Harnessing the versatility of PLGA nanoparticles for targeted Cre-mediated recombination

Ngoc B Nguyen; Cheng-Han Chen; Yulong Zhang; Peng Zhao; Benjamin M Wu; Reza Ardehali

doi:10.1016/j.nano.2019.02.027

Harnessing the versatility of PLGA nanoparticles for targeted Cre-mediated recombination

Nanomedicine. 2019 Jul:19:106-114. doi: 10.1016/j.nano.2019.02.027. Epub 2019 Apr 23.

Authors

Ngoc B Nguyen¹, Cheng-Han Chen², Yulong Zhang³, Peng Zhao⁴, Benjamin M Wu³, Reza Ardehali⁵

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA; Molecular, Cellular and Integrative Physiology Graduate Program, University of California, Los Angeles, Los Angeles, CA, USA.
² Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA.
⁵ Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA; Molecular, Cellular and Integrative Physiology Graduate Program, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: RArdehali@mednet.ucla.edu.

Abstract

Ligand-dependent Cre recombinases are pivotal tools for the generation of inducible somatic mutants. This method enables spatial and temporal control of gene activity through tamoxifen administration, providing new avenues for studying gene function and establishing animal models of human diseases. While this paved the way for developmental studies previously deemed impractical, the generation of tissue-specific transgenic mouse lines can be time-consuming and costly. Herein, we design a 'smart', biocompatible, and biodegradable nanoparticle system encapsulated with tamoxifen that is actively targeted to specific cell types in vivo through surface conjugation of antibodies. We demonstrate that these nanoparticles bind to cells of interest and activate Cre recombinase, resulting in tissue-specific Cre activation. This system provides a versatile, yet powerful approach to induce recombination in a ubiquitious Cre system for various biomedical applications and sets the stage for a time- and cost-effective strategy of generating new transgenic mouse lines.

Keywords: 4-hydroxytamoxifen; Antibody surface conjugation; Clonal analysis; Cre-mediated recombination; PLGA nanoparticles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / metabolism
DNA / metabolism
Drug Delivery Systems
Integrases / metabolism*
Macrophages / drug effects
Macrophages / metabolism
Mice, Transgenic
Monocytes / drug effects
Monocytes / metabolism
Nanoparticles / chemistry*
Nanoparticles / ultrastructure
Polylactic Acid-Polyglycolic Acid Copolymer / chemistry*
Recombination, Genetic*
Tamoxifen / pharmacology

Substances

Antibodies
Tamoxifen
Polylactic Acid-Polyglycolic Acid Copolymer
DNA
Cre recombinase
Integrases

Abstract

Publication types

MeSH terms

Substances

Grants and funding