Cascade-amplified self-immolative polymeric prodrug for cancer therapy by disrupting redox homeostasis

Prodrugs are a branch of medications that are pharmacologically inactive but can be readily converted to their active metabolites in vivo for therapeutic functions [1]. Prodrugs are usually developed to improve the absorption, biodistribution, metabolism, and excretion of drugs when these parameters are unsatisfactory by direct administration of the active form [2,3]. Polymeric prodrugs, in which the drug moieties are conjugated to polymers through labile bonds, have attracted extensive attention because they incorporate the advantages of both prodrugs and nanomedicines [[4], [5], [6], [7]]. Compared with small-molecule prodrugs, polymeric prodrugs accumulate in tumor tissue more effectively due to the enhanced permeability and retention (EPR) effect [8]. In addition, they also act as drug delivery systems for loading or conjugating other types of drugs, making polymeric prodrugs rational systems for combined therapy. Moreover, polymeric prodrugs can enhance the targetability and reduce side effects by their rationally designed structure in response to various tumor-specific stimuli, including acidic pH [9], glutathione (GSH) [10], reactive oxygen species (ROS) [11], and enzymes [12].

Quinone methide and its analogs (QMs) are a class of natural electrophiles generated in biological processes, such as the cytochrome P450-induced oxidation of 4-alkylphenols [13]. Recently, QMs have been recognized as active antitumor compounds. Their unique conjugated structure makes them versatile substrates for nucleophilic 1,6-addition reactions (such as Michael addition) with notable chemical reactivity [14]. As a result, they induce the alkylation of many biomolecules, such as nucleic acid [[15], [16], [17]] and proteins [18,19]. This property confers QMs with versatile potentials in theranostic applications [20]. In particular, QMs can rapidly consume GSH, which is an antioxidant excessively expressed by cancer cells to balance the elevated oxidative stress, counteract the destructive effects of high-level ROS, and improve cell survival in pathological and therapeutic conditions [21,22]. As the cells' detoxification molecule, GSH is also responsible for the acquired resistance and reduced therapeutic effect of medicines because it might competitively react with the active metabolites of drugs [23]. Therefore, the depletion of GSH by QMs in cancer cells was recently proposed as a promising approach to improve the therapeutic effects of many treatments, especially therapies related to the disruption of redox homeostasis in cancer cells [21,24].

As highly reactive molecules, QMs have very short half-lives in physiological conditions because they can react with many biomolecules containing nucleophilic groups, even H2O. Besides, QMs are also harmful to normal cells because they have no clear selectivity to cancer cells [25]. Therefore, it is necessary to develop prodrugs that produce QMs in situ within cancer cells to achieve targeted cancer therapy. Wijtmans et al. [26] demonstrated that the hybrid prodrug NO-ASA (a nitric oxide-releasing aspirin derivative containing a spacer that could generate QM) actually induced the anticancer therapeutic effect by generating QM molecules. More recently, several researchers have demonstrated that the 4-hydroxymethyl phenylboronic group generated QM stoichiometrically in response to hydrogen peroxide and therefore improved the therapeutic effect of chemotherapy, photodynamic therapy, and ferroptosis-related therapy [22,[27], [28], [29], [30]]. For example, Lee et al. [31,32] developed a dual stimuli-responsive hybrid drug that could be activated by acidic pH and H2O2 to generate QM and cinnamaldehyde, respectively. This system was proposed to disrupt the redox homeostasis of cancer cells since cinnamaldehyde increases ROS generation and QM quenches antioxidant GSH. Similarly, a molecule that could generate azaquinone methide (an analog of QM) and doxorubicin in response to protease has been reported to enhance the therapeutic effect of chemotherapy [33].

Unfortunately, the current prodrugs that produce QMs in cancer cells are either inefficient or almost a “zero-sum game.” For example, one H2O2 molecule should be simultaneously consumed to generate one QM molecule by the 4-hydroxymethyl phenylboronic group [31]. Therefore, this strategy is countery to the purpose of QM generation because it cannot effectively exacerbate oxidative stress. Recently, a class of self-immolative polymers (SIP) with controllable degradation bahavior has shown versatile potential applications such as precise therapeutics and label-free diagnostic systems [[34], [35], [36]]. Herein, we prepare a self-immolative polymeric prodrug (SPP) that sustainably generates large quantities of QM in tumor cells selectively. The SPP comprises a boronic ester-end-capped self-immolative backbone, which undergoes spontaneous stepwise head-to-tail degradation after the selective cleavage of terminal boronic ester in the tumor microenvironment containing an excessive amount of H2O2 (Fig. 1). Each degradation step is accompanied by the release of one azaquinone methide molecule. Because of this unique degradation mechanism, a large amount of QM is generated by only consuming one H2O2 molecule. In contrast to the conventional polymeric prodrugs, the backbone of SPP plays a role as the prodrug, resulting in high QM generation efficiency. Additionally, with hydrophilic poly(ethylene glycol) (PEG) sidechains, the SPPs easily self-assemble into micelles in aqueous solution and encapsulate hydrophobic drugs into the micelle core. Consequently, we introduce a hydrophobic drug, 2-methoxy-β-estradiol (2ME), as cargo in the SPP and obtain a cascade-amplified SPP ([email protected]). 2ME, a natural metabolite of 17β-estradiol, has been proven to increase the intracellular ROS level and thus elevate oxidative stress in cancer cells [37,38]. As a result, [email protected] would be selectively activated in cancer cells to degrade and generate a large amount of QM for GSH depletion. Moreover, the degradation of SPP results in the disassembly of the micelle, accelerating the release of 2ME into the cellular plasma, which in turn increases the ROS level in the cancer cell to trigger the degradation of more SPP chains. This domino-like cascade-amplified feedback loop significantly amplifies oxidative stress and disrupts the redox homeostasis in cancer cells, resulting in synergistic anticancer therapy both in vitro and in vivo.

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