Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery.
Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery.
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DOI：
10.1016/j.jconrel.2013.07.008
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发表时间：
2013-10-28
期刊：
影响因子：
--
通讯作者：
Sorg BS
中科院分区：
文献类型：
--
作者：
Choe SW;Terman DS;Rivers AE;Rivera J;Lottenberg R;Sorg BS
选择性给药到缺氧肿瘤壁龛仍然是一个重要的治疗挑战，需要新的概念方法。镰状红细胞（ssrbc）与外源性促氧化剂一起使用时，已经显示出靶向这种缺氧壁龛和诱导杀肿瘤特性的能力。在这里，我们确定在小鼠ss红细胞中包裹的模型治疗药物的递送是否可以通过体外光敏来增强，在缺氧肿瘤中，将自身溶血延迟到与ss红细胞最大定位一致的时间。4T1癌的高光谱成像显示大部分肿瘤（通常为50%或更多）的氧饱和度<10%。通过视频显微镜观察植入4T1肿瘤的背侧皮肤窗腔，我们发现同种异体ssrbc，而非正常红细胞（nrbc），在全身给药后12-24小时内选择性地在缺氧的4T1肿瘤中积累。我们进一步表明，体外光氧化可以编程ss红细胞，将模型治疗药物的溶血/释放推迟到与它们在缺氧肿瘤微血管中的最大隔离一致的点。在这些条件下，与非光敏ss红细胞、载药光敏nrbc和游离药物相比，载药光敏ss红细胞向肿瘤的药物递送量增加了3-4倍。这些结果表明，与光氧化的nrbc和非光氧化的ssrbc相比，光氧化的ssrbc在缺氧肿瘤中具有隔离和溶血作用，并且释放出更多的药物。因此，负载药物的ss红细胞的光氧化似乎利用了ss红细胞独特的肿瘤靶向性和载体特性来优化对缺氧肿瘤的药物递送。因此，这种程序化的和载药的ss红细胞代表了一种新的和有用的工具，可以增加对缺氧实体肿瘤的药物输送。
Selective drug delivery to hypoxic tumor niches remains a significant therapeutic challenge that calls for new conceptual approaches. Sickle red blood cells (SSRBCs) have shown an ability to target such hypoxic niches and induce tumoricidal properties when used together with exogenous pro-oxidants. Here we determine whether the delivery of a model therapeutic encapsulated in murine SSRBCs can be enhanced by ex vivo photosensitization under conditions that delay autohemolysis to a time that coincides with maximal localization of SSRBCs in a hypoxic tumor. Hyperspectral imaging of 4T1 carcinomas shows oxygen saturation levels <10% in a large fraction (commonly 50% or more) of the tumor. Using video microscopy of dorsal skin window chambers implanted with 4T1 tumors, we demonstrate that allogeneic SSRBCs, but not normal RBCs (nRBCs), selectively accumulate in hypoxic 4T1 tumors between 12-24 hours after systemic administration. We further show that ex vivo photo-oxidation can program SSRBCs to postpone hemolysis/release of a model therapeutic to a point that coincides with their maximum sequestration in hypoxic tumor microvessels. Under these conditions, drug-loaded photosensitized SSRBCs show a 3-4 fold greater drug delivery to tumors compared to non-photosensitized SSRBCs, drug-loaded photosensitized nRBCs, and free drug. These results demonstrate that photo-oxidized SSRBCs, but not photo-oxidized nRBCs, sequester and hemolyze in hypoxic tumors and release substantially more drug than photo-oxidized nRBCs and non-photo-oxidized SSRBCs. Photo-oxidation of drug-loaded SSRBCs thus appears to exploit the unique tumor targeting and carrier properties of SSRBCs to optimize drug delivery to hypoxic tumors. Such programmed and drug-loaded SSRBCs therefore represent a novel and useful tool for augmenting drug delivery to hypoxic solid tumors.
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影响因子：
9.7
作者：
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