Division of Pharmacy and Optometry, School of Health Science, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Division of Pharmacy and Optometry, School of Health Science, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK; BIOtech Center for Biomedical Technologies, Department of Industrial Engineering, University of Trento, Via delle Regole 101, 38123 Trento, Italy.
Biomater Adv. 2023 Nov;154:213649. doi: 10.1016/j.bioadv.2023.213649. Epub 2023 Oct 4.
The use of nanoparticle (NP) delivery systems in cancer treatment has received significant interest, however use of such systems in delivery of cytotoxic chemotherapy agents can be limited by low encapsulation efficiency and burst release of the cytotoxin, as well issues with throughput and reproducibility during the fabrication of drug-loaded NPs. In this study, we used a hydrodynamic flow-focusing microfluidic system to successfully produce poly(lactic-co-glycolic acid) (PLGA) NPs. The physico-chemical properties of PLGA NPs were controlled by changing the manufacturing parameters, such as flow rate ratio, total flow rate, PLGA and surfactant concentration. The NAMPT inhibitor-polymer conjugate, hydroxyl-FK866-PLGA, was synthesized and used to fabricate hydroxyl-FK866-PLGA NPs for the formulation of localized delivery systems able to release low doses of cytotoxins and enhance the efficacy of NAMPT inhibitors. Hydroxyl-FK866-PLGA NPs were prepared with optimized fabrication parameters, having average Z-size of 128 ± 8 nm (PDI < 0.2), ζ-potential of -14.8 ± 5.3 mV and high encapsulation efficiency (98.6 ± 5.8 %). The pH-dependent release of hydroxyl-FK866 was monitored over time in conditions mimicking the normal (pH 7.4) and inflamed/tumor (pH 6.4) microenvironments, observing a sustained release pattern (over two months) without any initial burst release. Finally, toxicity of hydroxyl-FK866-PLGA NPs were tested in selected human cell lines, the human leukemia monocytic cell line (THP-1), and the human triple negative breast cancer cell line (MDA-MB-231). Our work suggests that microfluidic systems are a promising technology for a rapid and efficient manufacturing of PLGA-based NPs for the controlled release of cytotoxins. Moreover, the use of drug-polymer conjugates is an effective approach for the manufacturing of polymeric NPs enabling high encapsulation efficiency and a prolonged and sustained pH-dependent drug release.
纳米粒子（NP）给药系统在癌症治疗中的应用受到了广泛关注，然而，在细胞毒性化疗药物的递送上，由于包封效率低和细胞毒素的爆发释放，以及在载药 NP 制造过程中的通量和重现性问题，这些系统的应用受到了限制。在本研究中，我们使用流体动力学流聚焦微流控系统成功地制备了聚（乳酸-共-乙醇酸）（PLGA） NPs。通过改变制造参数，如流速比、总流速、PLGA 和表面活性剂浓度，可以控制 PLGA NPs 的物理化学性质。NAMPT 抑制剂-聚合物偶联物，羟基-FK866-PLGA，被合成并用于制备羟基-FK866-PLGA NPs，以构建能够释放低剂量细胞毒素并增强 NAMPT 抑制剂疗效的局部递药系统。使用优化的制造参数制备了羟基-FK866-PLGA NPs，其平均 Z 尺寸为 128 ± 8nm（PDI < 0.2），ζ-电位为-14.8 ± 5.3mV，包封效率高（98.6 ± 5.8%）。在模拟正常（pH 7.4）和炎症/肿瘤（pH 6.4）微环境的条件下，监测了羟基-FK866 的 pH 依赖性释放随时间的变化，观察到了一种持续释放模式（超过两个月），没有任何初始突释。最后，在选定的人细胞系中测试了羟基-FK866-PLGA NPs 的毒性，这些细胞系包括人白血病单核细胞系（THP-1）和人三阴性乳腺癌细胞系（MDA-MB-231）。我们的工作表明，微流控系统是一种很有前途的技术，可以快速有效地制造用于细胞毒素控制释放的基于 PLGA 的 NPs。此外，使用药物-聚合物偶联物是制造能够实现高包封效率和延长且持续的 pH 依赖性药物释放的聚合物 NPs 的有效方法。
