Anionic Polymers Promote Mitochondrial Targeting of Delocalized Lipophilic Cations

Mitochondria are therapeutic targets in many diseases including cancer, metabolic disorders, and neurodegenerative diseases. Therefore, strategies to deliver therapeutics of interest to mitochondria are important for therapeutic development. As delocalized lipophilic cations (DLCs) preferentially ac...

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Bibliographic Details
Published in:Bioconjugate chemistry 2020-05, Vol.31 (5), p.1344-1353
Main Authors: Jiang, Ziwen, Liu, Hongxu, He, Huan, Yadava, Nagendra, Chambers, James J, Thayumanavan, S
Format: Article
Language:English
Subjects:
Cationic polymerization
Cations
Cell membranes
Conjugation
Drug Carriers - chemistry
Drug Carriers - metabolism
Entrapment
HeLa Cells
Humans
Hydrophobic and Hydrophilic Interactions
Kinetics
Lipophilic
Macromolecules
Membrane Potential, Mitochondrial
Metabolic disorders
Mitochondria
Mitochondria - metabolism
Neurodegenerative diseases
Polymers
Polymers - chemistry
Polymers - metabolism
Pyruvic acid
Therapeutic applications
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Summary:Mitochondria are therapeutic targets in many diseases including cancer, metabolic disorders, and neurodegenerative diseases. Therefore, strategies to deliver therapeutics of interest to mitochondria are important for therapeutic development. As delocalized lipophilic cations (DLCs) preferentially accumulate in mitochondria, DLC-conjugation has been utilized to facilitate therapeutic delivery systems with mitochondrial targeting capability. Here we report that upon DLC-conjugation, anionic polymers exhibit significantly improved mitochondrial targeting when compared to cationic polymers and charge-neutral polymers. Considering that the cell membrane generally bears a net negative charge, the observed phenomenon is unexpected. Notably, the DLC-conjugated anionic polymers circumvent endosomal entrapment. The rapid mitochondrial accumulation of DLC-conjugated anionic polymers is likely a membrane-potential-driven process, along with the involvement of the mitochondrial pyruvate carrier. Moreover, the structural variations on the side chain of DLC-conjugated anionic polymers do not compromise the overall mitochondrial targeting capability, widely extending the applicability of anionic macromolecules in therapeutic delivery systems.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.0c00079