Department of Neurosurgery , Mayo Clinic , Jacksonville , Florida 32224 , United States.
Department of Ophthalmology, Department of Neurosurgery, Department of Materials Science and Engineering, and Department of Chemical and Biomolecular Engineering , Johns Hopkins University , Baltimore , Maryland 21218 , United States.
Biomacromolecules. 2018 Aug 13;19(8):3361-3370. doi: 10.1021/acs.biomac.8b00640. Epub 2018 Jul 23.
Amphiphilic polymers can be used to form micelles to deliver water-insoluble drugs. A biodegradable poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE)-PEG triblock copolymer was developed that is useful for drug delivery. It was shown to successfully encapsulate and pH-dependently release a water-insoluble, small molecule anticancer drug, verteporfin. PEG-PBAE-PEG micelle morphology was also controlled through variations to the hydrophobicity of the central PBAE block of the copolymer in order to evade macrophage uptake. Spherical micelles were 50 nm in diameter, while filamentous micelles were 31 nm in width with an average aspect ratio of 20. When delivered to RAW 264.7 mouse macrophages, filamentous micelles exhibited a 89% drop in cellular uptake percentage and a 5.6-fold drop in normalized geometric mean cellular uptake compared to spherical micelles. This demonstrates the potential of high-aspect-ratio, anisotropically shaped PEG-PBAE-PEG micelles to evade macrophage-mediated clearance. Both spherical and filamentous micelles also showed therapeutic efficacy in human triple-negative breast cancer and small cell lung cancer cells without requiring photodynamic therapy to achieve an anticancer effect. Both spherical and filamentous micelles were more effective in killing lung cancer cells than breast cancer cells at equivalent verteporfin concentrations, while spherical micelles were shown to be more effective than filamentous micelles against both cancer cells. Spherical and filamentous micelles at 5 and 10 μM respective verteporfin concentration resulted in 100% cell killing of lung cancer cells, but both micelles required a higher verteporfin concentration of 20 μM to kill breast cancer cells at the levels of 80% and 50% respectively. This work demonstrates the potential of PEG-PBAE-PEG as a biodegradable, anisotropic drug delivery system as well as the in vitro use of verteporfin-loaded micelles for cancer therapy.
两亲性聚合物可用于形成胶束以递送水不溶性药物。已开发出一种可用于药物递送的可生物降解的聚（乙二醇）（PEG）-聚（β-氨基酯）（PBAE）-PEG 三嵌段共聚物。它被证明可以成功地包封并在 pH 依赖性下释放一种水不溶性小分子抗癌药物，维替泊芬。还通过改变共聚物中心 PBAE 嵌段的疏水性来控制 PEG-PBAE-PEG 胶束形态，以逃避巨噬细胞摄取。球形胶束的直径为 50nm，而丝状胶束的宽度为 31nm，平均纵横比为 20。当递送至 RAW 264.7 小鼠巨噬细胞时，与球形胶束相比，丝状胶束的细胞摄取百分比降低了 89%，归一化平均细胞摄取量降低了 5.6 倍。这表明具有高纵横比、各向异性形状的 PEG-PBAE-PEG 胶束具有逃避巨噬细胞介导的清除作用的潜力。球形和丝状胶束在人三阴性乳腺癌和小细胞肺癌细胞中也表现出治疗功效，而无需光动力疗法即可实现抗癌作用。在等效维替泊芬浓度下，球形和丝状胶束在杀死肺癌细胞方面均比乳腺癌细胞更有效，而球形胶束对两种癌细胞均比对丝状胶束更有效。在 5 和 10μM 各自维替泊芬浓度下，球形和丝状胶束均导致肺癌细胞的 100%细胞杀伤，但两种胶束均需要 20μM 的更高维替泊芬浓度才能分别使乳腺癌细胞的杀伤率达到 80%和 50%。这项工作证明了 PEG-PBAE-PEG 作为一种可生物降解的各向异性药物递送系统的潜力，以及载有维替泊芬的胶束在癌症治疗中的体外应用。
