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Tuning Surface Charge and PEGylation of Biocompatible Polymers for Efficient Delivery of Nucleic Acid or Adenoviral Vector

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Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
Theranostic Macromolecules Research Center, School of Chemical Engineering, Sungkyunkwan University, Suwon, Republic of Korea
§ Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea
*E-mail address: [email protected]. Tel: + 82 2 2220 0491. Fax: +82 2 2220 4850.
*E-mail address: [email protected]. Tel: +82 31 290 7282. Fax: +82 31 292 8790.
Cite this: Bioconjugate Chem. 2015, 26, 8, 1818–1829
Publication Date (Web):July 9, 2015
https://doi.org/10.1021/acs.bioconjchem.5b00357
Copyright © 2015 American Chemical Society

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    Abstract

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    As an effective and safe strategy to overcome the limits of therapeutic nucleic acid or adenovirus (Ad) vectors for in vivo application, various technologies to modify the surface of vectors with nonimmunogenic/biocompatible polymers have been emerging in the field of gene therapy. However, the transfection efficacy of the polymer to transfer genetic materials is still relatively weak. To develop more advanced and effective polymers to deliver not only Ad vectors, but also nucleic acids, 6 biocompatible polymers were newly designed and synthesized to different sizes (2k, 3.4k, or 5k) of poly(ethylene) glycol (PEG) and different numbers of amine groups (2 or 5) based on methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-l-glutamate (PNLG). We characterized size distribution and surface charge of 6 PNLGs after complexation with either nucleic acid or Ad. Among all 6 PNLGs, the 5 amine group PNLG showed the strongest efficacy in delivering nucleic acid as well as Ad vectors. Interestingly, cellular uptake results showed higher uptake ability in Ad complexed with 2 amine group PNLG than Ad/5 amine group PNLG, suggesting that the size of Ad/PNLGs is more essential than the surface charge for cellular uptake in polymers with charges greater than 30 mV. Moreover, the endosome escape ability of Ad/PNLGs increased depending on the number of amine groups, but decreased by PEG size. Cancer cell killing efficacy and immune response studies of oncolytic Ad/PNLGs showed 5 amine group PNLG to be a more effective and safe carrier for delivering Ad. Overall, these studies provide new insights into the functional mechanism of polymer-based approaches to either nucleic acid or Ad/nanocomplex. Furthermore, the identified ideal biocompatible PNLG polymer formulation (5 amine/2k PEG for nucleic acid, 5 amine/5k PEG for Ad) demonstrated high transduction efficiency as well as therapeutic value (efficacy and safety) and thus has strong potential for in vivo therapeutic use in the future.

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    1H NMR of MPEG-PBLG (A), MPEG-PN2LG (B), and MPEG-PN5LG, degree of polymerization and molecular weight of MPEG-PBLG diblock copolymers, average molecular weight of cationic polymers, status of CAR expression on the cancer cells, average size distribution (nm) and surface charge of pDNA/polymer polyplex, and average size distribution (nm) and surface charges (mV) of naked Ad or Ad/complex. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.bioconjchem.5b00357.

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