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Cationic Mucic Acid Polymer-Based siRNA Delivery Systems

Pan, Dorothy W. and Davis, Mark E. (2015) Cationic Mucic Acid Polymer-Based siRNA Delivery Systems. Bioconjugate Chemistry, 26 (8). pp. 1791-1803. ISSN 1043-1802. doi:10.1021/acs.bioconjchem.5b00324. https://resolver.caltech.edu/CaltechAUTHORS:20150720-082143721

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/acs.bioconjchem.5b00324DOIArticle
http://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.5b00324PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/acs.bioconjchem.5b00324PublisherSupporting Information
ORCID:
AuthorORCID
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2015 American Chemical Society. Received: June 8, 2015; Revised: June 24, 2015; Publication Date (Web): July 8, 2015. We thank Alasdair McDowell and David VanderVelde for assistance with CryoTEM imaging and NMR spectroscopy, respectively. This project was financially supported by National Cancer Institute Grant CA 151819 and a donation from Avidity NanoMedicines. The authors declare the following competing financial interest(s): M.E. Davis is a consultant to and has stock in Avidity NanoMedicines.
Funders:
Funding AgencyGrant Number
National Cancer InstituteCA 151819
Avidity NanoMedicinesUNSPECIFIED
Issue or Number:8
DOI:10.1021/acs.bioconjchem.5b00324
Record Number:CaltechAUTHORS:20150720-082143721
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150720-082143721
Official Citation:Cationic Mucic Acid Polymer-Based siRNA Delivery Systems Dorothy W. Pan and Mark E. Davis Bioconjugate Chemistry 2015 26 (8), 1791-1803 DOI: 10.1021/acs.bioconjchem.5b00324
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:58932
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jul 2015 21:25
Last Modified:10 Nov 2021 22:12

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