Martins Cláudia, Sarmento Bruno
I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
Methods Mol Biol. 2020;2059:213-224. doi: 10.1007/978-1-4939-9798-5_11.
Taxane chemotherapeutics have played a key role in the treatment of various types of cancer throughout the past years. However, the drawbacks inherent to the pharmaceutical formulation of taxanes are still a reality and mainly due to the low aqueous solubility of these medicines, as well as to the nontargeted therapy and consequent side effects. Nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) have sparked broad interest in this field and demonstrated capacity of improving taxanes' formulation. If, in one hand, the PLGA core of these NPs is able to solubilize drugs, on the other hand, the PEG shell promotes immune escape and presents chemical end groups for the attachment of targeting ligands. Advances in the design of these nanosystems resulted in the development of multitargeted PLGA/PEG NPs achieved by dual-ligand functionalization. The multitargeting offers a promising alternative to the delivery of taxanes across successive cell types or compartments and to the synergetic exploitation of more than one transporter on the cell surface. Besides the upgrade in the design of multitargeted PLGA/PEG NPs, their manufacturing has also evolved from bulk assembly to continuous-flow, high-throughput technologies such as microfluidics. This technology relies on microchannel platforms described to enable the production of large-scale batches of NPs in a better time-saving manner, with higher drug loading, reproducibility, and lower polydispersity. Herein, a detailed microfluidic method for the preparation of multitargeted, taxane-loaded PLGA/PEG NPs is described. Focus is given to the setting up of the microfluidic system and conditions required to manufacture these NPs by using polymers of PLGA and PEG previously elsewhere functionalized with two generic targeting ligands.
在过去几年中，紫杉烷类化疗药物在各类癌症的治疗中发挥了关键作用。然而，紫杉烷类药物制剂固有的缺点仍然存在，主要是由于这些药物的水溶性低，以及非靶向治疗和随之而来的副作用。聚乳酸-乙醇酸共聚物（PLGA）和聚乙二醇（PEG）纳米颗粒在该领域引起了广泛关注，并显示出改善紫杉烷类制剂的能力。一方面，这些纳米颗粒的PLGA核心能够溶解药物，另一方面，PEG外壳促进免疫逃逸，并提供用于连接靶向配体的化学端基。这些纳米系统设计的进展导致了通过双配体功能化实现的多靶向PLGA/PEG纳米颗粒的开发。多靶向为紫杉烷类药物跨连续细胞类型或区室的递送以及细胞表面多种转运蛋白的协同利用提供了一种有前景的替代方案。除了多靶向PLGA/PEG纳米颗粒设计的升级外，它们的制造也从批量组装发展到连续流、高通量技术，如微流控技术。该技术依赖于所述的微通道平台，能够以更好的节省时间的方式生产大规模批次的纳米颗粒，具有更高的载药量、重现性和更低的多分散性。本文描述了一种制备多靶向载紫杉烷PLGA/PEG纳米颗粒的详细微流控方法。重点是微流控系统的设置以及使用先前在其他地方用两种通用靶向配体功能化的PLGA和PEG聚合物制造这些纳米颗粒所需的条件。
