Integrin α2β1-targeting ferritin nanocarrier traverses the blood–brain barrier for effective glioma chemotherapy

Abstract

Background Ferritin, the natural iron storage protein complex, self-assembles into a uniform cage-like structure. Human H-ferritin (HFn) has been shown to transverse the blood–brain barrier (BBB) by binding to transferrin receptor 1 (TfR1), which is abundant in endothelial cells and overexpressed in tumors, and enters cells via endocytosis. Ferritin is easily genetically modified with various functional molecules, justifying that it possesses great potential for development into a nanocarrier drug delivery system. Results In this study, a unique integrin α2β1-targeting H-ferritin (2D-HFn)-based drug delivery system was developed that highlights the feasibility of receptor-mediated transcytosis (RMT) for glioma tumor treatment. The integrin targeting α2β1 specificity was validated by biolayer interferometry in real time monitoring and followed by cell binding, chemo-drug encapsulation stability studies. Compared with naïve HFn, 2D-HFn dramatically elevated not only doxorubicin (DOX) drug loading capacity (up to 458 drug molecules/protein cage) but also tumor targeting capability after crossing BBB in an in vitro transcytosis assay (twofold) and an in vivo orthotopic glioma model. Most importantly, DOX-loaded 2D-HFn significantly suppressed subcutaneous and orthotopic U-87MG tumor progression; in particular, orthotopic glioma mice survived for more than 80 days. Conclusions We believe that this versatile nanoparticle has established a proof-of-concept platform to enable more accurate brain tumor targeting and precision treatment arrangements. Additionally, this unique RMT based ferritin drug delivery technique would accelerate the clinical development of an innovative drug delivery strategy for central nervous system diseases with limited side effects in translational medicine. Graphic Abstract

Protein-Based Nanoparticles for the Imaging and Treatment of Solid Tumors: The Case of Ferritin Nanocages, a Narrative Review

“…The authors speculate that the different fate of FNs between endothelial and tumor cells could be due to the differences in expression of TfR1 [43]. More recently, α2β1-targeted Dox-loaded FN (αβ-FN-DOX) was shown to have enhanced activity compared to FN-DOX in controlling the tumor growth of glioblastoma in an orthotopic model of brain tumor (U-87MG) [44]. Interestingly, αβ-FN-DOX had a higher drug-loading capacity compared to FN-DOX (60 vs. 15%, respectively).…”

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

“…Polymer micelle is a commonly used nano-delivery system, which can enhance the water solubility of drugs, reduce the phagocytosis of the reticuloendothelial system and prolong drug circulation time 37 , 38 , 39 , 40 . Furthermore, based on the highly-expressed receptors in vascular endothelial cells and gliomas, such as neurokinin receptor (NK-R), α V β 3 integrin, low-density lipoprotein receptor associated protein 1 (LRP1), transferrin receptor, ligand modification of drug-loading micelles is implemented to realize tumor targeted release of drugs, so as to enhance the therapeutic effect of glioma 41 , 42 , 43 , 44 . Herein, the substance P (SP) peptide composed of 11 amino acids, which can specifically bind to neurokinin 1 receptor (NK-1R), is applied to the design of a glioma-targeting nanodrug delivery system 45 .…”

Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

“…Most importantly, as a drug vector, HFn nanoparticle can recognize and bind with transferrin receptor 1 (TfR1) on the surface of brain capillary endothelial cells [ 24 ]. Thus, HFn nanoparticles can actively penetrate BBB through TfR1 without additional modifications [ 25 ]. Moreover, HFn encapsulates drugs through depolymerizing/self-assembling, which greatly reducing the difficulty and cost of industrial production.…”