Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors.
Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors.
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DOI：
10.1158/0008-5472.can-12-1683
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发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Dewhirst MW
中科院分区：
文献类型：
--
作者：
Manzoor AA;Lindner LH;Landon CD;Park JY;Simnick AJ;Dreher MR;Das S;Hanna G;Park W;Chilkoti A;Koning GA;ten Hagen TL;Needham D;Dewhirst MW
传统上，纳米颗粒化疗的目标是通过提高药物对肿瘤的特异性来降低正常组织的毒性。EPR效应（增强的渗透性和滞留性）允许被动积聚到肿瘤间质。然而，由于血管渗透性的非均质性限制了纳米颗粒的渗透，大多数纳米颗粒的输送效果都不理想。此外，缓慢的药物释放限制了生物利用度。我们开发了一种局部热触发的快速药物释放脂质体，已经显示出实质性的抗肿瘤功效，并在人体试验中。在这里，我们证明了热敏脂质体在肿瘤血管内释放阿霉素。多柔比星在窗腔内给药小鼠肿瘤的实时共聚焦成像和侧腹肿瘤的组织学分析表明，血管内药物释放增加了间质间隙的游离药物。与游离药物或传统聚乙二醇脂质体相比，这增加了肿瘤细胞暴露于最大药物水平的时间和药物渗透距离。这些药物生物利用度的改进建立了一种新的药物递送模式：快速触发药物在肿瘤血液中的释放。
Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The EPR effect (Enhanced Permeability and Retention) can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Further, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial anti-tumor efficacy and is in human trials. Here, we demonstrate that thermally sensitive liposomes release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.