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Review
. 2020 Jun 25;10(41):24397-24409.
doi: 10.1039/d0ra04155f. eCollection 2020 Jun 24.

Disulfide based prodrugs for cancer therapy

Qiang Wang  1 , Jiankun Guan  1 , Jiangling Wan  1 , Zifu Li  1   2
Affiliations
Review

Disulfide based prodrugs for cancer therapy

Qiang Wang et al. RSC Adv. .

Abstract

Advances in the tumor microenvironment have facilitated the development of novel anticancer drugs and delivery vehicles for improved therapeutic efficacy and decreased side effects. Disulfide bonds with unique chemical and biophysical properties can be used as cleavable linkers for the delivery of chemotherapeutic drugs. Accordingly, small molecule-, peptide-, polymer- and protein-based multifunctional prodrugs bearing cleavable disulfide bonds are well accepted in clinical settings. Herein, we first briefly introduce a number of prodrugs and divide them into three categories, namely, disulfide-containing small molecule conjugates, disulfide-containing cytotoxic agent-targeted fluorescent agent conjugates, and disulfide-containing cytotoxic agent-macromolecule conjugates. Then, we discuss the complex redox environment and the underlying mechanism of free drug release from disulfide based prodrugs in in vivo settings. Based on these insights, we analyze the impact of electronics, steric hindrance and substituent position of the disulfide linker on the extracellular stability and intracellular cleavage rate of disulfide containing prodrugs. Current challenges and future opportunities for the disulfide linker are provided at the end.

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Conflict of interest statement

There are no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1. Chemical structures of disulfide-containing drug–drug conjugates. (A) Homodimers. (B) Heterodimers.
Fig. 2
Fig. 2. Structures of disulfide-containing multifunctional conjugates. (A) Fol or its analogue based targeting agents. (B) Theranostic agents.
Fig. 3
Fig. 3. Structures of reduction-sensitive prodrugs based on HES.
Fig. 4
Fig. 4. Plausible catabolism and free drug release mechanism of disulfide-containing prodrugs. RSH = Cys or GSH; RSSR = CySS or GSSG; R1 = cytotoxic agent 1; R2 = cytotoxic agent 2 or other functional small molecular (target agent, photosensitizer, immunomodulatory agent or peptide) or macromolecule (polymer or antibody); X = O or NH.
Fig. 5
Fig. 5. (A) Structures of PTX-ss-CIT with different substituent positions of disulfide bond containing carbon chain. (B) Tamb-ss-DM1 with different sterically hindered disulfide bonds. (C) Structure of DOX-DTMB-Fol with aromatic disulfide linker.
None
Qiang Wang
None
Zifu Li
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