Stimuli-sensitive nano-drug delivery with programmable size changes to enhance accumulation of therapeutic agents in tumors

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.纳米药物递送系统（nano-based drug delivery systems）在癌症治疗领域具有巨大应用前景。当前，载药纳米颗粒（drug-carrying nanoparticles）在肿瘤部位的富集效率不足，限制了其临床转化成效。本研究结合血管内与血管外药物释放的双重范式，提出了一种具备可编程尺寸变化特性的高效纳米药物递送系统。装载于大尺寸纳米颗粒（一级纳米颗粒，primary nanoparticles）内的载药小尺寸纳米颗粒（二级纳米颗粒，secondary nanoparticles），可在聚焦超声（focused ultrasound）产生的温度场作用下于微血管网络（microvascular network）中释放，此举可使药物递送系统的尺寸缩小7.5至150倍。随后，小尺寸纳米颗粒可凭借高跨血管转运效率进入肿瘤组织，实现更高的药物富集度与更深的组织穿透深度。响应肿瘤微环境（tumor microenvironment）的酸性pH（结合氧分布特征），二级纳米颗粒可缓慢释放阿霉素（doxorubicin），即持续释药。为预测治疗剂的递送性能与分布特征，本研究首先基于血管出芽生成模型（sprouting angiogenesis model）构建了半真实微血管网络，并通过开发的多室模型（multi-compartment model）研究了治疗剂的转运过程。研究结果表明，缩小一级与二级纳米颗粒的尺寸可提升肿瘤细胞杀伤率（cell death rate）。此外，通过提升药物在细胞外间隙（extracellular space）的生物利用度（bioavailability），可更持久地抑制肿瘤生长。本研究提出的纳米药物递送系统在临床应用中极具潜力。此外，所构建的数学模型可推广至更多药物递送系统的性能预测场景。