Dpto. Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41012 Seville, Spain.
PRO2TECS. Departamento de Ingeniería Química, Facultad de Ciencias Experimentales, Campus El Carmen, 21071 Huelva, Spain.
Int J Pharm. 2018 Oct 25;550(1-2):429-438. doi: 10.1016/j.ijpharm.2018.08.026. Epub 2018 Sep 6.
In recent years, the preparation of valuable drug delivery systems (DDS) from self-assembled amphiphilic copolymers has attracted much attention since these nanomaterials provide new opportunities to solve problems such as the lack of solubility in water of lipophilic drugs, improve their bioavailability, prolong their circulation time and decrease the side effects associated with their administration. In the current study two types of biocompatible pH-responsive nanoparticles derived from poly(2-hydroxyethyl methacrylate) (pHEMA) have been used as drug nano-carriers, being one of them core cross-linked to circumvent their instability upon dilution in human fluids. The present paper deals with the optimization of the loading process of the labile, hydrophobic and highly active anticancer drug, Camptothecin (CPT) into the nanoparticles with regard to four independent variables: CPT/polymer ratio, sonication, temperature and loading time. Forty experiments were carried out and a Box-Behnken experimental design was used to evaluate the significance of the independent variables related to encapsulation efficiency and drug retention capacity. The enhanced drug loading and encapsulation efficiency values (58% and >92%, respectively) of CPT were achieved by the core cross-linked NPs in 2 h at 32 °C at CPT/polymer ratio 1.5:1 w/w and 14 min of sonication. The optimized CPT-loaded NPs were studied by dynamic light scattering and scanning electron microscopy, and an increase in size of the loaded-NP compared to the unloaded counterparts was found. Other twenty experiments were conducted to study the enability to retain CPT into the conjugates at different ionic strength values and times. The stability studies demonstrated that the core cross-linked nanocarriers displayed an excellent drug retention capacity (>90%) at 25 °C for 15 days in every ionic-strength environments whereas the non-cross-linked ones were more stable at physiological ionic strength. The optimized systems proved to be a major step forward to encapsulate and retain CPT in the NP nuclei, what makes them ideal devices to control the delivery of CPT upon the triggered acidic conditions of solid tumors.
近年来，自组装两亲性嵌段共聚物制备有价值的药物传递系统（DDS）引起了广泛关注，因为这些纳米材料为解决疏水性药物在水中溶解度低、提高其生物利用度、延长其循环时间和降低给药相关副作用等问题提供了新的机会。在本研究中，使用了两种类型的生物相容的 pH 响应性纳米粒子作为药物纳米载体，其中一种为核交联以避免在稀释于人体液时的不稳定性。本文涉及对不稳定的疏水性和高活性抗癌药物喜树碱（CPT）负载到纳米粒子中的负载过程进行优化，涉及四个独立变量：CPT/聚合物比、超声、温度和加载时间。进行了 40 次实验，并使用 Box-Behnken 实验设计来评估与包封效率和药物保留能力相关的独立变量的重要性。通过核交联 NPs 在 32°C 下，CPT/聚合物比为 1.5:1 w/w 和 14 分钟超声处理，实现了 CPT 的载药率和包封效率的提高（分别为 58%和>92%）。对优化的载 CPT 纳米粒子进行了动态光散射和扫描电子显微镜研究，发现与未负载的纳米粒子相比，负载的 NP 尺寸有所增加。进行了另外 20 次实验，以研究在不同离子强度值和时间下将 CPT 保留在缀合物中的能力。稳定性研究表明，在 25°C 下，在每种离子强度环境中，核交联纳米载体在 15 天内显示出出色的药物保留能力（>90%），而非交联的纳米载体在生理离子强度下更稳定。优化后的系统在将 CPT 封装并保留在 NP 核中证明是向前迈进了一大步，使其成为控制在实体瘤酸性条件下 CPT 释放的理想装置。
