Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery.
Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery.
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DOI：
10.1002/wnan.1355
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Lanza GM
中科院分区：
文献类型：
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作者：
Pan D;Pham CT;Weilbaecher KN;Tomasson MH;Wickline SA;Lanza GM
Sn2脂肪酶不稳定磷脂前体药物结合接触促进药物递送提供了纳米医学的重要进展。许多纳入纳米系统的药物，无论是否靶向，在到达靶点的循环过程中基本上都丢失了。然而，有利地改变药代动力学和全身给药的分布体积可以提供更高的疗效和更低的毒性，从而导致新的缓释纳米赋形剂。然而，实现Paul Erhlich的“神奇子弹”治疗疾病的概念在很大程度上尚未实现，因为纳米药物不稳定，纳米系统对靶细胞的药物递送能力低，内吞噬纳米颗粒有效载荷的细胞内生物利用度差，以及血管外颗粒渗透到病理部位的实质性生物屏障。如图所示，Sn2磷脂前体药物与接触促进药物递送相结合，可防止药物在循环过程中过早扩散损失，并提高靶细胞的生物利用度。Sn2磷脂前药方法同样适用于血管受限的脂包被颗粒和胶束，这些胶束的大小与穿透骨髓自然开窗内皮或炎症微循环的薄壁小静脉的蛋白质大小相同。一度，纳米医学被其忠实的反对者视为“圣杯之旅”，甚至该领域的许多人都在吸收关于人类生物学和粒子的长期学习曲线的痛苦。然而，纳米医学的创新，如Sn2磷脂前药，终于实现了有意义的转化成功。
Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success.