pH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma.

Abstract

To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.

• Authors: Yi Zhao, Yao Peng, Zhongzhen Yang, Jiaqi Lu, Ru Li, Yuesen Shi, Yaxin Du, Ze Zhao, Li Hai, Yong Wu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 235 Pg. 114281 (May 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 35344903 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Indazoles
• Ligands
• Liposomes
• Prodrugs
• Doxorubicin
• Glucose
• lonidamine

Topics

• Cell Line, Tumor
• Doxorubicin
• Glioma (drug therapy)
• Glucose
• Humans
• Hydrogen-Ion Concentration
• Indazoles
• Ligands
• Liposomes (therapeutic use)
• Oxidation-Reduction
• Prodrugs (pharmacology, therapeutic use)