Mahmoud Dina Ashraf, Ding Lili, Ferdous Zannatul, Zhang Zhifen, Chen Juan, Spiegel Jennifer L, Sykes Edward Alexander, Harrison Robert, Zheng Gang, Le Trung
Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Biological Sciences Platform, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada.
Front Surg. 2025 Sep 3;12:1594001. doi: 10.3389/fsurg.2025.1594001. eCollection 2025.
The treatment of inner and middle ear diseases remains a significant challenge, often requiring surgical intervention as the only option. In this study, we investigated porphysomes, self-assembled porphyrin-based nanoparticles, as a minimally invasive drug delivery platform for inner ear applications and as photothermal agents for cholesteatoma ablation. Three porphysome formulations were evaluated: parent porphysomes (PS), porphyrin-stabilized nanoemulsions (nPS), and EDTA-lipid incorporated porphysomes (ePS). Rats received intratympanic injections of each formulation, and fluorescence imaging performed 1 h postinjection demonstrated concentration-dependent inner ear penetration for all formulations. Notably, no signs of ototoxicity were observed based on histological and functional assessments of hearing and balance. Among ePS-treated rats, the 250 and 1,000 μM groups showed significantly higher inner ear fluorescence compared with the 50 μM group. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) tests were performed at baseline and 2 and 6 weeks postinjection. No significant threshold shifts were detected in PS and ePS groups compared with controls. In contrast, nPS-treated rats exhibited a significant ABR threshold elevation at 6 weeks ( < 0.02). At 6 weeks, minor yet statistically significant DPOAE threshold differences were observed at 16 kHz (PS group) and 32 kHz (all porphysome groups); however, all shifts remained below 0 dB, indicating no functional hearing loss. Vestibular assessments, including swim and beam tests, revealed no significant impairments. Upon laser activation, all porphysome formulations induced substantial temperature elevation (Δ = 31 ± 3.76°C, < 0.05) and histological burn effects in cholesteatoma tissues. These findings support the potential of porphysomes as a safe, minimally invasive drug delivery system and photothermal agent for the treatment of inner and middle ear disorders.
内耳和中耳疾病的治疗仍然是一项重大挑战，通常需要手术干预作为唯一选择。在本研究中，我们研究了卟啉体，即基于卟啉的自组装纳米颗粒，作为用于内耳应用的微创药物递送平台以及用于胆脂瘤消融的光热剂。评估了三种卟啉体制剂：母体卟啉体（PS）、卟啉稳定的纳米乳剂（nPS）和掺入EDTA-脂质的卟啉体（ePS）。大鼠接受每种制剂的鼓室内注射，注射后1小时进行的荧光成像显示所有制剂的内耳渗透均呈浓度依赖性。值得注意的是，根据听力和平衡的组织学和功能评估，未观察到耳毒性迹象。在接受ePS治疗的大鼠中，250和1000 μM组的内耳荧光明显高于50 μM组。在基线以及注射后2周和6周进行听觉脑干反应（ABR）和畸变产物耳声发射（DPOAE）测试。与对照组相比，PS组和ePS组未检测到明显的阈值变化。相比之下，接受nPS治疗的大鼠在6周时ABR阈值显著升高（<0.02）。在6周时，在16 kHz（PS组）和32 kHz（所有卟啉体组）观察到微小但具有统计学意义的DPOAE阈值差异；然而，所有变化均保持在0 dB以下，表明没有功能性听力损失。包括游泳和光束测试在内的前庭评估显示没有明显损伤。激光激活后，所有卟啉体制剂均在胆脂瘤组织中引起显著的温度升高（Δ=31±3.76°C，<0.05）和组织学烧伤效应。这些发现支持了卟啉体作为一种安全、微创的药物递送系统和光热剂用于治疗内耳和中耳疾病的潜力。
