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<p>Targeted small-molecule ligands and nanoparticle-based delivery systems represent two powerful strategies for enhancing the delivery of therapeutic agents to cancer. However, small-molecule ligands often suffer from on-target, off-tumor effects due to target expression in normal tissues, while nanoparticle-based systems, although effective at accumulating in tumor tissues via the enhanced permeability and retention (EPR) effect, generally lack specificity for intracellular targets within tumor tissues. Here, we report a convergent delivery strategy that integrates a translocator protein (TSPO)-targeting small-molecule photosensitizer (BS333) with a pH-responsive liposomal carrier (pRL) to enable selective and effective photodynamic therapy (PDT). Incorporation of BS333 into the pH-responsive pRL significantly enhanced tumor selectivity; in vivo fluorescence imaging using a surrogate ligand (FITC-CB86) showed that the pRL system achieved a 2.3-fold higher tumor-to-kidney ratio than free ligand (1.89 vs. 0.83, <i>P</i> = 0.0093). Furthermore, compared to the non-targeting small-molecule photosensitizer loaded pRL (IR780@pRL), BS333@pRL demonstrated markedly improved mitochondrial targeting and functional efficacy. Confocal microscopy revealed near-complete colocalization of BS333 with mitochondrial markers, in contrast to the diffuse and less specific signal of IR780. This TSPO-specific targeting was further supported by significant signal loss upon TSPO blockade. Functionally, BS333@pRL combined with photoirradiation induced a nearly 3-fold greater mitochondrial depolarization than IR780@pRL (7.94 vs. 2.76, green/red fluorescence ratio), confirming enhanced mitochondria-directed photodynamic disruption. In vivo, BS333@pRL with photoirradiation led to 83% tumor reduction and 100% survival over 28 days, while BS333@NL and IR780@pRL with photoirradiation showed only 0% and 40% survival, respectively, highlighting the advantages of both TSPO-targeting and pH-responsive nanoparticle delivery. This study presents a rationally designed, mitochondria-targeted, pH-activated PDT delivery platform with high therapeutic efficacy and minimal off-target toxicity, offering a promising approach for targeted cancer therapy by leveraging both small-molecule ligands and nanoparticle-based delivery.</p>

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A three-step mitochondria-targeted photodynamic therapy platform integrating TSPO ligands and pH-responsive liposomes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Sang Hee Lee,
  • Jeong-Seob Lee,
  • Won Chang Lee,
  • Miyeon Jeon,
  • Wooseung Lee,
  • Jongyeong Jeon,
  • Beom Jin Park,
  • Bokyung Kim,
  • Jinyoung Park,
  • Nunzio Denora,
  • Sang Eun Kim,
  • Hyung-Jun Im,
  • Byung Chul Lee

摘要

Targeted small-molecule ligands and nanoparticle-based delivery systems represent two powerful strategies for enhancing the delivery of therapeutic agents to cancer. However, small-molecule ligands often suffer from on-target, off-tumor effects due to target expression in normal tissues, while nanoparticle-based systems, although effective at accumulating in tumor tissues via the enhanced permeability and retention (EPR) effect, generally lack specificity for intracellular targets within tumor tissues. Here, we report a convergent delivery strategy that integrates a translocator protein (TSPO)-targeting small-molecule photosensitizer (BS333) with a pH-responsive liposomal carrier (pRL) to enable selective and effective photodynamic therapy (PDT). Incorporation of BS333 into the pH-responsive pRL significantly enhanced tumor selectivity; in vivo fluorescence imaging using a surrogate ligand (FITC-CB86) showed that the pRL system achieved a 2.3-fold higher tumor-to-kidney ratio than free ligand (1.89 vs. 0.83, P = 0.0093). Furthermore, compared to the non-targeting small-molecule photosensitizer loaded pRL (IR780@pRL), BS333@pRL demonstrated markedly improved mitochondrial targeting and functional efficacy. Confocal microscopy revealed near-complete colocalization of BS333 with mitochondrial markers, in contrast to the diffuse and less specific signal of IR780. This TSPO-specific targeting was further supported by significant signal loss upon TSPO blockade. Functionally, BS333@pRL combined with photoirradiation induced a nearly 3-fold greater mitochondrial depolarization than IR780@pRL (7.94 vs. 2.76, green/red fluorescence ratio), confirming enhanced mitochondria-directed photodynamic disruption. In vivo, BS333@pRL with photoirradiation led to 83% tumor reduction and 100% survival over 28 days, while BS333@NL and IR780@pRL with photoirradiation showed only 0% and 40% survival, respectively, highlighting the advantages of both TSPO-targeting and pH-responsive nanoparticle delivery. This study presents a rationally designed, mitochondria-targeted, pH-activated PDT delivery platform with high therapeutic efficacy and minimal off-target toxicity, offering a promising approach for targeted cancer therapy by leveraging both small-molecule ligands and nanoparticle-based delivery.