PO.IM01.12 · 免疫学
一种用于低剂量光动力治疗诱导抗肿瘤免疫激活的porphyrin-HDL纳米颗粒
A porphyrin-HDL nanoparticle for low-dose photodynamic therapy-induced antitumor immune activation
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
光动力治疗（PDT）是一种可临床转化的治疗方式，利用光敏剂、氧气和光照诱导肿瘤细胞死亡和抗肿瘤免疫。基于卟啉体的纳米颗粒（LC-ePS）作为光敏剂，在3小时给药-光照间隔（DLI）下蓄积于肿瘤血管系统和细胞外基质中。LC-ePS介导的PDT诱导强大的全身免疫，包括抵御肿瘤再攻击的持久抗肿瘤记忆。这与免疫缺陷的NSG小鼠形成对比，后者中LC-ePS PDT丧失治疗效果，表明持久的肿瘤控制需要功能性的宿主免疫。然而，传统纳米颗粒的疗效受限于其较差的肿瘤穿透性和血管周围滞留，这限制了对肿瘤细胞的直接消融及随后的免疫激活。为解决这一问题，我们设计了尺寸显著更小的porphyrin-HDL纳米颗粒（PLP）。该平台尺寸约为20 nm，能够更深地穿透肿瘤并被细胞快速摄取，从而增强PDT疗效。PLP纳米颗粒通过含卟啉脂质的HDL自组装方法合成，在最小化尺寸的同时保持光反应性。在荷CT26肿瘤的BALB/c小鼠中，静脉给予PLP，并施加不同的PDT光剂量以确定完全消融所需的最小光通量。与LC-ePS相比，PLP显示出显著增强的光动力效力。LC-ePS在10 mg/kg剂量下、3小时DLI时需要135 J/cm²才能实现肿瘤完全消融，而PLP在低2.5倍的药物剂量（4 mg/kg）和低2.5倍以上的光剂量（50 J/cm²）下即实现了肿瘤完全根除。这些剂量降低提示，PLP优越的PDT疗效源于其增强的细胞内摄取和改善的组织穿透，共同在体内提供了更高的光化学效率。总之，PLP纳米平台代表了光动力治疗的重大进展，提供了更深的肿瘤穿透、显著降低的治疗剂量需求以及强大的免疫调节潜力。这些特性共同使PLP成为将有效的局部肿瘤消融与强大的全身抗肿瘤免疫相结合的有前景的策略。正在进行的工作重点是进一步优化体内固有免疫激活和适应性T细胞反应。
查看英文原文 English abstract
Photodynamic therapy (PDT) is a clinically translatable modality that uses a photosensitizer, oxygen, and light to induce tumor cell death and antitumor immunity. Porphysome-based nanoparticles (LC-ePS) act as photosensitizers and accumulate in the tumor vasculature and extracellular matrix at a 3-hour drug-light interval (DLI). LC-ePS-mediated PDT induces robust systemic immunity, including durable antitumor memory that protects against tumor rechallenge. This is compared to immunodeficient NSG mice where LC-ePS PDT lost therapeutic efficacy, indicating that durable tumor control requires functional host immunity. However, the efficacy of conventional nanoparticles is limited by their poor tumor penetration and perivascular sequestration, which restricts direct tumor cell ablation and subsequent immune activation. To address this, porphyrin-HDL nanoparticles (PLP) were engineered with a markedly smaller size. At ~20 nm, this platform enables deeper penetration into tumors with rapid cellular uptake, enhancing PDT efficacy. PLP nanoparticles were synthesized via an HDL self-assembly approach with porphyrin lipids, maintaining photoreactivity while minimizing size. In BALB/c mice bearing CT26 tumors, PLP were administered intravenously, and varying PDT light doses were applied to determine the minimal fluence for complete ablation. PLP demonstrated markedly enhanced photodynamic potency compared with LC-ePS. Whereas LC-ePS at10mg/kg required 135 J/cm² at a 3-hour DLI to achieve complete tumor ablation, PLP achieved full tumor eradication at a 2.5-fold lower drug dose (4mg/kg) and with >2.5-fold lower light dose (50 J/cm²). These dose-reduction suggest that the superior PDT efficacy of PLP arises from its enhanced intracellular uptake and improved tissue penetration, collectively offering higher photochemical efficiency in vivo. Overall, the PLP nanoplatform represents a significant advance in photodynamic therapy, offering deeper tumor penetration, markedly reduced therapeutic doses requirement, and strong immunomodulatory potential. Together, these features position PLP as a promising strategy for integrating effective local tumor ablation with robust systemic antitumor immunity. Ongoing work is focused on further optimizing in vivo innate immune activation and adaptive T-cell responses.
利益披露 Disclosure
Y. Yang, None.