In Situ Formation of Nanotheranostics to Overcome the Blood-Brain Barrier and Enhance Treatment of Orthotopic Glioma.

Glioblastoma is one of the most lethal cancers and needs effective therapeutics. The development of coordination-driven metal-organic nanoassemblies, which can cross the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) and have multiple desired functions, may provide a promising solution to this issue. Here, we report an in situ assembled nanoplatform based on RGD peptide-modified bisulfite-zincII-dipicolylamine-Arg-Gly-Asp (Bis(DPA-Zn)-RGD) and ultrasmall Au-ICG nanoparticles. Attributed to its positive charges and neovascular targeting properties, Bis(DPA-Zn)-RGD can be selectively delivered to the tumor site, and then assembled in situ into large nanoclusters with subsequently administered Au-ICG nanoparticles. Au nanoparticles with ultrasmall size (∼7 nm) can successfully cross the BBB. The obtained nanoclusters exhibit strong near-infrared-red (NIR) absorption and an enhanced tumor retention effect, enabling precise orthotopic fluorescence/photoacoustic imaging. With the aid of image guidance, the photothermal effect of the nanoclusters is observed to suppress tumor progression with the inhibition efficiency reaching up to 93.9%. Meanwhile, no photothermal damage can be found for normal brain tissues. These results, herein, suggest a feasible nanotheranostic agent with the ability to overcome the BBB and BBTB for imaging and therapy of orthotopic brain tumors.