Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
Int J Nanomedicine. 2019 Aug 16;14:6589-6600. doi: 10.2147/IJN.S212861. eCollection 2019.
The family of oncogenes () are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting -driven tumors has been a long-standing challenge in cancer therapy. Mutant activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate.
We exploit macropinocytosis pathway to deliver nanoparticles (NPs) in cancer cells harboring activating mutations.
NPs were synthesized by the desolvation method. The physicochemical properties and stability of NPs were characterized by dynamic light scattering and transmission electron microscopy. Uptake of fluorescently labelled NPs in wild-type and mutant cells were quantitively determined by flow cytometry and qualitatively by fluorescent microscopy. NP uptake by -driven macropinocytosis was confirmed by pharmacological inhibition and genetic knockdown.
We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of than monomeric albumin (ie, dissociated form of clinically used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these NPs exhibit significantly increased uptake in mutant cancer cells than wild-type S cells by macropinocytosis.
The uptake of albumin nanoparticles is driven by . This NP-based strategy targeting -driven macropinocytosis is a facile approach toward improved delivery into -driven cancers.
癌基因家族（）是癌症中最常见的突变，调节驱动肿瘤进展的关键信号通路。因此，针对驱动肿瘤的药物输送一直是癌症治疗中的一个长期挑战。突变激活癌细胞通过巨胞饮作用主动摄取营养物质，包括葡萄糖、脂质和白蛋白，以满足其生存和增殖的能量需求。
我们利用巨胞饮途径将纳米颗粒（NPs）递送到携带激活突变的癌细胞中。
通过去溶剂法合成 NPs。通过动态光散射和透射电子显微镜对 NPs 的物理化学性质和稳定性进行了表征。通过流式细胞术和荧光显微镜对野生型和突变型细胞中荧光标记的 NPs 的摄取进行了定量测定。通过药理学抑制和基因敲低证实了 NP 通过驱动的巨胞饮作用的摄取。
我们已经合成了稳定的白蛋白 NPs，与单体白蛋白（即临床使用的 nab-紫杉醇的解离形式）相比，其在具有激活突变的癌细胞中的摄取量显著增加。通过药理学抑制和半定量荧光显微镜研究，这些 NPs 通过巨胞饮作用在突变型癌细胞中的摄取量明显高于野生型 S 细胞。
白蛋白纳米颗粒的摄取是由驱动的。这种针对驱动的巨胞饮作用的基于 NP 的策略是一种针对驱动的癌症的简便的改善递送方法。
