An oral redox-sensitive self-immolating prodrug strategyby Tao Sun, Andrea Morger, Bastien Castagner, Jean-Christophe Leroux

Chem. Commun.


Latent Fluorophores Based on a Self-Immolative Linker Strategy and Suitable for Protease Sensing †

Jean-Alexandre Richard, Yves Meyer, Valérie Jolivel, Marc Massonneau, Raphaël Dumeunier, David Vaudry, Hubert Vaudry, Pierre-Yves Renard, Anthony Romieu

Technically Speaking

K. Self

Self-Immolative Polymersomes for High-Efficiency Triggered Release and Programmed Enzymatic Reactions

Guhuan Liu, Xiaorui Wang, Jinming Hu, Guoying Zhang, Shiyong Liu


This journal is©The Royal Society of Chemistry 2015 Chem. Commun., 2015, 51, 5721--5724 | 5721

Cite this:Chem. Commun., 2015, 51, 5721

An oral redox-sensitive self-immolating prodrug strategy†

Tao Sun, Andrea Morger, Bastien Castagner*‡ and Jean-Christophe Leroux*

We report a novel oral prodrug approach where a solubilizing polymer conjugated to the drug is designed to be released by the action of an exogenously administered agent in the intestine.

A redox-sensitive self-immolating design was implemented, and the reconversion kinetics were studied for three reducible prodrugs.

The oral delivery of poorly water-soluble drugs is a critical challenge in pharmaceutical sciences. Approximately 40% of drugs are poorly water-soluble and this number is believed to be much higher for candidates currently in development.1 Over the years, a host of formulations, such as solubilizing adjuvants (co-solvents, surfactants, and complexing agents) or molecular dispersion, have been developed to increase solubility and dissolution rates, which are key steps in the absorption process.2

Most reported strategies rely on supramolecular interactions between drugs and adjuvants, which may suffer from stability issues such as disassembly and precipitation upon dilution when encountering the variable and harsh conditions of the gastro-intestinal (GI) tract.

Prodrugs are commonly used to overcome a drug’s unfavourable intrinsic physicochemical properties.3 Surprisingly, only few prodrug strategies have been described to enhance the oral bioavailability of poorly water soluble drugs. The most advanced approach is the phosphorylation of a hydroxyl group of the drug.3a The resulting phosphate ester undergoes reconversion by the action of alkaline phosphatase at the intestinal brush border membrane, followed by absorption of the released hydrophobic compound (Scheme 1a).4 This strategy requires a careful control over the release rate of the free drug at the intestinal barrier since fast reconversion will lead to precipitation of the free drug, while slow reconversion will result in the elimination of the intact prodrug in the feces.4 The release kinetics greatly depends on the structure of the drug and there is inter-patient variability in alkaline phosphatase levels in the GI tract.5 Furthermore, this strategy is limited to hydroxyl group-containing drugs.

More recently, redox-sensitive sulfenamide prodrugs of amidecontaining drugs have been described.6 However, due to the requirement of enterocyte surface-based reconversion, this approach relies on endogenous free-thiol-containing protein extending from the apical surface of the cell, which will vary between patients. Ideally, an oral prodrug strategy for poorly soluble drugs would allow control over the reconversion rates in the GI tract.

Here, we report a redox-sensitive oral prodrug platform designed to undergo reconversion under the action of a co-administered agent (Scheme 1b). Though the redox-triggered release in cytosol based on disulphide bonds is a prevalent

Scheme 1 The (a) phosphate ester3a and (b) proposed redox-sensitive self-immolative prodrug strategies for orally administered poorly watersoluble drugs.

Institute of Pharmaceutical Sciences, Department of Chemistry and Applied

Biosciences, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.

E-mail:; Fax: +41 44 633 13 14 † Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc00405e ‡ Present address: Department of Pharmacology & Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal (Quebec) H3G 1Y6, Canada.


Received 15th January 2015,

Accepted 20th February 2015

DOI: 10.1039/c5cc00405e



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View Journal | View Issue 5722 | Chem. Commun., 2015, 51, 5721--5724 This journal is©The Royal Society of Chemistry 2015 strategy adopted in cancer therapy,7 such an approach is still relatively novel for the design of oral prodrugs. In the GI tract, the redox potential is not buffered and most thiol reducing agents come from our diet.8 Thus, we chose a disulphide trigger in order to allow cleavage by the safe dietary supplement N-acetyl-cysteine (NAC). The use of an exogenous reconversion agent should allow more control over the reconversion rates and reduce inter-patient variability. A poly(ethylene glycol) (PEG) moiety provides water solubility and its cleavage in the small-intestine allows the release and concomitant absorption of the free drug. The design and synthesis of the prodrug are presented here, as well as the reconversion kinetics of the prodrug as a function of NAC under conditions mimicking the GI tract. To explore the scope of this strategy, we synthesized the prodrugs of 7-ethyl-10-hydroxycamptothecin (SN-38)9 and mitomycin C (MMC),10 both anticancer agents, as well as phenytoin, an anticonvulsant.11

We started by selecting a linker with rapid self-immolation kinetics since the success of this strategy relies on a rate limiting disulphide cleavage. The self-immolation process is generally driven by cyclisation,12 elimination reactions,13 or a combination of both.14 Compared with the cyclisation strategy, the 1,6-benzyl elimination has the advantage of being more independent and less sensitive to the drug structure. Besides, the self-immolation is rapid in aqueous solution.13a This linker strategy should also be applicable to a variety of hydroxyl and amine-containing drugs via a carbonate or carbamate moiety. PEG was chosen as the solubilizing group because it is safe, inert, and commercially available. A PEG chain of 5000 Da has a sufficiently large size to improve the solubility of common hydrophobic drugs.

We started by preparing model 1, where p-nitrophenol ( pNP) was used as a drug surrogate for rapid reconversion kinetic measurement in aqueous buffer solutions using UV absorbance (Fig. 1, Fig. S1 and S2, ESI†). The kinetic study was carried out in buffers at pH 4.5 (pH value of postprandial stomach)15 and 6.8 (pH value of proximal small-intestine).16 At the intestinal pH, the prodrug was relatively stable in the absence of NAC (ca. 20% release over 4 h) but was completely cleaved in 2 h in the presence of 0.5 mM NAC. The reconversion was found to be slower at pH 4.5, requiring 10 mM NAC for complete reconversion in 90 min, compared to 0.5 mMNAC at pH 6.8. This is most likely due to the slow thiol exchange reaction at acidic pH. This is desirable, to avoid prodrug reconversion in the acidic environment of the stomach, where little drug absorption is expected to take place. These results show that the reconversion should mostly occur under pH conditions encountered in the small intestine and that it is modulated by NAC. Prodrug surrogate 1 was found to be unstable at pH 1.2 (pH value of empty stomach,