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Analyzing 2000 in Vivo Drug Delivery Data Points Reveals Cholesterol Structure Impacts Nanoparticle Delivery
ACS Nano ( IF 15.8 ) Pub Date : 2018-07-17 00:00:00 , DOI: 10.1021/acsnano.8b03640 Kalina Paunovska 1 , Carmen J Gil 1 , Melissa P Lokugamage 1 , Cory D Sago 1 , Manaka Sato 1 , Gwyn N Lando 1 , Marielena Gamboa Castro 1 , Anton V Bryksin 2 , James E Dahlman 1
ACS Nano ( IF 15.8 ) Pub Date : 2018-07-17 00:00:00 , DOI: 10.1021/acsnano.8b03640 Kalina Paunovska 1 , Carmen J Gil 1 , Melissa P Lokugamage 1 , Cory D Sago 1 , Manaka Sato 1 , Gwyn N Lando 1 , Marielena Gamboa Castro 1 , Anton V Bryksin 2 , James E Dahlman 1
Affiliation
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Lipid nanoparticles (LNPs) are formulated using unmodified cholesterol. However, cholesterol is naturally esterified and oxidized in vivo, and these cholesterol variants are differentially trafficked in vivo via lipoproteins including LDL and VLDL. We hypothesized that incorporating the same cholesterol variants into LNPs—which can be structurally similar to LDL and VLDL—would alter nanoparticle targeting in vivo. To test this hypothesis, we quantified how >100 LNPs made with six cholesterol variants delivered DNA barcodes to 18 cell types in wild-type, LDLR–/–, and VLDLR–/– mice that were both age-matched and female. By analyzing ∼2000 in vivo drug delivery data points, we found that LNPs formulated with esterified cholesterol delivered nucleic acids more efficiently than LNPs formulated with regular or oxidized cholesterol when compared across all tested cell types in the mouse. We also identified an LNP containing cholesteryl oleate that efficiently delivered siRNA and sgRNA to liver endothelial cells in vivo. Delivery was as—or more—efficient as the same LNP made with unmodified cholesterol. Moreover, delivery to liver endothelial cells was 3 times more efficient than delivery to hepatocytes, distinguishing this oleate LNP from hepatocyte-targeting LNPs. RNA delivery can be improved by rationally selecting cholesterol variants, allowing optimization of nanoparticle targeting.
中文翻译：
分析 2000 个体内药物递送数据点揭示胆固醇结构影响纳米颗粒递送
脂质纳米粒子 (LNP) 使用未修饰的胆固醇配制而成。然而，胆固醇在体内自然酯化和氧化，并且这些胆固醇变体通过包括LDL和VLDL在内的脂蛋白在体内有差异地运输。我们假设将相同的胆固醇变体纳入 LNP（结构上与 LDL 和 VLDL 相似）将改变纳米颗粒体内的靶向性。为了检验这一假设，我们量化了由六种胆固醇变体制成的超过 100 个 LNP 如何将 DNA 条形码传递给年龄匹配的雌性野生型、LDLR –/–和 VLDLR –/–小鼠中的 18 种细胞类型。通过分析〜2000个体内药物递送数据点，我们发现与小鼠中所有测试的细胞类型相比，用酯化胆固醇配制的LNP比用常规或氧化胆固醇配制的LNP更有效地递送核酸。我们还鉴定了一种含有胆固醇油酸酯的 LNP，它可以在体内有效地将 siRNA 和 sgRNA 递送至肝内皮细胞。递送效率与用未经修饰的胆固醇制成的相同 LNP 相同或更高。此外，递送至肝内皮细胞的效率比递送至肝细胞的效率高 3 倍，这将这种油酸盐 LNP 与靶向肝细胞的 LNP 区分开来。通过合理选择胆固醇变体可以改善 RNA 递送，从而优化纳米颗粒靶向。
更新日期：2018-07-17
中文翻译：
分析 2000 个体内药物递送数据点揭示胆固醇结构影响纳米颗粒递送
脂质纳米粒子 (LNP) 使用未修饰的胆固醇配制而成。然而，胆固醇在体内自然酯化和氧化，并且这些胆固醇变体通过包括LDL和VLDL在内的脂蛋白在体内有差异地运输。我们假设将相同的胆固醇变体纳入 LNP（结构上与 LDL 和 VLDL 相似）将改变纳米颗粒体内的靶向性。为了检验这一假设，我们量化了由六种胆固醇变体制成的超过 100 个 LNP 如何将 DNA 条形码传递给年龄匹配的雌性野生型、LDLR –/–和 VLDLR –/–小鼠中的 18 种细胞类型。通过分析〜2000个体内药物递送数据点，我们发现与小鼠中所有测试的细胞类型相比，用酯化胆固醇配制的LNP比用常规或氧化胆固醇配制的LNP更有效地递送核酸。我们还鉴定了一种含有胆固醇油酸酯的 LNP，它可以在体内有效地将 siRNA 和 sgRNA 递送至肝内皮细胞。递送效率与用未经修饰的胆固醇制成的相同 LNP 相同或更高。此外，递送至肝内皮细胞的效率比递送至肝细胞的效率高 3 倍，这将这种油酸盐 LNP 与靶向肝细胞的 LNP 区分开来。通过合理选择胆固醇变体可以改善 RNA 递送，从而优化纳米颗粒靶向。
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