Mini-review
β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: An update

https://doi.org/10.1016/j.ejmech.2013.12.045Get rights and content

Highlights

  • This review summarizes ten years of progresses in the field of glucuronide prodrugs.

  • Glucuronide prodrugs can be activated in the microenvironment of most solid tumors.

  • Numerous glucuronide prodrugs have already demonstrated their efficacy in vivo.

Abstract

The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of β-glucuronidase-responsive albumin binding prodrugs.

Introduction

In recent years, the design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues has become one of the major challenges in medicinal chemistry. Within this framework, numerous research efforts focused on the development of self-responsive chemical systems programmed to deliver potent cytotoxics selectively at the tumor site [1], [2]. Such systems are usually complex molecular assemblies that build into their structure (1) a targeting unit enabling the recognition of a tumor-associated specificity and (2) either an enzymatic or a chemical trigger that can be activated exclusively in cancerous tissues to induce the release of the drug in a stringently controlled fashion.

The vast majority of the drug delivery systems that have been developed until now were designed to target cancer cell surface specificities (e.g. a membrane receptor or an antigen) [3]. In this approach, the molecular assembly includes either a monoclonal antibody or low-molecular-weight ligand that displays a high affinity for the corresponding tumor-associated cell surface marker. When cancer cell surface is detected by the targeting unit, the whole system is internalized via receptor-mediated endocytosis [4]. Once inside the cell, activation of the trigger leads to the release of the active drug selectively in the intracellular medium. Several drug delivery systems of this type are currently being assessed clinically for diverse applications in oncology [5], [6]. Furthermore, the antibody–drug conjugate Adcetris (formally Brentuximab vedotin) reached the market in 2011 for the treatment of Hodgkin lymphoma [7], [8].

However, the “Achilles’heel” of drug delivery systems designed to target cell surface specificities relies on the heterogeneity of cancerous tissues. Indeed, all the cells of a tumor mass are not identical exhibiting different concentrations of a given cell surface marker. Thus, only cancer cells that express the selected tumor-associated marker at a sufficient level are directly affected by this class of targeting systems. In this context, the use of enzyme-responsive prodrugs that can be selectively activated by the corresponding enzyme naturally overexpressed in the tumor microenvironment [9] offers a valuable alternative to this targeting approach. In this case, the anticancer agent is released in the extracellular medium and can further penetrate passively inside various types of surrounding malignant cells whatever their membrane characteristics.

As early as 1947, Fishman and Anlyan have reported the presence of elevated β-glucuronidase activity in tumors as compared to normal tissues [10], [11]. This observation was confirmed thereafter by several research groups who detected high concentrations of this enzyme in a wide range of malignancies including breast, lung, ovarian and gastrointestinal tract carcinomas as well as melanomas [12], [13], [14]. In tumors, β-glucuronidase is secreted extracellularly in necrotic areas by inflammatory cells (monocytes/granulocytes) while in healthy tissues its activity is confined in lysosomes [14]. In 1988, Tietze [15] was the first who proposed to target this enzymatic specificity of the tumor microenvironment by means of β-glucuronidase-responsive prodrugs in the course of a prodrug monotherapy (PMT [13]). Since then, numerous prodrugs have been investigated with the aim to deliver potent anticancer drugs selectively in the vicinity of malignant cells.

Not surprisingly, since high level of β-glucuronidase can be found in most solid tumors, this strategy was applied for the targeting of various classes of cytotoxics such as anthracyclines, taxanes, camptothecin derivatives, nitrogen mustards, histone deacetylase inhibitors, hedgehog inhibitors, auristatins and duocarmycins. With a few exceptions, these prodrugs include a self-immolative linker [16] between the carbohydrate trigger and the drug. The glucuronide moiety is thereby sufficiently far away from the antitumor agent to allow an easy recognition of the enzymatic substrate by β-glucuronidase. The release of the drug proceeds then via a two steps process including (1) the enzymatic hydrolysis of the glycosidic bound and (2) the spontaneous decomposition of the linker leading to the expulsion of the active compound (Fig. 1).

The linker plays a major role in the success of this targeting strategy. Besides facilitating the enzymatic reaction, the linker must decompose rapidly after β-glucuronidase-catalyzed activation of the trigger. This allows avoiding the diffusion of the linker-drug intermediate outside of the tumor site that could result in non-specific delivery of the cytotoxic compound in all the body. Furthermore, a suitable design of the linker can improve significantly prodrug properties such as toxicity, pharmacokinetics, organ distribution or bioavailability.

As a general statement, β-glucuronidase-responsive prodrugs are far less toxic than the parent drugs. The reduced toxicity is mainly due to the hydrophilicity imparted by the glucuronide moiety that prevents passive cellular uptake and further intracellular prodrug activation by lysosomal β-glucuronidase within non-malignant cells. As a result, glucuronide prodrugs can be administered at relatively high doses without inducing side effects with respect to the corresponding anticancer agents. Thus, by combining a low toxicity and a selective activation in the tumor microenvironment, glucuronide prodrugs allow the increased drug deposition in the tumor while reducing drug concentration in normal tissues. To date, several glucuronide prodrugs have been evaluated in vivo leading to superior efficacy compared to standard chemotherapy. These results have already been summarized in excellent reviews up to 2003 [17], [18]. In this paper, we present an update of the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of β-glucuronidase-responsive albumin binding prodrugs.

Section snippets

Glucuronide prodrugs of paclitaxel

Paclitaxel (Taxol®) [19] is a member of the taxanes family currently used in clinic to treat a variety of malignancies including ovarian, breast and non-small-cell lung cancer. At therapeutic doses this drug induces a number of undesirable side effects such as myelosuppression and sensory neuropathy. Moreover, as paclitaxel exhibits poor water solubility, it has to be co-injected with a detergent, Cremophor EL, which causes hypersensitivity reactions. To circumvent these problems, Schmidt and

Glucuronide prodrugs of histone deacetylase inhibitors

Recently, the inhibition of histone deacetylases [27] has emerged as a new strategy in cancer chemotherapy [28]. Over the past 15 years, an increasing number of structurally diverse histone deacetylases inhibitors (HDACi) have been studied as potential therapeutic agents [29], [30], [31], [32] and more than ten different HDACi were evaluated clinically [33]. Among them, the suberoylanilide hydroxamic acid or SAHA (Zolinza™), reached the market for the treatment of cutaneous T-cell lymphoma in

Glucuronide prodrugs of cyclopamine

Aberrant activation of the Hedgehog (Hh) signaling pathway [50] has been observed in a wide range of malignancies such as breast [51], prostate [52], gastric [53], lung [54] and brain tumors [55]. As a result, many efforts have been devoted to the discovery of small-molecule Hh inhibitors for cancer chemotherapy [56]. Cyclopamine, a natural alkaloid from Veratrum californicum (the hellebore or corn-lily), was the first Hh inhibitor to be identified [57]. This compound already demonstrated

Glucuronide prodrugs of camptothecin derivatives

Camptothecin (CPT) is an alkaloid isolated from Camptotheca acuminate [65] that displays potent antitumor activity by inhibition of topoisomerase I [66]. While CPT showed promising results in preliminary clinical trials, its use was limited by extremely poor water solubility. This drawback led to the development of more water-soluble derivatives among which Topotecan [67] and Irinotecan [68] have been approved for clinical use. However, these two CPT analogs induce serious side effects such as

Glucuronide prodrug of duocarmycin derivatives

The duocarmycins are a family of antineoplastic agents with low picomolar potency against a wide range of cancer cell lines [74], [75]. The cytotoxic activity is believed to derive from their ability to bind and alkylate DNA in AT-rich region of the minor groove [76], although other modes of action have been suggested recently [77], [78], [79], [80]. However, the duocarmycins display side effects in vivo including hepatotoxicity and myelosuppression which represent a major limitation for their

Glucuronide prodrug of monomethylauristatin E

Monomethylauristatin E (MMAE) is a potent inhibitor of tubulin polymerization with subnanomolar cytotoxic activity in vitro. Because of its high toxicity, MMAE has only limited efficacy in vivo at a dose that is not lethal to animals. However, this drug already shown a remarkable efficiency in human when targeted to cancer cells in the form of Brentuximab Vedotin [7], [8]. This alternative also proved its validity in vivo with other enzyme-responsive drug carriers of MMAE where the therapeutic

Glucuronide prodrugs of anthracyclines

Anthracyclines, like daunorubicin, doxorubicin and epirubicin are potent antitumor agents that have been widely used in clinic for the treatment of numerous malignancies such as leukemias, lymphomas, soft-tissues sarcomas, breast, uterine and ovarian cancers [99]. Anthracyclines are however notorious for causing cumulative and irreversible cardiotoxicity, which considerably limits their usefulness [100], [101]. Thus, β-glucuronidase-responsive prodrugs of anthracyclines have received

Conclusion

Since Tietze has proposed to target extracellular β-glucuronidase in the tumor microenvironment, a wide number of structurally diverse glucuronide prodrugs have been designed with the aim to enhance the selectivity of cancer chemotherapy. Conducted in the nineties, the first evaluations of this strategy led to encouraging outcomes in several animal models. These studies also highlighted the problems which have to be solved in order to improve this therapeutic approach, such as the insufficient

Acknowledgments

The authors thank La Ligue Nationale contre le Cancer (Comities of Charente, Charentes-Maritime, Vienne and Deux Sèvres) and Agence Nationale de la Recherche (ARN, Programme Blanc – SIMI 7, ProTarget) for their support.

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