Overcoming Endosomal Entrapment in Drug Delivery

Overview

Journal Bioconjug Chem

Publisher American Chemical Society

Specialty Biochemistry

Date 2018 Dec 12

PMID 30525488

Citations 125

Authors

Dehua Pei

Marina Buyanova

Affiliations

Soon will be listed here.

Abstract

Intracellular delivery of biological agents such as peptides, proteins, and nucleic acids generally rely on the endocytic pathway as the major uptake mechanism, resulting in their entrapment inside the endosome and lysosome. The recent discovery of cell-penetrating molecules of exceptionally high endosomal escape and cytosolic delivery efficiencies and elucidation of their mechanism of action represent major breakthroughs in this field. In this Topical Review, we provide an overview of the recent progress in understanding and enhancing the endosomal escape process and the new opportunities opened up by these recent findings.

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References

Wittrup A, Ai A, Liu X, Hamar P, Trifonova R, Charisse K . Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat Biotechnol. 2015; 33(8):870-6. PMC: 4663660. DOI: 10.1038/nbt.3298. View

Rozema D, Ekena K, Lewis D, Loomis A, Wolff J . Endosomolysis by masking of a membrane-active agent (EMMA) for cytoplasmic release of macromolecules. Bioconjug Chem. 2003; 14(1):51-7. DOI: 10.1021/bc0255945. View

Maier O, Galan D, Wodrich H, Wiethoff C . An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. Virology. 2010; 402(1):11-9. PMC: 3028504. DOI: 10.1016/j.virol.2010.03.043. View

Juliano R . The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 2016; 44(14):6518-48. PMC: 5001581. DOI: 10.1093/nar/gkw236. View

Smith B, Daniels D, Coplin A, Jordan G, McGregor L, Schepartz A . Minimally cationic cell-permeable miniature proteins via alpha-helical arginine display. J Am Chem Soc. 2008; 130(10):2948-9. DOI: 10.1021/ja800074v. View

Lachelt U, Wagner E . Nucleic Acid Therapeutics Using Polyplexes: A Journey of 50 Years (and Beyond). Chem Rev. 2015; 115(19):11043-78. DOI: 10.1021/cr5006793. View

Wang C, Wang Y, Li Y, Bodemann B, Zhao T, Ma X . A nanobuffer reporter library for fine-scale imaging and perturbation of endocytic organelles. Nat Commun. 2015; 6:8524. PMC: 4600749. DOI: 10.1038/ncomms9524. View

Haensler J, Szoka Jr F . Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem. 1993; 4(5):372-9. DOI: 10.1021/bc00023a012. View

Alipour M, Hosseinkhani S, Sheikhnejad R, Cheraghi R . Nano-biomimetic carriers are implicated in mechanistic evaluation of intracellular gene delivery. Sci Rep. 2017; 7:41507. PMC: 5269746. DOI: 10.1038/srep41507. View

10.

Stewart M, Lorenz A, Dahlman J, Sahay G . Challenges in carrier-mediated intracellular delivery: moving beyond endosomal barriers. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015; 8(3):465-78. DOI: 10.1002/wnan.1377. View

11.

Verdine G, Walensky L . The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. 2007; 13(24):7264-70. DOI: 10.1158/1078-0432.CCR-07-2184. View

12.

Salomone F, Breton M, Leray I, Cardarelli F, Boccardi C, Bonhenry D . High-yield nontoxic gene transfer through conjugation of the CM₁₈-Tat₁₁ chimeric peptide with nanosecond electric pulses. Mol Pharm. 2014; 11(7):2466-74. DOI: 10.1021/mp500223t. View

13.

Peraro L, Deprey K, Moser M, Zou Z, Ball H, Levine B . Cell Penetration Profiling Using the Chloroalkane Penetration Assay. J Am Chem Soc. 2018; 140(36):11360-11369. PMC: 6205923. DOI: 10.1021/jacs.8b06144. View

14.

Palm-Apergi C, Lonn P, Dowdy S . Do cell-penetrating peptides actually "penetrate" cellular membranes?. Mol Ther. 2012; 20(4):695-7. PMC: 3322330. DOI: 10.1038/mt.2012.40. View

15.

Pattni B, Chupin V, Torchilin V . New Developments in Liposomal Drug Delivery. Chem Rev. 2015; 115(19):10938-66. DOI: 10.1021/acs.chemrev.5b00046. View

16.

Rydstrom A, Deshayes S, Konate K, Crombez L, Padari K, Boukhaddaoui H . Direct translocation as major cellular uptake for CADY self-assembling peptide-based nanoparticles. PLoS One. 2011; 6(10):e25924. PMC: 3187819. DOI: 10.1371/journal.pone.0025924. View

17.

Qian Z, Rhodes C, McCroskey L, Wen J, Appiah-Kubi G, Wang D . Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization. Angew Chem Int Ed Engl. 2016; 56(6):1525-1529. PMC: 5296932. DOI: 10.1002/anie.201610888. View

18.

DAstolfo D, Pagliero R, Pras A, Karthaus W, Clevers H, Prasad V . Efficient intracellular delivery of native proteins. Cell. 2015; 161(3):674-690. DOI: 10.1016/j.cell.2015.03.028. View

19.

Jenssen H, Hamill P, Hancock R . Peptide antimicrobial agents. Clin Microbiol Rev. 2006; 19(3):491-511. PMC: 1539102. DOI: 10.1128/CMR.00056-05. View

20.

Takeuchi T, Futaki S . Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms. Chem Pharm Bull (Tokyo). 2016; 64(10):1431-1437. DOI: 10.1248/cpb.c16-00505. View