Active targeted delivery of theranostic thermo/pH dual-responsive magnetic Janus nanoparticles functionalized with folic acid/fluorescein ligands for enhanced DOX combination therapy of rat glioblastoma

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Materials for biology and medicine, 2024-06, Vol.12 (24), p.5957-5973
• Main Authors: Ali, Bahareh Haji, Khoee, Sepideh, Mafakheri, Fariba, Sadri, Elahe, Mahabadi, Vahid Pirhajati, Karimi, Mohammad Reza, Shirvalilou, Sakine, Khoei, Samideh
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Apoptosis - drug effects; BAX gene; Bcl-2 protein; Bioaccumulation; Blood-brain barrier; Body weight; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain tumors; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Confocal microscopy; Diagnostic agents; Doxorubicin; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug Delivery Systems; Drug Liberation; Effectiveness; Fluorescence; Fluorescence microscopy; Fluorescent dyes; Fluorescent indicators; Folic acid; Folic Acid - chemistry; Fourier transforms; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - pathology; Glioblastoma cells; Glioma; Hepatotoxicity; Humans; Hydrogen-Ion Concentration; Hyperthermia; Imaging techniques; In vivo methods and tests; Infrared analysis; Infrared spectroscopy; Internalization; Ligands; Light scattering; Magnetic measurement; Magnetite Nanoparticles - chemistry; Male; Microscopy; Nanoparticles; Neuroimaging; Pharmacology; Photon correlation spectroscopy; Physiochemistry; Pigments; Rats; Rats, Wistar; Temperature; Theranostic Nanomedicine; Transmission electron microscopy; Tumor cells; Tumors; Zeta potential
• ISSN: 2050-750X; 2050-7518; 2050-7518
• DOI: 10.1039/d3tb02429f

Doxorubicin (DOX), a chemotherapy drug, has demonstrated limited efficacy against glioblastoma, an aggressive brain tumor with resistance attributed to the blood-brain barrier (BBB). This study aims to overcome this challenge by proposing the targeted delivery of magnetic Janus nanoparticles (MJNPs) functionalized with folic acid ligands, fluorescent dye, and doxorubicin (DOX/MJNPs-FLA). The properties of these nanoparticles were comprehensively evaluated using bio-physiochemical techniques such as Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), zeta potential analysis, high-resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometry (VSM), fluorescence microscopy, MTT assay, hemolysis assay, and liver enzyme level evaluation. Dual-controlled DOX release was investigated under different pH and temperature conditions. Additionally, the impact of DOX/MJNPs-FLA on apoptosis induction in tumor cells, body weight, and survival time of cancerous animals was assessed. The targeted delivery system was assessed using C6 and OLN-93 cell lines as representatives of cancerous and healthy cell lines, respectively, alongside Wistar rat tumor-bearing models. Results from Prussian blue staining and confocal microscopy tests demonstrated the effective targeted internalization of MJNPs-FLA by glioblastoma cells. Additionally, we investigated the biodistribution of the nanoparticles utilizing fluorescence imaging techniques. This enabled us to track the distribution pattern of MJNPs-FLA in vivo , shedding light on their movement and accumulation within the biological system. Furthermore, the combination of chemotherapy and magnetic hyperthermia exhibited enhanced efficacy in inducing apoptosis, as evidenced by the increase of the pro-apoptotic Bax gene and a decrease in the anti-apoptotic Bcl-2 gene. Remarkably, this combination treatment did not cause any hepatotoxicity. This study highlights the potential of DOX/MJNPs-FLA as carriers for therapeutic and diagnostic agents in the context of theranostic applications for the treatment of brain malignancies. Additionally, it demonstrates the promising performance of DOX/MJNPs-FLA in combination treatment through passive and active targeting. Doxorubicin loaded magnetic Janus nanoparticles coated with PCL and chitosan modified with folic acid and fluorescein were able to pass the blood brain-barrier via the external magnetic field and folic acid ligand-receptor interaction.