Reconstruction of TNF-α with specific isoelectric point released from SPIONs basing on variable charge to enhance pH-sensitive controlled-release

• Published in: Nanomedicine Vol. 60; p. 102758
• Main Authors: Yan, Lin, Chen, Yadi, Zhang, Shihao, Zhu, Chunjie, Xiao, Shangying, Xia, Haishan, Chen, Xiaohua, Guo, Dan, Lv, Xiaohua, Rao, Lei, Zhuang, Manjiao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024
• Subjects: Isoelectric point; pH-sensitive controlled release; SPION; TNF-α; Tumor microenvironment; pH-sensitive controlled release; TNF-α; Tumor microenvironment; SPION; Isoelectric point
• ISSN: 1549-9634; 1549-9642; 1549-9642
• DOI: 10.1016/j.nano.2024.102758

The clinical application of tumor necrosis factor-α (TNF-α) is limited by its short half-life, subeffective concentration in the targeted area and severe systemic toxicity. In this study, the recombinant polypeptide S4-TNF-α was constructed and coupled with chitosan-modified superparamagnetic iron oxide nanoparticles (S4-TNF-α-SPIONs) to achieve pH-sensitive controlled release and active tumor targeting activity. The isoelectric point (pI) of S4-TNF-α was reconstructed to approach the pH of the tumor microenvironment. The negative-charge S4-TNF-α was adsorbed to chitosan-modified superparamagnetic iron oxide nanoparticles (CS-SPIONs) with a positive charge through electrostatic adsorption at physiological pH. The acidic tumor microenvironment endowed S4-TNF-α with a zero charge, which accelerated S4-TNF-α release from CS-SPIONs. Our studies showed that S4-TNF-α-SPIONs displayed an ideal pH-sensitive controlled release capacity and improved antitumor effects. Our study presents a novel approach to enhance the pH-sensitive controlled-release of genetically engineered drugs by adjusting their pI to match the pH of the tumor microenvironment. Scheme 1 Schematic illustration of the preparation of S4-TNF-α-SPIONs and pH-sensitive controlled/magnetic targeting of S4-TNF-α-SPION in vivo. CS distributed on the surface endowed the SPIONs with a positive charge. The pI of TNF-α was adjusted to the pH of the tumor microenvironment by adding acidic or basic amino acids. The reconstructed TNF-α was adsorbed to the SPIONs via electrostatic adsorption to generate TNF-α-SPIONs at pH 7.4. SPIONs delivered TNF-α to the targeted area with the help of an external MF. The acidic pH of the tumor microenvironment endowed TNF-α with a zero charge, which decreased TNF-α adsorption on the SPIONs to realize pH-sensitive controlled release. [Display omitted]