</p></div>

<div>Abstract<p>Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood–tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the α_vβ₃ integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. <i>In vivo</i> efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment. <i>Cancer Res; 75(7); 1356–65. ©2015 AACR</i>.</p></div>