Comparison of nose-to-brain and systemic delivery of STING agonist-loaded liposomes for glioblastoma treatment
Makaleler > Tam Makale · 2025
Yazarlar: Mustafa KOTMAKÇI, Busra Bara, Zafer Yildirim, Ezgi Oner, Banu Yaman, Taner Akalin, Erkin Ozgiray, Buket Kosova, Vildan BOZOK
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, SCI İndekslerine Giren Dergi, Uluslararası, Wos, 2025, cilt 109, ss 1-15
DOI: 10.1016/j.jddst.2025.107000
Özet
<p>Background: Glioblastoma (GBM) is an aggressive brain tumour known for its highly immunosuppressive microenvironment. The stimulator of interferon genes (STING)-mediated immune activation has shown promise in different tumour models using various agonists and delivery systems. Here, we aimed to develop a liposomal formulation for non-invasive intranasal delivery of diABZI, a STING agonist, and investigate its efficacy in triggering immune responses. After characterization, in vitro evaluation of lipsosomes was performed using monocyte and GBM cell lines. Therapeutic potential was further assessed in vivo using a bioluminescence-traceable, syngeneic orthotopic mouse GBM model. Results: First, we prepared neutral and cationic liposomes, both PEGylated and non-PEGylated. Based on their characteristics such as diameter, polydispersity index, zeta potential, and cellular uptake, subsequent research was continued with cationic liposomes (cL) and cationic PEGylated liposomes (cL(PEG)). Both cL and cL(PEG) showed excellent encapsulation efficiency (>99.5 %) of diABZI with similar in vitro release profiles. The particle size of cL-diABZI increased dramatically in the presence of serum, whereas cL(PEG)-diABZI demonstrated greater stability with minimal size alteration. Furthermore, cL-diABZI exhibited higher serum protein adsorption compared to the cL(PEG)-diABZI. Therefore, we used PEGylated cationic liposome formulation for further in vitro and in vivo experiments. cL(PEG)-diABZI formulation successfully stimulated interferon response in the THP1 human monocytic cell line. Single-dose intranasal or systemic delivery prolonged survival in GBM-bearing mice. A significant increase in mRNA levels of interferon-stimulated genes and elevated interferon beta protein were detected. Moreover, enhanced granzyme B expression and lymphocyte infiltration demonstrated immune activation in the GBM tissue. Conclusions: Our results reveal the successful development of novel diABZI-loaded liposomes useful for nose-to-brain treatment of GBM, representing a non-invasive approach to deliver immunostimulators. This strategy holds promise for overcoming treatment barriers in GBM by increasing immunogenicity while minimizing cytotoxicity.</p>