Abstract
Oxygen dependence and anabatic hypoxia are the major factors responsible for the poor outcome of photodynamic therapy (PDT) against cancer. Combining of PDT and hypoxia-activatable bioreductive therapy has achieved remarkably improved antitumor efficacy compared to single PDT modality. However, controllable release and activation of prodrug and safety profiles of nanocarrier are still challenging in the combined PDT/hypoxia-triggered bioreductive therapy. Herein, we developed a near infrared (NIR) light-decomposable nanomicelle, consisting of PEGylated cypate (pCy) and mPEG-polylactic acid (mPEG2k-PLA2k) for controllable delivery of hypoxia-activated bioreductive prodrug (tirapazamine, TPZ) (designated TPZ@pCy), for combating metastatic breast cancer via hypoxia-enhanced phototherapies. TPZ@pCy was prepared by facile nanoprecipitation method, with good colloidal stability, excellent photodynamic and photothermal potency, favorable light-decomposability and subsequent release and activation of TPZ under irradiation. In vitro experiments demonstrated that TPZ@pCy could be quickly internalized by breast cancer cells, leading to remarkable synergistic tumor cell-killing potential. Additionally, metastatic breast tumor-xenografted mice with systematic administration of TPZ@pCy showed notable tumor accumulation, promoting tumor ablation and lung metastasis inhibition with negligible toxicity upon NIR light illumination. Collectively, our study demonstrates that this versatile light-decomposable polymeric micelle with simultaneous delivery of photosensitizer and bioreductive agent could inhibit tumor growth as well as lung metastasis, representing a promising strategy for potent hypoxia-enhanced phototherapies for combating metastatic breast cancer.
Highlights
During the past decade, photodynamic therapy (PDT), with minimal invasiveness, negligible systemic toxicity, and barely intrinsic or/and acquired resistance, has been regarded as a promising alternative approach applied in clinic management of various types of cancer [1–3]
The severe hypoxic microenvironment can be utilized by introducing hypoxia-triggered bioreductive prodrugs that would be effectively activated for killing tumor cells over the course of PDT, which can act as a supplementary strategy to potentiate the antitumor efficacy [13–17]
PEGylated cypate was synthesized by conjugating cypate with mPEG2k -NH2 via amide bond [32], obtaining a dark greenish powder. pCy can spontaneously self-assemble into nanomicelle in which the hydrophobic cypate constitutes the core and the hydrophilic PEG
Summary
Photodynamic therapy (PDT), with minimal invasiveness, negligible systemic toxicity, and barely intrinsic or/and acquired resistance, has been regarded as a promising alternative approach applied in clinic management of various types of cancer [1–3]. Photosensitizers are activated, subsequent transferring energy or electrons to surrounding molecular oxygen for generating cytotoxic reactive oxygen species (ROS), which can irreversible kill tumor cell to achieve antitumor effect [2–5]. Pharmaceutics 2022, 14, 253 generation of oxygen during PDT [7,10–12] These approaches have showed negligible strengthened efficacy due to heterogeneity and complicated pathological condition of tumors. The severe hypoxic microenvironment can be utilized by introducing hypoxia-triggered bioreductive prodrugs that would be effectively activated for killing tumor cells over the course of PDT, which can act as a supplementary strategy to potentiate the antitumor efficacy [13–17]. Tirapazamine (TPZ), a bioreductive prodrug which is a harmless parent compound at normoxia, can generate free-radical intermediate cytotoxic species by various intracellular reductase catalytic reactions under hypoxic conditions, resulting in highly selective toxicity towards hypoxic tumor cells [14,18–20]. Smart vehicles that can effectively deliver hydrophobic drugs and preserve their activity are highly desirable
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