Zhao Haizheng, Duong Hoang Hanh Phuoc, Yung Lin Yue Lanry
Department of Chemical and Biomolecular Engineering, National University of Singapore, 119260, Singapore.
Macromol Rapid Commun. 2010 Jul 1;31(13):1163-9. doi: 10.1002/marc.200900876. Epub 2010 May 11.
Folate has been applied as a targeting moiety for various anticancer drug-delivery agents to avoid non-specific attack of normal tissues as well as to increase cellular uptake at the target tumor cells. Polymer micelles made of poly[(D,L-lactide)-co-glycolide)]-poly(ethylene glycol)-folate (PLGA-PEG-FOL) was fabricated as a tumor targeting carrier for encapsulating the anticancer drug doxorubicin. To accelerate the drug release in the endosome after folate-mediated cellular uptake, pH-sensitive poly(β-amino ester)-PEG-FOL (PAE-PEG-FOL) was added together with PLGA-PEG-FOL to form mixed micelles. The results showed that the drug release can be triggered at different pH due to the ionization of PAE. The IC(50) of PLGA-PEG-FOL micelles is 0.46 × 10(-6) M. With 20% PAE in the mixed micelles (20:80 mixed micelles), the IC(50) decreases to 0.34 × 10(-6) M, which is comparable to that of pure PAE-PEG-FOL micelles at pH 7.4. As a result of the pH sensitivity, the PAE-PEG-FOL micelles are not stable at pH 6.5 or lower, and the drug may be released from the micelles into the extracellular environment before uptake by the cells. The 20:80 mixed micelles are relatively stable at this condition. As a result, the micelles retain more drug in the micelles for a higher degree of cellular uptake by folate receptor-mediated endocytosis, and exhibit higher cytotoxicity.
叶酸已被用作各种抗癌药物递送剂的靶向部分，以避免对正常组织的非特异性攻击，并增加靶肿瘤细胞的细胞摄取。由聚（D，L-丙交酯-共-乙交酯）-聚乙二醇-叶酸（PLGA-PEG-FOL）制成的聚合物胶束被制备为用于封装抗癌药物阿霉素的肿瘤靶向载体。为了在叶酸介导的细胞摄取后加速药物在内体中的释放，将pH敏感的聚（β-氨基酯）-PEG-FOL（PAE-PEG-FOL）与PLGA-PEG-FOL一起添加以形成混合胶束。结果表明，由于PAE的电离，药物释放可在不同pH下触发。PLGA-PEG-FOL胶束的IC50为0.46×10-6 M。在混合胶束中含有20% PAE（20:80混合胶束）时，IC50降至0.34×10-6 M，这与纯PAE-PEG-FOL胶束在pH 7.4时的IC50相当。由于pH敏感性，PAE-PEG-FOL胶束在pH 6.5或更低时不稳定，药物可能在被细胞摄取之前从胶束释放到细胞外环境中。20:80混合胶束在这种条件下相对稳定。因此，胶束在胶束中保留更多药物，以便通过叶酸受体介导的内吞作用实现更高程度的细胞摄取，并表现出更高的细胞毒性。
