Cationic Mucic Acid Polymer-Based siRNA Delivery Systems
| Autor: | Mark E. Davis, Dorothy W. Pan |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Polymers
Biomedical Engineering Pharmaceutical Science Bioengineering Mucic acid Conjugated system Polyethylene Glycols chemistry.chemical_compound Mice Drug Delivery Systems Cations Polymer chemistry PEG ratio Copolymer Animals Humans Tissue Distribution RNA Small Interfering Pharmacology chemistry.chemical_classification Mice Inbred BALB C Chemistry Organic Chemistry technology industry and agriculture Cationic polymerization Sugar Acids Polymer Monomer Nanoparticles Ethylene glycol Hydrophobic and Hydrophilic Interactions Biotechnology HeLa Cells |
| Zdroj: | Bioconjugate chemistry. 26(8) |
| ISSN: | 1520-4812 |
| Popis: | Nanoparticle (NP) delivery systems for small interfering RNA (siRNA) that have good systemic circulation and high nucleic acid content are highly desired for translation into clinical use. Here, a family of cationic mucic acid-containing polymers is synthesized and shown to assemble with siRNA to form NPs. A cationic mucic acid polymer (cMAP) containing alternating mucic acid and charged monomers is synthesized. When combined with siRNA, cMAP forms NPs that require steric stabilization by poly(ethylene glycol) (PEG) that is attached to the NP surface via a 5-nitrophenylboronic acid linkage (5-nitrophenylboronic acid–PEGm (5-nPBA–PEGm)) to diols on mucic acid in the cMAP in order to inhibit aggregation in biological fluids. As an alternative, cMAP is covalently conjugated with PEG via two methods. First, a copolymer is prepared with alternating cMAP–PEG units that can form loops of PEG on the surface of the formulated siRNA-containing NPs. Second, an mPEG–cMAP–PEGm triblock polymer is synthesized that could lead to a PEG brush configuration on the surface of the formulated siRNA-containing NPs. The copolymer and triblock polymer are able to form stable siRNA-containing NPs without and with the addition of 5-nPBA–PEGm. Five formulations, (i) cMAP with 5-nPBA–PEGm, (ii) cMAP–PEG copolymer both (a) with and (b) without 5-nPBA–PEGm, and (iii) mPEG–cMAP–PEGm triblock polymer both (a) with and (b) without 5-nPBA–PEGm, are used to produce NPs in the 30–40 nm size range, and their circulation times are evaluated in mice using tail vein injections. The mPEG–cMAP–PEGm triblock polymer provides the siRNA-containing NP with the longest circulation time (5–10% of the formulation remains in circulation at 60 min postdosing), even when a portion of the excess cationic components used in the formulation is filtered away prior to injection. A NP formulation using the mPEG–cMAP–PEGm triblock polymer that is free of excess components could contain as much as ca. 30 wt % siRNA. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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