Abstract

Nano-based drug delivery systems hold significant promise for cancer therapies. Presently, the poor accumulation of drug-carrying nanoparticles in tumors has limited their success. In this study, based on a combination of the paradigms of intravascular and extravascular drug release, an efficient nanosized drug delivery system with programmable size changes is introduced. Drug-loaded smaller nanoparticles (secondary nanoparticles), which are loaded inside larger nanoparticles (primary nanoparticles), are released within the microvascular network due to temperature field resulting from focused ultrasound. This leads to the scale of the drug delivery system decreasing by 7.5 to 150 times. Subsequently, smaller nanoparticles enter the tissue at high transvascular rates and achieve higher accumulation, leading to higher penetration depths. In response to the acidic pH of tumor microenvironment (according to the distribution of oxygen), they begin to release the drug doxorubicin at very slow rates (i.e., sustained release). To predict the performance and distribution of therapeutic agents, a semi-realistic microvascular network is first generated based on a sprouting angiogenesis model and the transport of therapeutic agents is then investigated based on a developed multi-compartment model. The results show that reducing the size of the primary and secondary nanoparticles can lead to higher cell death rate. In addition, tumor growth can be inhibited for a longer time by enhancing the bioavailability of the drug in the extracellular space. The proposed drug delivery system can be very promising in clinical applications. Furthermore, the proposed mathematical model is applicable to broader applications to predict the performance of drug delivery systems.

摘要

基于纳米的药物输送系统对癌症治疗具有重大前景。目前，载药纳米粒子在肿瘤中的不良积累限制了它们的成功。在这项研究中，基于血管内和血管外药物释放范例的组合，引入了一种具有可编程尺寸变化的高效纳米药物递送系统。由于聚焦超声产生的温度场，加载在较大纳米颗粒（初级纳米颗粒）内部的载药较小纳米颗粒（次级纳米颗粒）在微血管网络中释放。这导致药物输送系统的规模缩小了 7.5 到 150 倍。随后，较小的纳米颗粒以高经血管速率进入组织并实现更高的积累，从而导致更高的穿透深度。为了响应肿瘤微环境的酸性 pH 值（根据氧气的分布），它们开始以非常缓慢的速率（即持续释放）释放药物多柔比星。为了预测治疗剂的性能和分布，首先基于发芽血管生成模型生成半真实的微血管网络，然后基于开发的多室模型研究治疗剂的运输。结果表明，减小初级和次级纳米粒子的尺寸可以导致更高的细胞死亡率。此外，通过提高药物在细胞外空间的生物利用度，可以更长时间地抑制肿瘤生长。所提出的药物输送系统在临床应用中非常有前途。此外，