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

## TL;DR

A new nanoparticle version of temozolomide improves drug stability and overcomes resistance in glioblastoma.

## Contribution

A squalenoylated temozolomide nanoparticle was developed to reverse drug resistance in glioblastoma.

## Key findings

- SQ-TMZ NPs showed enhanced stability and low toxicity under physiological conditions.
- The nanoparticles increased cytotoxicity in TMZ-resistant glioblastoma cells by inducing ROS and DNA damage.
- In vivo imaging confirmed BBB penetration and tumor targeting by SQ-TMZ NPs.

## Abstract

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.