Oncoprotein Inhibitor Rigosertib Loaded in ApoE-Targeted Smart Polymersomes Reveals High Safety and Potency against Human Glioblastoma in Mice.
Huazhen QinYu JiangJian ZhangChao DengZhiyuan ZhongPublished in: Molecular pharmaceutics (2019)
The unbiased cytotoxicity and blood-brain barrier (BBB) impermeability render common chemotherapeutics nonviable for treating glioblastoma (GBM) patients. Although rigosertib (RGS), a RAS effector protein inhibitor, has shown low toxicity to healthy cells and high efficacy toward various cancer cells by inactivating PI3K-Akt, it hardly overcomes the BBB barricade. Here, we report that RGS loaded in apolipoprotein E derived peptide (ApoE)-targeted chimaeric polymersomes (ApoE-CP) is safe and highly potent against human GBM in vivo. ApoE-CP exhibited stable loading of RGS in its lumen, giving RGS nanoformulations (ApoE-CP-RGS) with a size of 60 nm and reduction-triggered drug release behavior. Notably, ApoE-CP-RGS induction markedly enhanced the G2/M cell cycle arrest and inhibitory effect in U-87 MG glioblastoma cells compared with the nontargeted CP-RGS and free RGS. The therapeutic outcomes in orthotopic U-87 MG GBM models demonstrated that ApoE-CP-RGS brought about effective GBM inhibition, greatly prolonged survival time, and depleted adverse effects. Rigosertib formulated in ApoE-targeted chimaeric polymersomes has emerged as a novel, highly specific, efficacious, and nontoxic treatment for glioblastoma.
Keyphrases
- cell cycle arrest
- cognitive decline
- pi k akt
- blood brain barrier
- high fat diet
- cell death
- cancer therapy
- drug delivery
- signaling pathway
- induced apoptosis
- endothelial cells
- drug release
- mild cognitive impairment
- end stage renal disease
- cell proliferation
- chronic kidney disease
- prognostic factors
- type diabetes
- dendritic cells
- metabolic syndrome
- ejection fraction
- adipose tissue
- brain injury
- endoplasmic reticulum stress
- wild type
- photodynamic therapy
- cerebral ischemia
- mass spectrometry
- subarachnoid hemorrhage
- high resolution mass spectrometry
- liquid chromatography
- tandem mass spectrometry
- replacement therapy