Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA; Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, ul. F. Joliot-Curie 14A, 50-383 Wroclaw, Poland.
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
J Control Release. 2022 Jan;341:431-442. doi: 10.1016/j.jconrel.2021.11.034. Epub 2021 Nov 24.
Achievement of a high dose of drug in the tumor while minimizing its systemic side effects is one of the important features of an improved drug delivery system. Thus, developing responsive carriers for site-specific delivery of chemotherapeutic agents has become a main goal of research efforts. One of the known hallmarks of cancerous tumors is hypoxia, which offers a target for selective drug delivery. The stimuli-sensitive micellar system developed by us, (PEG-azobenzene-PEI-DOPE (PAPD) has proven to be effective in vitro. The proposed construct developed, PAPD, contains an azobenzene group as a hypoxia-sensitive moiety that triggers the shedding of the PEG layer from the nanoparticle surface under conditions of hypoxia to improve cellular uptake. Using microfluidics, we show significantly improved cellular association and penetration under hypoxia in both single cells and in a 3D tumor model. Employing an in vivo model, we demonstrate slower tumor growth that did not induce systemic side effects, including weight loss in an experimental animal model, when compared to the free drug treatment. This complex-in-nature but simple-in-design system for the simultaneous delivery of siRNA to silence the P-glycoprotein and doxorubicin with active tumor targeting and proven therapeutic efficacy represents a universal platform for the delivery of other hydrophobic chemotherapeutic agents and siRNA molecules which can be further modified.
在肿瘤中实现高剂量药物，同时将其全身副作用最小化，是改良药物输送系统的重要特征之一。因此，开发用于化疗药物的靶向传递的响应性载体已成为研究工作的主要目标之一。癌症肿瘤的一个已知特征是缺氧，这为选择性药物输送提供了一个靶标。我们开发的刺激响应性胶束系统（PEG-偶氮苯-PEI-DOPE（PAPD））已被证明在体外有效。所提出的构建物 PAPD 包含一个作为缺氧敏感部分的偶氮苯基团，在缺氧条件下触发 PEG 层从纳米颗粒表面脱落，以提高细胞摄取。使用微流控技术，我们在单细胞和 3D 肿瘤模型中都显示出在缺氧条件下显著改善的细胞关联和穿透性。在体内模型中，与游离药物治疗相比，我们证明了较慢的肿瘤生长，没有诱导全身性副作用，包括实验动物模型中的体重减轻。这种复杂的设计但简单的设计的用于同时输送 siRNA 以沉默 P-糖蛋白和阿霉素的系统，具有主动的肿瘤靶向和经过验证的治疗效果，代表了用于输送其他疏水性化疗药物和 siRNA 分子的通用平台，这些药物和 siRNA 分子可以进一步修饰。
