A Novel Squalenoylated Temozolomide Nanoparticle with Long Circulating Properties Reverses Drug Resistance in Glioblastoma

• Published in: International journal of molecular sciences Vol. 26; no. 10; p. 4723
• Main Authors: Feng, Jiao, Wen, Chengyong, Zhang, Xiao, Zhu, Xiaolong, Ma, Mengmeng, Zhao, Xiaohong, Sui, Xinbing
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.05.2025; MDPI
• Subjects: Animals; Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - pharmacology; Apoptosis; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cancer; Cell Line, Tumor; Cells; Chemotherapy; Cytotoxicity; DNA damage; Drug resistance; Drug Resistance, Neoplasm - drug effects; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma multiforme; Glioma; Humans; Medical prognosis; Mice; Nanoparticles; Nanoparticles - chemistry; Reactive Oxygen Species - metabolism; Spectrum analysis; Squalene - chemistry; Temozolomide; Temozolomide - administration & dosage; Temozolomide - chemistry; Temozolomide - pharmacokinetics; Temozolomide - pharmacology; China; MGMT expression; temozolomide resistance; glioblastoma; squalenoylation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms26104723

Temozolomide (TMZ) remains the frontline chemotherapy for gliomas; yet its clinical efficacy is significantly compromised by inherent instability and the emergence of resistance mechanisms. To surmount these challenges, we engineered a squalenoylated TMZ nanoparticle (SQ-TMZ NPs) via conjugation of TMZ with squalene, enabling enhanced drug stability and improved therapeutic potency against glioblastoma cells. The resulting SQ-TMZ NPs exhibited a precisely controlled nanoscale architecture (~126 nm), demonstrating exceptional stability under physiological and storage conditions, with minimal hemolytic toxicity (<5%). Notably, these nanoparticles conferred superior cytotoxicity in TMZ-resistant glioblastoma T98G cells, attributed to the amplification of intracellular reactive oxygen species (ROS) and DNA damage, along with MGMT (O-6-methylguanine-DNA methyltransferase) expression suppression. Furthermore, in vivo imaging confirmed their efficient blood–brain barrier (BBB) penetration and selective tumor accumulation. This study presents a transformative approach by integrating prodrug self-assembly with targeted drug delivery to not only enhance TMZ stability but also decisively reverse glioblastoma resistance, offering a compelling therapeutic advancement.