Biomimetic brain-targeted nanoparticles with persistent luminescence for sustained and autofluorescence-free imaging and synergetic therapy of gliomas

Brain tumors, especially gliomas, are the most common solid tumors affecting both children and adults. Some types of gliomas, such as glioblastoma (GBM), are characterized by the metastatic growth and unclear boundary between the tumor tissue and surrounding normal brain tissue, which in turn make them difficult to treat with surgery. The average survival of GBM patients is approximately 5-12 months with aggressive surgical resection and conventional therapy, because of the failure of most drugs to cross the blood-brain barrier (BBB) and the strong cytotoxicity of the drugs to normal tissues.

Magnetic resonance imaging (MRI), with the help of contrast agents (CAs) to define the tumor margins in clinic, is the major imaging modality for diagnosis and therapeutic evaluation of gliomas. However, the CAs cannot cross the BBB and show no effect on the enhancement of the MRI signal to define tumor margins if BBB is not damaged. Moreover, the transient circulation lifetime and non-targeting specificity of the CAs further hinder their application. Therefore, probes with BBB permeability, optimized circulation lifetime, and high targeting specificity are needed.

The near-infrared (NIR) emitting persistent luminescence nanoparticles, which enable sustained and autofluorescence-free imaging of gliomas, and the T7 peptide with a dual function of BBB and glioma targeting will be selected. We propose to make TRPD, the red blood cell membrane (RCM)-coated T7-conjugated doxorubicin (DOX)-loaded persistent luminescence nanoparticles, for the imaging and synergetic therapy of gliomas. The prepared TRPD possessed five key features, including: (i) diagnosis and synergetic therapy; (ii) BBB penetration; (iii) background interference-free and renewable imaging; (iv) tumor targeting; (v) prolonged circulation lifetime and drug release. Several important preliminary results were obtained to support our hypothesis, including (i) TRPD was successfully formed; (ii) in vitro cytotoxicity of TRPD to glioma cells was confirmed; (iii) in vivo renewable and autofluorescence-free imaging of the subcutaneous glioma model by TRPD was obtained; (iv) prolonged circulation lifetime and drug release of DOX was achieved. For the biosafety of TRPD, there were studies using the similar synthesis method for the conjugations of different ligands and cell membranes. It was reported that there was no immunogenicity concern for the materials involved and the nanoparticle product.

In this project, the physical and chemical characterizations, and in vitro and in vivo evaluations on the properties, efficacy, and safety of TRPD will be conducted using the orthotopic glioma mice model. We strongly believe that this proposed study will be a pioneering work for diagnostic imaging and synergetic therapy of gliomas. The results of this study will benefit the targeted therapies of brain-related diseases and bring in new BBB permeable CAs for the non-invasive brain imaging.