Yu Qing, Roberts Megan G, Houdaihed Loujin, Liu Yang, Ho Kuan, Walker Gilbert, Allen Christine, Reilly Raymond M, Manners Ian, Winnik Mitchell A
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 1H6, Canada.
Nanoscale. 2021 Jan 7;13(1):280-291. doi: 10.1039/d0nr08076d. Epub 2020 Dec 18.
The efficient penetration of drug nanocarriers into tumors is an important prerequisite for therapeutic and diagnostic success. The physicochemical properties of nanocarriers, including size, shape and surface chemistry have been shown to influence their transport in biological systems. Recent studies have shown that elongated nanoparticles (NPs) can exhibit advantageous properties in comparison to spherical NPs, but these experiments have involved a variety of different materials, many of which are characterized by a broad size distribution. Here we describe a series of rigid rod-like micelles of uniform width, with narrow length distributions, and common surface chemistry, and examine their cell uptake and penetration into multicellular tumor spheroids (MCTSs) formed from two human breast cancer cell lines (MDA-MB-436 and MDB-MB-231). These micelles were prepared from a polyferrocenylsilane (PFS) diblock copolymer (BCP) with a corona block consisting of a statistical polymer of aminopropyl methacrylamide and oligo(ethyleneglycol methacrylate) (PFS-b-PAPMA-stat-POEGMA). The rigid rod micelles, with a common width (12 nm) and lengths ranging from 80 to 2000 nm, were prepared by seeded growth crystallization-driven self-assembly in ethanol and then transferred to water. To consider whether changing the shape of these micelles affects its uptake and penetration behavior, analogous spherical micelles were prepared by direct nanoprecipitation into water. Both micelle shape and length were found to influence cellular uptake and penetration into 500 μm MCTSs. Laser confocal fluorescence microscopy was used to examine penetration of these micelles into three-dimensional MCTS up to 90 μm depth. Micelles with an elongated shape and short length (80 nm) demonstrated the deepest penetration into the MCTSs formed by MDA-MB-436 cells. Micelles with lengths of 200 nm also showed substantial penetration into these MCTS, but the extent and depth of tumor penetration of the rod-like micelles decreased with increasing aspect ratio. MCTS of MDA-MB-231 cells had a less dense, more open structure than those formed by MDA-MB-436 cells. Here more extensive penetration was observed, particularly for the longer micelle samples.
药物纳米载体有效渗透到肿瘤中是治疗和诊断成功的重要前提。纳米载体的物理化学性质，包括大小、形状和表面化学，已被证明会影响它们在生物系统中的运输。最近的研究表明，与球形纳米颗粒相比，细长的纳米颗粒（NPs）可能具有优势特性，但这些实验涉及多种不同材料，其中许多材料的特点是尺寸分布较宽。在这里，我们描述了一系列宽度均匀、长度分布窄且表面化学性质相同的刚性棒状胶束，并研究了它们对由两种人类乳腺癌细胞系（MDA-MB-436和MDB-MB-231）形成的多细胞肿瘤球体（MCTSs）的细胞摄取和渗透情况。这些胶束由聚二茂铁硅烷（PFS）二嵌段共聚物（BCP）制备而成，其冠层嵌段由甲基丙烯酰胺丙基和聚（乙二醇甲基丙烯酸酯）的统计聚合物（PFS-b-PAPMA-stat-POEGMA）组成。通过在乙醇中进行晶种生长结晶驱动的自组装制备出宽度为12 nm、长度范围为80至2000 nm的刚性棒状胶束，然后转移到水中。为了研究改变这些胶束的形状是否会影响其摄取和渗透行为，通过直接纳米沉淀到水中制备了类似的球形胶束。发现胶束形状和长度都会影响细胞摄取以及对500μm MCTSs的渗透。使用激光共聚焦荧光显微镜检查这些胶束对深度达90μm的三维MCTS的渗透情况。形状细长且长度较短（80 nm）的胶束对由MDA-MB-436细胞形成的MCTSs的渗透最深。长度为200 nm的胶束也显示出对这些MCTS的大量渗透，但棒状胶束的肿瘤渗透程度和深度随着纵横比的增加而降低。MDA-MB-231细胞的MCTS比MDA-MB-436细胞形成的MCTS结构密度更低、更开放。在这里观察到了更广泛的渗透，特别是对于较长的胶束样品。
