Quaternary Ammonium Salts Anchored on Cross-Linked (R)‑(+)-Lipoic Acid Nanoparticles for Drug-Resistant Tumor Therapy

• Published in: ACS applied materials & interfaces 2021-12, Vol.13 (48), p.56850-56857
• Main Authors: Zhou, Xueying, Dai, Xin, Tan, Juan, Wu, Xiao, Zhou, Xiaodong, Liao, Chunyan, Zhang, Shiyong
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Biological and Medical Applications of Materials and Interfaces; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cell Line; Cell Survival - drug effects; Cross-Linking Reagents - chemical synthesis; Cross-Linking Reagents - chemistry; Cross-Linking Reagents - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Humans; Materials Testing; Mice; Molecular Structure; Nanoparticles - chemistry; Particle Size; Quaternary Ammonium Compounds - chemistry; Quaternary Ammonium Compounds - pharmacology; Salts - chemistry; Salts - pharmacology; Stereoisomerism; Structure-Activity Relationship; Thioctic Acid - chemistry; Thioctic Acid - pharmacology
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.1c16293

A membrane-lytic mechanism-based nanodrug is developed for drug-resistant tumor therapy by anchoring the small-molecule quaternary ammonium salt (QAS) on cross-linked (R)-(+)-lipoic acid nanoparticles (cLANs). The anchoring of QAS on the nanoparticle avoids the direct attack of long alkyl chains to the cell membrane under physiological conditions, while after entering tumor cells, the QAS is released from the dissociated cLANs, migrates to the phospholipid bilayer via electrostatic interaction, and destroys the cell membrane by the puncture of long alkyl chains. Since the QAS is designed to finally be hydrolyzed to amino acid betaine and food additive cetanol and the cLANs degrade to dihydrolipoic acid (DHLA, reduced form of dietary antioxidant lipoic acid in cells), the QAS@cLANs hold superior biosafety. In addition to the drug-resistant tumors, the QAS@cLANs demonstrate significant inhibition of metastatic tumors. This work provides not only a general and clinic-promising treatment for the refractory tumors but also opens a door for the medicinal use of QAS.