Glioblastoma (GBM) is the most common and deadly brain tumor in adults, with a 5-year survival rate of less than 10%. Currently, temozolomide (TMZ) is the first-line anticancer drug for GMB, but its drug resistance has always plagued people for long. It is known that the acquired mismatch repair defects and overexpression of O6-methylguanine-DNA-methyltransferase (MGMT) are involved in the TMZ resistance. Therefore, it is urgent to find new treatment options and drugs other than TMZ with different action mechanism to solve the urgent problems.
In a recent study published inNature Biomedical Engineering (2021, DOI: 10.1038/s41551-021-00728-7), the research group led by Prof. XIAO Haihua from the Institute of Chemistry, Chinese Academy of Sciences and Prof. W. Mark Saltzman？ from School of Engineering and Applied Sciences at Yale University developed a  platinum-based nanodrug to tackle TMZ resistance.
Firstly, the researchers designed a reduction-responsive biodegradable polymer to encapsulate a platinum(IV) prodrug of oxaliplatin and a platinum(II) DNA intercalator 56MESS separately to form two nanoparticles. Secondly, the researchers established a TMZ-resistant patient-derived GMB primary cell line (GBM-PDC^Resistant) and an acquired drug-resistant transgenic engineered GMB cell line (GBM-Transgenic^Resistant) to screen the above mentioned two platinum-based nanoparticles in vitro, and they found that both of them can reverse TMZ resistance. Thirdly, the researchers further developed a TMZ-resistant patient-derived xenograft mouse model of GMB (GBM-PDX^Resistant) in vivo. Subsequently, with the help of advanced convection-enhanced delivery technology (CED), these nanoparticles were able to directly deliver the drugs to the target brain area for bypassing the blood-brain barrier in mice. They found that nanoparticles loaded with the DNA intercalator 56MESS can work better to inhibit the growth of drug-resistant GMB tumors and prolong their survival rate. Finally, through RNA-sequencing, the researchers found that the signal transduction and metabolic pathways altered by 56MESS-based nanoparticles are quite different from those of TMZ, confirming the unique mechanism of action.
This work provides a new perspective of reduction-responsive polymers to deliver platinum-based drugs combined with advanced CED techniques to treat resistant GBM.