Construction of aptamer-siRNA chimera and glutamine modified carboxymethyl-β-cyclodextrin nanoparticles for the combination therapy against lung squamous cell carcinoma

• Published in: Biomedicine & pharmacotherapy Vol. 174; p. 116506
• Main Authors: Hao, Yanfei, Yang, Jintao, Liu, Dongxu, Zhang, Hong, Ou, Tongwen, Xiao, Li, Chen, Wen
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-05-2024; Elsevier
• Subjects: Animals; Apoptosis - drug effects; aptamer; Aptamers, Nucleotide - pharmacology; B7-H1 Antigen - metabolism; beta-Cyclodextrins - chemistry; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; Cell Line, Tumor; chemotherapy; Combined Modality Therapy; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Glutamine; Humans; immunotherapy; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; lung squamous cell carcinoma; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles - chemistry; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - pharmacology; Xenograft Model Antitumor Assays; PBS; NSCLC; CRS; EDC; DMSO; Gln; DOX; MTT; glutamine; chemotherapy; β-CD; FAM; TUNEL; PEI; aptamer; immunotherapy; PD-L1; NHS; lung squamous cell carcinoma
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2024.116506

Combination therapy has become the most important treatment for advanced non-small cell lung cancer (NSCLC), which can significantly improve the prognosis of patients. However, poor targeting and adverse reactions limited its clinical application. Here, we constructed an AS1411 aptamer-programmed cell death ligand-1 (PD-L1) siRNA chimera/polyethylenimine/glutamine/β-cyclodextrin/doxorubicin (Chimera/ PEI/Gln/β-CD/DOX) nanoparticle for the combination therapy (chemotherapy combined with immunotherapy). Scanning electron microscopy showed that PEI/Gln/β-CD/DOX nanoparticle was conical, with a diameter of about 250–500 nm. AS1411 aptamer-PD-L1 siRNA chimera can effectively bind NSCLC cells and inhibit PD-L1 expression, further activating T cells and CD8+T cells. Glutamine modification effectively promoted the doxorubicin uptake by cancer cells and induced their apoptosis. Animal experiments showed that our nanoparticles effectively treated the transplanted tumor, and the adverse reactions were reduced. Compared with the Aptamer/β-CD/DOX group, the volume and ki-67 index of transplanted tumors in the Chimera/β-CD/DOX group were significantly decreased, while the apoptosis ratio was increased. Immunohistochemical results showed that Compared with the Aptamer/β-CD/DOX group, the number of T cells and CD8+T cells in the Chimera/β-CD/DOX group was increased by 1.34 and 1.41 times. Glutamine modification enhanced the chemotherapeutic efficacy and anti-tumor immune response in vivo. Our study provided a new method for the combination therapy of lung squamous cell carcinoma.
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•Aptamer-siRNA chimera achieves specific binding and target gene silencing.•Glutamine modification enhances the phagocytosis of nanoparticles.•Chimera/PEI/Gln/β-CD/DOX nanoparticles can be used for the comprehensive treatment of lung squamous cell carcinoma.