Reversible Covalent Cross-Linked Polycations with Enhanced Stability and ATP-Responsive Behavior for Improved siRNA Delivery
| Autor: | Minjie Sun, Minghua Zhang, Zhanwei Zhou, Yadong Liu, David Oupicky, Qingyan Zhang, Chenzi Li |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Polymers and Plastics Bioengineering CHO Cells macromolecular substances 02 engineering and technology 010402 general chemistry 01 natural sciences Biomaterials Mice chemistry.chemical_compound Adenosine Triphosphate Cricetulus Cell Line Tumor Cricetinae Polyamines Materials Chemistry Animals Polyethyleneimine Hyaluronic Acid Phenylboronic acid Cytotoxicity Polyethylenimine Gene Transfer Techniques technology industry and agriculture Cationic polymerization 021001 nanoscience & nanotechnology Boronic Acids Polyelectrolytes Polyelectrolyte 0104 chemical sciences Mice Inbred C57BL Cross-Linking Reagents RNAi Therapeutics chemistry Covalent bond Biophysics Nucleic acid RNA Interference 0210 nano-technology Adenosine triphosphate |
| Zdroj: | Biomacromolecules. 19:3776-3787 |
| ISSN: | 1526-4602 1525-7797 |
| DOI: | 10.1021/acs.biomac.8b00922 |
| Popis: | Cationic polyplex as commonly used nucleic acid carriers faced several shortcomings, such as high cytotoxicity, low serum stability, and slow cargo release at the target site. The traditional solution is covering a negative charged layer (e.g., hyaluronic acid, HA) via electrostatic interaction. However, it was far from satisfactory for the deshielding by physiological anions in circulation (e.g., serum proteins, phosphate). In this study, we proposed a new strategy of reversible covalent cross-linking to enhance stability in circulation and enable stimuli-disassembly of polyplexes in tumor cells. Here, 25k polyethylenimine (PEI) was chosen as model polycations for veriying the hypothesis. HA-PEI conjugation was formed by the cross-linking of adenosine triphosphate grafted HA (HA-ATP) with phenylboronic acid grafted PEI (PEI-PBA) via the chemical reaction between PBA and ATP. Compared with noncovalent polyplex by electrostatic interaction (HA/PEI), HA-PEI exhibited much better colloidal stability and serum stability. The covered HA-ATP layer on PEI-PBA could maintain stable in the absence of physiological anions, while HA layer on PEI in HA/PEI group showed obvious detachment after anion's competition. More importantly, the covalent cross-linking polyplex could selectively release siRNA in the ATP rich environment of cytosol and significantly improve siRNA silence. Besides, the covalent cross-linking with HA-ATP could effectively reduce the cytotoxicity of cationic polyplex, improve the uptake by B61F10 cells and promote the endosomal escape. Consequently, this strategy of HA-PEI conjugation significantly enhanced the siRNA transfection in the absence or presence of FBS (fetal bovine serum) on B16F10 cells and CHO cells. Taken together, the reversible covalent cross-linking approach shows obvious superiority compared with the noncovalent absorption strategy. It held great potential to be developed to polish up the performance of cationic polyplex on reducing the toxicity, enhancing the serum tolerance and achieving controlled release of siRNA at target site. |
| Databáze: | OpenAIRE |
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