Laboratory Experimental Oncology, Department of Pathology, Erasmus MC, 3015GD Rotterdam, The Netherlands.
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Theranostics. 2021 Mar 31;11(12):5700-5712. doi: 10.7150/thno.55163. eCollection 2021.
Increasing the bioavailable drug level in a tumor is the key to enhance efficacy of chemotherapy. Thermosensitive smart drug delivery systems (SDDS) in combination with local hyperthermia facilitate high local drug levels, thus improving uptake in the tumor. However, inability to rapidly and efficiently absorb the locally released drug results in reduced efficacy, as well as undesired redistribution of the drug away from the tumor to the system. Based on this paradigm we propose a novel approach in which we replaced doxorubicin (DXR), one of the classic drugs for nanocarrier-based delivery, with idarubicin (IDA), a hydrophobic anthracycline used solely in the free form for treatment hematologic cancers. We established a series of and experiments to in depth study the kinetics of SDDS-based delivery, drug release, intratumor biodistribution and subsequent cell uptake. We demonstrate that IDA is taken up over 10 times more rapidly by cancer cells than DXR . Similar trend is observed in online imaging and less drug redistribution is shown for IDA, together resulting in 4-times higher whole tumor drug uptake for IDA vs. DXR. Together his yielded an improved intratumoral drug distribution for IDA-SDDS, translating into superior tumor response compared to DXR-SDDS treatment at the same dose. Thus, IDA - a drug that is not used for treatment of solid cancers - shows superior therapeutic index and better outcome when administered in externally triggered SDDS. We show that a shift in selection of chemotherapeutics is urgently needed, away from the classic drugs towards selection based on properties of a chemotherapeutic in context of the nanoparticle and delivery mode, to maximize the therapeutic efficacy.
提高肿瘤内的生物利用度药物水平是增强化疗效果的关键。热敏智能药物传递系统（SDDS）与局部热疗相结合，有利于局部高药物水平，从而提高肿瘤的摄取率。然而，由于无法快速有效地吸收局部释放的药物，导致疗效降低，以及药物从肿瘤向全身的不期望分布。基于这一范例，我们提出了一种新的方法，即用伊达比星（IDA）替代多柔比星（DXR），后者是用于纳米载体递送的经典药物之一，IDA 是一种仅以游离形式用于治疗血液系统癌症的疏水性蒽环类药物。我们进行了一系列体内和体外实验，以深入研究基于 SDDS 的递药、药物释放、肿瘤内生物分布和随后的细胞摄取动力学。我们证明 IDA 被癌细胞摄取的速度比 DXR 快 10 倍以上。在在线成像中也观察到类似的趋势，并且 IDA 的药物重分布较少，导致 IDA 与 DXR 相比，整个肿瘤的药物摄取量增加了 4 倍。综上所述，这导致 IDA-SDDS 的肿瘤内药物分布得到改善，与相同剂量的 DXR-SDDS 治疗相比，肿瘤反应更好。因此，IDA-一种不用于治疗实体瘤的药物-在外部触发的 SDDS 中显示出更高的治疗指数和更好的结果。我们表明，迫切需要从经典药物向基于化疗药物在纳米颗粒和递药模式背景下的特性进行选择转变，以最大限度地提高治疗效果。
