4.7 Article

Polyethylenimine-Conjugated Hydroxyethyl Cellulose for Doxorubicin/Bcl-2 siRNA Co-Delivery Systems

Journal

PHARMACEUTICS
Volume 15, Issue 2, Pages -

Publisher

MDPI
DOI: 10.3390/pharmaceutics15020708

Keywords

gene; drug delivery systems; hydroxyethyl cellulose; polyethylenimine; serum stability; doxorubicin; Bcl-2 siRNA; drug resistance; anti-cancer effect

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In this study, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for the co-delivery of doxorubicin/Bcl-2 siRNA. HECP2ks were successfully synthesized and characterized. The results showed that HECP2ks effectively condensed pDNA into positively charged and nano-sized complexes, exhibiting low cytotoxicity and high transfection efficiency. HECP2k 10X demonstrated superior cellular uptake, endosome escape, and synergistic anti-cancer effects through co-delivery of Dox and Bcl-2 siRNA. Therefore, HECP2k shows great potential as a promising co-delivery carrier for Dox/Bcl-2 siRNA.
Hydroxyethyl cellulose (HEC), widely known for its biocompatibility and water solubility, is a polysaccharide with potential for pharmaceutical applications. Here, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for doxorubicin/Bcl-2 siRNA co-delivery systems. HECP2ks were synthesized by reductive amination of PEI2k with periodate-oxidized HEC. The synthesis of the polymers was characterized using H-1 NMR, C-13 NMR, primary amine quantification, FT-IR, and GPC. Via agarose gel electrophoresis and Zeta-sizer measurement, it was found that HECP2ks condensed pDNA to positively charged and nano-sized complexes (100-300 nm, similar to 30 mV). The cytotoxicity of HECP2ks was low and HECP2k 10X exhibited higher transfection efficiency than PEI25k even in serum condition, showing its high serum stability from ethylene oxide side chains. Flow cytometry analysis and confocal laser microscopy observation verified the superior cellular uptake and efficient endosome escape of HECP2k 10X. HECP2k 10X also could load Dox and Bcl-2 siRNA, forming nano-particles (HECP2k 10X@Dox/siRNA). By median effect analysis and annexin V staining analysis, it was found that HECP2k 10X@Dox/siRNA complexes could cause synergistically enhanced anti-cancer effects to cancer cells via induction of apoptosis. Consequently, it was concluded that HECP2k possesses great potential as a promising Dox/Bcl-2 siRNA co-delivery carrier.

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