Two-dimensional chemotherapy simulations demonstrate fundamental transport and tumor response limitations involving nanoparticles.
Two-dimensional chemotherapy simulations demonstrate fundamental transport and tumor response limitations involving nanoparticles.
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二维化疗模拟证明了涉及纳米颗粒的基本运输和肿瘤反应限制。
DOI：
10.1200/jco.2005.23.16_suppl.2118
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发表时间：
2005
影响因子：
2.8
通讯作者：
V. Cristini
中科院分区：
文献类型：
--
作者：
V. Cristini
Zheng等人（2004）开发了一种多尺度二维肿瘤模拟器，能够显示肿瘤病变进展，包括扩散限制性休眠、新血管形成（血管生成）以及随后的快速生长和组织侵袭。在本文中，我们扩展他们的模拟器来描述化疗药物输送到一个高灌注的肿瘤病变和肿瘤细胞对治疗的反应。我们基于自洽的参数估计进行2-D模拟，该参数估计证明了将抗癌药物递送到肿瘤中的基本对流和扩散运输限制，无论这种递送是通过游离药物施用（例如，静脉滴注），或通过注射到血流中的100 nm纳米颗粒，外渗并释放药物，然后扩散到肿瘤组织中，或通过能够直接扩散并靶向单个肿瘤细胞的更小的1-10 nm纳米颗粒。即使在涉及以下内容的最佳情况下：纳米颗粒持续（“智能”）释放药物;一种细胞类型的同质肿瘤，对药物敏感且不会产生耐药性;靶向纳米颗粒递送，导致宿主组织毒性低;校准模型参数以确保足够的药物或纳米颗粒血液浓度，以快速杀死体外所有细胞;我们的分析显示，基本的转运限制是严重的，并且肿瘤内的药物水平远低于体外，使得肿瘤的大部分具有不足的药物浓度。我们的模拟预测的细胞死亡率的比较表明，在体内肿瘤收缩率是几个数量级小于在体外相同的化疗载体浓度在血清和体外，和一些收缩后，肿瘤可能会达到一个新的质量平衡远高于可检测的水平。我们还证明，辅助抗血管生成治疗“正常化”的脉管系统可能会改善运输的限制，虽然导致不必要的肿瘤碎片。最后，我们的研究结果表明，具有主动转运机制的小纳米颗粒（例如，趋化性）将克服预测的局限性并导致改善的肿瘤反应。
Zheng et al. (2004) developed a multiscale, two-dimensional tumor simulator with the capability of showing tumoral lesion progression through the stages of diffusion-limited dormancy, neo-vascularization (angiogenesis) and consequent rapid growth and tissue invasion. In this paper we extend their simulator to describe delivery of chemotherapeutic drugs to a highly perfused tumoral lesion and the tumor cells' response to the therapy. We perform 2-D simulations based on a self-consistent parameter estimation that demonstrate fundamental convective and diffusive transport limitations in delivering anticancer drug into tumors, whether this delivery is via free drug administration (e.g., intravenous drip), or via 100 nm nanoparticles injected into the bloodstream, extravasating and releasing the drug that then diffuses into the tumoral tissue, or via smaller 1-10 nm nanoparticles that are capable of diffusing directly and targeting the individual tumor cell. Even in a best-case scenario involving: constant ("smart") drug release from the nanoparticles; a homogenous tumor of one cell type, which is drug-sensitive and does not develop resistance; targeted nanoparticle delivery, with resulting low host tissue toxicity; and for model parameters calibrated to ensure sufficient drug or nanoparticle blood concentration to rapidly kill all cells in vitro ; our analysis shows that fundamental transport limitations are severe and that drug levels inside the tumor are far less than in vitro , leaving large parts of the tumor with inadequate drug concentration. A comparison of cell death rates predicted by our simulations reveals that the in vivo rate of tumor shrinkage is several orders of magnitude less than in vitro for equal chemotherapeutic carrier concentrations in the blood serum and in vitro, and after some shrinkage the tumor may achieve a new mass equilibrium far above detectable levels. We also demonstrate that adjuvant anti-angiogenic therapy "normalizing" the vasculature may ameliorate transport limitations, although leading to unwanted tumor fragmentation. Finally, our results suggest that small nanoparticles equipped with active transport mechanisms (e.g., chemotaxis) would overcome the predicted limitations and result in improved tumor response.
DOI：
10.1073/pnas.95.8.4607
发表时间：
1998-04-14
影响因子：
11.1
作者：
Hobbs, SK;Monsky, WL;Jain, RK
通讯作者：
Jain, RK