Targeted glioblastoma therapy by integrating brain-targeting peptides and corn-derived cancer cell-penetrating proteins into nanoparticles to cross blood-brain tumor barriers

Dong Zhang, Jianglong Kong, Xueying Huang, Jie Zeng, Qiaohui Du, Tao Yang, Hui Yue, Qing Bao, Yao Miao, Yajing Xu, Honglin Jiang, Fang Lei, Mei Yang, Yi Wang*, Chuanbin Mao*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

2 Citations (Scopus)

Abstract

Targeted brain tumor therapy by nanoparticles (NPs) remains a daunting challenge due to the difficulty for NPs to go through the blood-brain barriers (BBB) and blood-brain tumor barriers (BBTB). In addition, Dactolisib (Dac) is an effective dual PI3K/mTOR inhibitor for cancer treatment. It was the first PI3K inhibitor to enter clinical trials but exhibited toxicity to normal tissues if not delivered to tumor sites by a tumor-targeting carrier. To explore Dac for glioblastoma (GBM) therapy while avoiding its toxicity, we developed a new brain tumor-targeting drug delivery system self-assembled from zein, a cell membrane-penetrating amphiphilic protein originally present in corn. Specifically, the amphiphilicity of zein drove it to self-assemble into NPs that encapsulated Dac with high efficiency. RVG29, a 29-mer brain-targeting peptide, was chemically conjugated to zein constituting the NPs, forming Dac-encapsulated NPs (zein-RVG-Dac_NPs). In vitro assays were conducted to verify the capability of the NPs in penetrating BBB/BBTB, targeting GBM cancer cells and killing them. ELISA was employed to assess the expression of nicotinic acetylcholine receptors (nAChR) on the cancer cells to understand the mechanism of cancer cell membrane penetration by the NPs. The NPs were intravenously injected into orthotopic GBM mice models to demonstrate the brain tumor targeting as well as the effective GBM therapy due to the targeted delivery of Dac to brain tumors. The treated tumors were immunohistochemically analyzed to verify the tumor destruction. To confirm the biosafety of the NPs in treating GBM, we also histopathologically evaluated the major normal organs and chemically analyzed the blood biomarkers. We found that a combination of zein and RVG29 facilitated the zein-RVG-Dac_NPs to cross the BBB/BBTB and became uptaken by the GBM cells through the nAChR-mediated pathways, enabling the NPs to cross BBB/BBTB and deliver Dac selectively to GBM cells. Hence, administration of the NPs through tail veins significantly increased the accumulation of Dac in the orthotopic brain tumor of mice and effectively inhibited tumor growth. Neither toxicity nor adverse effects in the major organs were found due to the excellent biocompatibility of zein and the targeted delivery of Dac into brain tumor cells. Hence, integrating a cell-penetrating natural protein (zein) and a brain-targeting peptide (RVG29) can form NPs that can effectively penetrate BBB/BBTB and then enter brain tumor cells to release Dac, leading to highly effective targeted brain cancer therapy. Such NPs can be extended to the development of therapeutics for treating different brain diseases due to their unique combination of biocompatibility and brain-targeting capability.

Original languageEnglish
Article number100347
JournalMaterials Today Nano
Volume23
Early online date29 Apr 2023
DOIs
Publication statusPublished - Aug 2023

Scopus Subject Areas

  • Electronic, Optical and Magnetic Materials
  • Biomaterials
  • Condensed Matter Physics
  • Materials Chemistry

User-Defined Keywords

  • Blood-brain tumor barrier
  • Cancer therapy
  • Glioblastoma
  • Zein

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