PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro.
PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro.
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DOI：
10.1038/srep33234
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发表时间：
2016-09-30
影响因子：
4.6
通讯作者：
Evans CL
中科院分区：
文献类型：
--
作者：
Hung HI;Klein OJ;Peterson SW;Rokosh SR;Osseiran S;Nowell NH;Evans CL
光动力学治疗方案使用称为光敏剂的光激活分子，对许多恶性肿瘤具有高度选择性，并且可以绕过某些具有挑战性的治疗抗性机制。光敏剂如小阳离子分子EtNBS（5-乙基氨基-9-二乙基-氨基苯并[a]吩噻嗪氯化物）已被证明对驻留在酸性和缺氧肿瘤微环境中的癌细胞有效。然而，在较高剂量下，这些光敏剂通过不依赖于光的机制诱导“暗毒性”。在这项研究中，我们评估了使用纳米颗粒封装来克服这一限制。有趣的是，发现将化合物包封在聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒（PLGA-EtNBS）内显著降低EtNBS暗毒性，同时在常氧和缺氧条件下完全保留分子的细胞毒性。这种双重效应可归因于释放机制：EtNBS保持包封，直到外部光照射，这刺激氧非依赖性、自由基介导的过程，降解PLGA纳米颗粒并释放分子。由于这些PLGA封装的EtNBS纳米颗粒能够深入渗透到3D球状体培养物的缺氧和酸性核心中，因此它们可以安全有效地治疗其他无反应的肿瘤区域。
Photodynamic therapy regimens, which use light-activated molecules known as photosensitizers, are highly selective against many malignancies and can bypass certain challenging therapeutic resistance mechanisms. Photosensitizers such as the small cationic molecule EtNBS (5-ethylamino-9-diethyl-aminobenzo[a]phenothiazinium chloride) have proven potent against cancer cells that reside within acidic and hypoxic tumour microenvironments. At higher doses, however, these photosensitizers induce “dark toxicity” through light-independent mechanisms. In this study, we evaluated the use of nanoparticle encapsulation to overcome this limitation. Interestingly, encapsulation of the compound within poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-EtNBS) was found to significantly reduce EtNBS dark toxicity while completely retaining the molecule’s cytotoxicity in both normoxic and hypoxic conditions. This dual effect can be attributed to the mechanism of release: EtNBS remains encapsulated until external light irradiation, which stimulates an oxygen-independent, radical-mediated process that degrades the PLGA nanoparticles and releases the molecule. As these PLGA-encapsulated EtNBS nanoparticles are capable of penetrating deeply into the hypoxic and acidic cores of 3D spheroid cultures, they may enable the safe and efficacious treatment of otherwise unresponsive tumour regions.