Optimization of Ultra-Small Nanoparticles for Enhanced Drug Delivery

Abstract Nanoparticle delivery of drugs to the brain is hindered by the blood-brain barrier (BBB). In malignant glioma (MG), small disruptions in the BBB may allow nanoparticles smaller than 20 nm to penetrate the dysfunctional barrier. We previously developed ultra-small nanoparticles called hyper-cell permeable micelles (HCPMis) with a radius of ∼12 nm and found that a PEGylated HCPMi system showed enhanced cell permeability and cellular uptake, and remarkable anti-tumor properties in MG treatment. However, no study had examined the delivery of temozolomide (TMZ), the first-line drug for MG, with the HCPMi platform. Herein, we use a simple PEGylation increment system (30 wt % PEG, 40 wt % PEG and 50 wt % PEG) to develop a robust optimized HCPMi nanoplatform for TMZ delivery. All optimized HCPMi systems showed greater stability than the non-PEGylated parent formulation. Compared with commercially available micelles (DSPE-PEG 2000 ), all optimized HCPMi systems showed greater cellular uptake in vitro . Although a higher percentage of PEGylation was associated with better cellular uptake and anti-cancer properties, the difference was statistically insignificant. Furthermore, in vitro cytotoxicity assays revealed that all optimized HCPMi-encapsulated TMZ formulations showed significantly stronger anti-cancer properties than the parent drug TMZ and TMZ encapsulated DSPE-PEG 2000 , thus indicating the feasibility of using this nanoplatform for the delivery of TMZ to treat brain malignancies.