Click Chemistry and Drug Delivery: A Bird's-eye View

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2023 May 30

PMID 37250163

Authors

Shameer M Kondengadan

Shubham Bansal

Ce Yang

Dongning Liu

Zach Fultz

Binghe Wang

Affiliations

Soon will be listed here.

Abstract

Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls.

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References

Pan Z, Zhang J, Ji K, Chittavong V, Ji X, Wang B . Organic CO Prodrugs Activated by Endogenous ROS. Org Lett. 2017; 20(1):8-11. DOI: 10.1021/acs.orglett.7b02775. View

Wolbers F, ter Braak P, Le Gac S, Luttge R, Andersson H, Vermes I . Viability study of HL60 cells in contact with commonly used microchip materials. Electrophoresis. 2006; 27(24):5073-80. DOI: 10.1002/elps.200600203. View

Zhang Y, Zhang H, He P, Yi X, Liu X, Xiao C . A PEGylated alternating copolymeric prodrug of sulfur dioxide with glutathione responsiveness for Irinotecan delivery. J Mater Chem B. 2020; 9(1):187-194. DOI: 10.1039/d0tb02097d. View

van Dijk M, Rijkers D, Liskamp R, van Nostrum C, Hennink W . Synthesis and applications of biomedical and pharmaceutical polymers via click chemistry methodologies. Bioconjug Chem. 2009; 20(11):2001-16. DOI: 10.1021/bc900087a. View

Ji X, Pan Z, Li C, Kang T, De La Cruz L, Yang L . Esterase-Sensitive and pH-Controlled Carbon Monoxide Prodrugs for Treating Systemic Inflammation. J Med Chem. 2019; 62(6):3163-3168. DOI: 10.1021/acs.jmedchem.9b00073. View

De La Cruz L, Benoit S, Pan Z, Yu B, Maier R, Ji X . Click, Release, and Fluoresce: A Chemical Strategy for a Cascade Prodrug System for Codelivery of Carbon Monoxide, a Drug Payload, and a Fluorescent Reporter. Org Lett. 2018; 20(4):897-900. DOI: 10.1021/acs.orglett.7b03348. View

Chio T, Gu H, Mukherjee K, Tumey L, Bane S . Site-Specific Bioconjugation and Multi-Bioorthogonal Labeling via Rapid Formation of a Boron-Nitrogen Heterocycle. Bioconjug Chem. 2019; 30(5):1554-1564. PMC: 6585445. DOI: 10.1021/acs.bioconjchem.9b00246. View

Serna N, Sanchez-Garcia L, Unzueta U, Diaz R, Vazquez E, Mangues R . Protein-Based Therapeutic Killing for Cancer Therapies. Trends Biotechnol. 2017; 36(3):318-335. DOI: 10.1016/j.tibtech.2017.11.007. View

Kolb H, Finn M, Sharpless K . Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew Chem Int Ed Engl. 2001; 40(11):2004-2021. DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5. View

10.

Hapuarachchige S, Si G, Huang C, Lesniak W, Mease R, Guo X . Dual-Modality PET-SPECT Image-Guided Pretargeting Delivery in HER2(+) Breast Cancer Models. Biomacromolecules. 2021; 22(11):4606-4617. PMC: 8578463. DOI: 10.1021/acs.biomac.1c00918. View

11.

Soellner M, Nilsson B, Raines R . Reaction mechanism and kinetics of the traceless Staudinger ligation. J Am Chem Soc. 2006; 128(27):8820-8. DOI: 10.1021/ja060484k. View

12.

Mamat C, Gott M, Steinbach J . Recent progress using the Staudinger ligation for radiolabeling applications. J Labelled Comp Radiopharm. 2017; 61(3):165-178. DOI: 10.1002/jlcr.3562. View

13.

Chen Y, Yuan X, Tang M, Shi M, Yang T, Liu K . Degrading FLT3-ITD protein by proteolysis targeting chimera (PROTAC). Bioorg Chem. 2021; 119:105508. DOI: 10.1016/j.bioorg.2021.105508. View

14.

Cunha E, Chen X, Sanz-Gaitero M, Mills D, Luecke H . Cryo-EM structure of Helicobacter pylori urease with an inhibitor in the active site at 2.0 Å resolution. Nat Commun. 2021; 12(1):230. PMC: 7801526. DOI: 10.1038/s41467-020-20485-6. View

15.

Sletten E, Bertozzi C . Bioorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew Chem Int Ed Engl. 2009; 48(38):6974-98. PMC: 2864149. DOI: 10.1002/anie.200900942. View

16.

Arkenberg M, Nguyen H, Lin C . Recent advances in bio-orthogonal and dynamic crosslinking of biomimetic hydrogels. J Mater Chem B. 2020; 8(35):7835-7855. PMC: 7574327. DOI: 10.1039/d0tb01429j. View

17.

Thomas D, Liu X, Kantrow S, Lancaster Jr J . The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2. Proc Natl Acad Sci U S A. 2001; 98(1):355-60. PMC: 14594. DOI: 10.1073/pnas.98.1.355. View

18.

Azoulay M, Tuffin G, Sallem W, Florent J . A new drug-release method using the Staudinger ligation. Bioorg Med Chem Lett. 2006; 16(12):3147-9. DOI: 10.1016/j.bmcl.2006.03.073. View

19.

Tu J, Svatunek D, Parvez S, Eckvahl H, Xu M, Peterson R . Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups. Chem Sci. 2020; 11(1):169-179. PMC: 7012038. DOI: 10.1039/c9sc04649f. View

20.

Dang Y, Ruan L, Tian Y, Xu Z, Zhang W . Nitric Oxide Prodrug Delivery and Release Monitoring Based on a Galactose-Modified Multifunctional Nanoprobe. Anal Chem. 2021; 93(21):7625-7634. DOI: 10.1021/acs.analchem.1c00287. View