Drug induced mitochondria dysfunction to enhance photodynamic therapy of hypoxic tumors

Fast proliferation of malignant cells and insufficient neovascularization induce a hypoxic microenvironment during tumor occurrence and development [[1], [2], [3]]. Hypoxia may in turn accelerate tumor invasion, metastasis and angiogenesis, leading to the treatment resistance and even adverse effects [4]. Especially, the hypoxic characteristic would directly restrict the antitumor efficiency of oxygen (O2)-dependent therapies [5,6]. Among which, even though photodynamic therapy (PDT) is a robust treatment for superficial tumors, the applicability of O2-dependent PDT is limited in deep and hypoxic tumors [[7], [8], [9]]. In recent years, great efforts have been made to improve the PDT efficacy by directly or indirectly replenishing the O2 concentration of tumor [[10], [11], [12], [13], [14], [15]]. However, traditional strategies of O2 delivery and H2O2 decomposition are still confronted huge challenges owing to the insufficient tumor microvessels, inadequate O2 production and premature O2 loss. Therefore, an effective alternative tactic is urgently demanded to elevate PDT efficiency against hypoxic tumors.

Rather than trying to increase the O2 supply to the cells, it may be more feasible to increase the oxygenation of hypoxic tumor by reducing the O2 consumption [16,17]. Under the hypoxic condition, tumor cells typically obtain energy through glycolysis for survival, but recent studies have proposed that tumors supply energy in addition to mitochondrial respiration [18,19]. Among which, oxidative phosphorylation (OXPHOS) of mitochondria is the most O2 consumption process, which relies on electron transport chain (ETC) complexes I-IV presented in the inner mitochondrial membrane [20]. It has been demonstrated that targeting ETC complexes could inhibit OXPHOS and decrease O2 availability, resulting in an increased oxygenation around tumor tissues [21,22]. Of note, ivermectin (IVM), an antiparasitic drug, has been surprisingly found to induce oxidative stress and energy crisis by facilitating mitochondria dysfunction [23]. More interestingly, IVM manifests the function on ETC complex I, which might share a similar mechanism on OXPHOS and ultimately cause a reduction in O2 consumption [24]. Additionally, numerous studies have demonstrated the potential application of IVM in various tumors, which might provide a chemotherapeutic synergism for PDT [[25], [26], [27], [28], [29], [30]]. Even so, IVM-assistant PDT is rarely reported for tumor treatment.

In this study, IVM was verified to alleviate tumor hypoxia by inhibiting OXPHOS, which could strengthen oxygen-dependent photodynamic therapy (PDT) using chlorin e6 (Ce6) as a photosensitizer. Furthermore, FDA-approved Pluronic F127 micelle was used as the drug carrier to co-deliver Ce6 and IVM (Scheme 1), which showed a good stability and uniformity. Compared with free Ce6, the drug loaded nanomicell called FIC could increase the passive tumor targeting through the enhanced penetration and retention (EPR) effect and improve the cellular internalization behavior. Moreover, FIC was capable of inhibiting mitochondrial respiration to reduce the oxygen consumption, contributing to remitting tumor hypoxia and elevating reactive oxygen species (ROS) production. In vitro and in vivo experiments demonstrated that FIC exhibited a potent antitumor activity with negligible systemic toxicity, which remedied the defect of PDT against hypoxic tumors.

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