Abstract
BackgroundGlioma is the deadliest brain cancer in adults because the blood–brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma single-photon emission computed tomography (SPECT) imaging and anticancer drug delivery.ResultsThis multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol (mPEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99mTc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac2O), the CTX-modified PEI (mPEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The formed mPEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the mPEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99mTc via DTPA, the 99mTc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging.ConclusionsThese results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.
Highlights
Glioma is the deadliest brain cancer in adults because the blood–brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system
As a ligand of the chloride ion channel, chlorotoxin (CTX), a small peptide purified from scorpion venom, has been proven to have the ability to penetrate the BBB and show high affinity binding to glioma cells via chloride ion channel and matrix metalloproteinase 2 [31]
As shown in Additional file 1: Fig. S1a and S1b, the peaks at 3.5– 3.7 ppm could be assigned to the aromatic protons of Polyethylene glycol (PEG), while the peaks at 1.0–1.5 ppm were attributed to the protons of CTX (Fig. 1c)
Summary
Glioma is the deadliest brain cancer in adults because the blood–brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. Some receptors and transporters, including but not limited to transferrin receptor, low density lipoprotein receptor, insulin receptor, nicotinic acetylcholine receptor, amino acid transporter, choline transporter, hexose transporter, and monocarboxylic acid transporter, have been determined to be involved in receptor/transporter-mediated transcytosis across BBB [19,20,21,22,23,24,25,26] These findings have motivated numerous researchers around the world to focus on the development of novel brain targeting systems for glioma imaging and treatment. A variety of CTX peptide modified NPs, for instance, CTX-conjugated iron oxides, liposomes, dendrimers, quantum dots, and rare-earth up-conversion NPs, have been studied as potential candidates in this field [37, 38] These NPs can be used as imaging agents for diagnosis or as drug carriers for treatment, and as multifunctional systems for theranostic applications. Among these NPs, dendritic polymers such as poly(amidoamine) and polyetherimide (PEI) dendrimers, have been considered as promising templates to construct theranostic nanosystems for various kinds of tumors, including brain cancer [39, 40]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
