Development of curcumin-loaded zein nanoparticles for transport across the blood-brain barrier and inhibition of glioblastoma cell growth.

Huaiying Zhang,Alexander Kros,Guangyue Zu,Yong Liu,Inge S Zuhorn,Winant L Van Os,Jeroen Bussmann,Xiaobo Tian,Reinier Bron,Laís Ribovski

doi:10.1039/d0bm01536a

Abstract

Glioblastoma (GBM) is a devastating primary brain tumor resistant to conventional therapies. A major obstacle to GBM treatment is the blood-brain barrier (BBB), or blood-glioma barrier, which prevents the transport of systemically administered (chemotherapeutic) drugs into the tumor. This study reports the design of dodecamer peptide (G23)-functionalized polydopamine (pD)-coated curcumin-loaded zein nanoparticles (CUR-ZpD-G23 NPs) that efficiently traversed the BBB, and delivered curcumin to glioblastoma cells. The NPs enhanced the cellular uptake of curcumin by C6 glioma cells compared to free curcumin, and showed high penetration into 3D tumor spheroids. Functionalization of the NPs with G23 stimulated BBB crossing and tumor spheroid penetration. Moreover, the NPs markedly inhibited proliferation and migration and induced cell death in liquid and soft agar models of C6 glioma cell growth. Fluorescence microscopy and flow cytometry studies showed that the CUR-ZpD-G23 NPs increased cellular ROS production and induced apoptosis of C6 glioma cells. Following in vivo intravenous injection in zebrafish, ZpD-G23 NPs demonstrated the ability to circulate, which is a first prerequisite for their use in targeted drug delivery. In conclusion, zein-polydopamine-G23 NPs show potential as a drug delivery platform for therapy of GBM, which requires further validation in in vivo glioblastoma models.

Highlights

At the blood–brain barrier (BBB) the process of selective transcellular transport of target molecules via carrier-mediated transport, cation-induced absorptive transcytosis, or receptor-mediated transcytosis, provide gateways for the delivery of nanoparticles into the brain.[6,7]Many kinds of nanoparticles (NPs) have recently been employed to enhance the delivery of existing and novel therapeutics across the BBB.[6,8,9,10] Among them, biodegradable NPs from natural polymers, such as protein-based polymers, have attracted remarkable attention as potential drug delivery carriers for their low cost and low toxicity.[11]
G23 peptide with a C-terminal cysteine was synthesized by GL Biochem Ltd (Shanghai, China) with a purity of 93.6% as analyzed by high-performance liquid chromatography (HPLC) and mass spectrometry
The resulting pD-coated zein NPs all showed a good dispersibility with low PDI and a strong negative surface charge, which was due to the deprotonation of the phenolic hydroxyl groups

Summary

Introduction

At the BBB the process of selective transcellular transport of target molecules via carrier-mediated transport, cation-induced absorptive transcytosis, or receptor-mediated transcytosis, provide gateways for the delivery of nanoparticles into the brain.[6,7]. Many kinds of nanoparticles (NPs) have recently been employed to enhance the delivery of existing and novel therapeutics across the BBB.[6,8,9,10] Among them, biodegradable NPs from natural polymers, such as protein-based polymers, have attracted remarkable attention as potential drug delivery carriers for their low cost and low toxicity.[11] Zein, an alcoholsoluble protein, extracted from corn, has emerged as an ideal drug delivery system because of its excellent biocompatibility and biodegradability. Weak chemical reactivity appears to be a major problem that limits their

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Conclusion