Centre for Advanced Macromolecular Design, School of Chemistry , The University of New South Wales , Sydney , New South Wales 2052 , Australia.
Australia Nuclear Science and Technology Organisation , Lucas Heights , New South Wales 2234 , Australia.
Biomacromolecules. 2019 Apr 8;20(4):1545-1554. doi: 10.1021/acs.biomac.8b01707. Epub 2019 Mar 4.
Drug delivery carriers are now widely established because they can increase the therapeutic efficiency of drugs. In general, the aim in this field is to create effective carriers that have large amounts of drugs loaded to minimize drug carrier material that needs to be disposed of. However, there has been little attention so far in the literature on the effect of the amount of loaded drugs on the biological activity. In this paper, we are trying to answer the question of how the drug-loading content will affect the in vitro activity. We use two methods to load paclitaxel (PTX) into micelles based on the glycopolymer, poly(1- O-methacryloyl-β-d-fructopyranose)- block-poly(methyl methacylate) (Poly(1- O-MAFru)- b-PMMA). In the one-step method, the drug is loaded into the particles during the self-assembly process. However, the size of nanoparticle increased with the PTX content from 26 to 50 nm, triggering enhanced cellular uptake by MCF-7 and MDA-MB-231, which was caused by changes in diameter size and not by changes in drug concentration. To keep the nanoparticle size constant, preformed micelles were loaded with PTX (two-step process). The increasing amount of loaded drug led to decreased cellular uptake and reduced cytotoxicity by the cancer cell lines. Small-angle neutron scattering and small-angle X-ray scattering, supported by transmission electron microscopy and dynamic light scattering, exposed the PTX location in the shell. This caused shrinkage of the shell and lower levels of shell hydration, resulting in lower cellular uptake and lower cytotoxicity. Upon the release of PTX, the shell regained its original level of hydration. We could show that because drug loading causes morphology changes, in either the shell or the size, it is impossible to separate the parameters that will influence the biological activity. Although the same phenomenon may not apply to every drug delivery system, it needs to be considered that except for the well-known parameters that affect cell uptake-size, shape, surface chemistry, type of nanoparticle, and presence of bioactive groups-the amount of loaded drugs might change the physicochemical parameters of the nanoparticle and thus the in vitro and potentially the in vivo outcomes.
药物输送载体现在已经得到广泛应用，因为它们可以提高药物的治疗效率。一般来说，该领域的目标是创造有效的载体，使大量药物负载，以最小化需要处理的药物载体材料。然而，到目前为止，文献中很少关注药物负载量对生物活性的影响。在本文中，我们试图回答药物负载量将如何影响体外活性的问题。我们使用两种方法将紫杉醇（PTX）负载到基于糖聚合物的胶束中，即聚（1-O-甲基丙烯酰基-β-D-呋喃果糖）-嵌段-聚（甲基甲基丙烯酸甲酯）（Poly（1-O-MAFru）-b-PMMA）。在一步法中，药物在自组装过程中被载入颗粒中。然而，随着 PTX 含量从 26 增加到 50nm，纳米颗粒的尺寸增加，引发 MCF-7 和 MDA-MB-231 的细胞摄取增加，这是由于粒径大小的变化而不是药物浓度的变化引起的。为了保持纳米颗粒的尺寸不变，用 PTX 对预形成的胶束进行负载（两步法）。负载药物的量增加导致细胞摄取减少，癌细胞系的细胞毒性降低。小角中子散射和小角 X 射线散射，辅以透射电子显微镜和动态光散射，暴露了 PTX 在壳中的位置。这导致壳的收缩和较低的壳水合水平，从而导致较低的细胞摄取和较低的细胞毒性。当 PTX 释放时，壳恢复其原始的水合水平。我们可以表明，由于药物负载会导致形态变化，无论是在壳还是尺寸上，都不可能分离出影响生物活性的参数。尽管这种现象可能不适用于每种药物输送系统，但需要考虑到，除了影响细胞摄取的已知参数-大小、形状、表面化学、纳米颗粒类型和存在生物活性基团-负载药物的量可能会改变纳米颗粒的物理化学参数，从而改变体外和潜在的体内结果。
