Thiol-Disulfide Exchange As a Route for Endosomal Escape of Polymeric Nanoparticles

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2022 Jul 22

PMID 35866880

Authors

Pintu Kanjilal

Kingshuk Dutta

S Thayumanavan

Affiliations

Soon will be listed here.

Abstract

Endosomal entrapment has remained the major bottleneck for cytosolic delivery of nanoparticle-based delivery systems. Uncovering fundamentally new pathways for endosomal escape is therefore highly sought. Herein, we report that disulfide bonds can enhance endosomal escape through contacts with cellular exofacial thiols, in addition to facilitating cellular uptake. Our results are supported through comparative analysis of polymeric nanogels with variable accessibility to disulfide bonds by placing these functionalities at the core or the shell of the nanogels. The findings here inform future chemical design of delivery vehicles.

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References

Shi J, Kantoff P, Wooster R, Farokhzad O . Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2016; 17(1):20-37. PMC: 5575742. DOI: 10.1038/nrc.2016.108. View

Jiang Z, Cui W, Prasad P, Touve M, Gianneschi N, Mager J . Bait-and-Switch Supramolecular Strategy To Generate Noncationic RNA-Polymer Complexes for RNA Delivery. Biomacromolecules. 2018; 20(1):435-442. DOI: 10.1021/acs.biomac.8b01321. View

Bej R, Ghosh A, Sarkar J, Das B, Ghosh S . Thiol-Disulfide Exchange Reaction Promoted Highly Efficient Cellular Uptake of Pyridyl Disulfide Appended Nonionic Polymers. Chembiochem. 2020; 21(20):2921-2926. DOI: 10.1002/cbic.202000303. View

Anson F, Liu B, Kanjilal P, Wu P, Hardy J, Thayumanavan S . Evaluating Endosomal Escape of Caspase-3-Containing Nanomaterials Using Split GFP. Biomacromolecules. 2021; 22(3):1261-1272. PMC: 8477791. DOI: 10.1021/acs.biomac.0c01767. View

Anson F, Kanjilal P, Thayumanavan S, Hardy J . Tracking exogenous intracellular casp-3 using split GFP. Protein Sci. 2020; 30(2):366-380. PMC: 7784757. DOI: 10.1002/pro.3992. View

Lin C, Engbersen J . Effect of chemical functionalities in poly(amido amine)s for non-viral gene transfection. J Control Release. 2008; 132(3):267-72. DOI: 10.1016/j.jconrel.2008.06.022. View

Pei D, Buyanova M . Overcoming Endosomal Entrapment in Drug Delivery. Bioconjug Chem. 2018; 30(2):273-283. PMC: 6501178. DOI: 10.1021/acs.bioconjchem.8b00778. View

Oupicky D, Li J . Bioreducible polycations in nucleic acid delivery: past, present, and future trends. Macromol Biosci. 2014; 14(7):908-22. PMC: 4410047. DOI: 10.1002/mabi.201400061. View

Rennick J, Johnston A, Parton R . Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat Nanotechnol. 2021; 16(3):266-276. DOI: 10.1038/s41565-021-00858-8. View

10.

Revia R, Stephen Z, Zhang M . Theranostic Nanoparticles for RNA-Based Cancer Treatment. Acc Chem Res. 2019; 52(6):1496-1506. PMC: 6701180. DOI: 10.1021/acs.accounts.9b00101. View

11.

Gasparini G, Sargsyan G, Bang E, Sakai N, Matile S . Ring Tension Applied to Thiol-Mediated Cellular Uptake. Angew Chem Int Ed Engl. 2015; 54(25):7328-31. DOI: 10.1002/anie.201502358. View

12.

Selby L, Cortez-Jugo C, Such G, Johnston A . Nanoescapology: progress toward understanding the endosomal escape of polymeric nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017; 9(5). DOI: 10.1002/wnan.1452. View

13.

Zhuang J, Jiwpanich S, Deepak V, Thayumanavan S . Facile Preparation of Nanogels Using Activated Ester Containing Polymers. ACS Macro Lett. 2015; 1(1):175-179. PMC: 4286329. DOI: 10.1021/mz200123f. View

14.

Fu J, Yu C, Li L, Yao S . Intracellular Delivery of Functional Proteins and Native Drugs by Cell-Penetrating Poly(disulfide)s. J Am Chem Soc. 2015; 137(37):12153-60. DOI: 10.1021/jacs.5b08130. View

15.

Nam H, Kim J, Kim S, Yockman J, Kim S, Bull D . Cell penetrating peptide conjugated bioreducible polymer for siRNA delivery. Biomaterials. 2011; 32(22):5213-22. PMC: 3128881. DOI: 10.1016/j.biomaterials.2011.03.058. View

16.

Dutta K, Kanjilal P, Das R, Thayumanavan S . Synergistic Interplay of Covalent and Non-Covalent Interactions in Reactive Polymer Nanoassembly Facilitates Intracellular Delivery of Antibodies. Angew Chem Int Ed Engl. 2020; 60(4):1821-1830. PMC: 7855684. DOI: 10.1002/anie.202010412. View

17.

Laurent Q, Martinent R, Lim B, Pham A, Kato T, Lopez-Andarias J . Thiol-Mediated Uptake. JACS Au. 2021; 1(6):710-728. PMC: 8395643. DOI: 10.1021/jacsau.1c00128. View

18.

Qin X, Yu C, Wei J, Li L, Zhang C, Wu Q . Rational Design of Nanocarriers for Intracellular Protein Delivery. Adv Mater. 2019; 31(46):e1902791. DOI: 10.1002/adma.201902791. View

19.

Pack D, Hoffman A, Pun S, Stayton P . Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005; 4(7):581-93. DOI: 10.1038/nrd1775. View

20.

Vermeulen L, Brans T, Samal S, Dubruel P, Demeester J, De Smedt S . Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles. ACS Nano. 2018; 12(3):2332-2345. DOI: 10.1021/acsnano.7b07583. View