Li Xia, Szewczuk Myron R, Malardier-Jugroot Cecile
Department of Chemistry and Chemical Engineering, Royal Military College of Canada.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
Drug Des Devel Ther. 2016 Dec 15;10:4101-4110. doi: 10.2147/DDDT.S123386. eCollection 2016.
Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior. Moreover, the structure is stable only at neutral pH and collapses in the acidic tumor microenvironment, releasing drugs on-site from its core. The delivery vehicle is investigated using human pancreatic PANC-1 cancer cells and RAW-Blue™ mouse macrophage reporter cell line, both of which have overly expression of folic acid receptors. To trace the cellular uptake by both cell lines, curcumin was selected as a dye and drug mimic owing to its fluorescence nature and hydrophobic properties. Fluorescent microscopy of FA-DABA-SMA loaded with curcumin revealed a significant internalization of the dye by human pancreatic PANC-1 cancer cells compared to those with unfunctionalized polymers (SMA). Moreover, the FA-DABA-SMA polymers exhibit rodlike association specific to the cells. Both empty SMA and FA-DABA-SMA show little toxicity to PANC-1 cells as characterized by WST-1 cell proliferation assay. These results clearly indicate that FA-DABA-SMA polymers show potential as an active tumor targeting drug delivery system with the ability to internalize hydrophobic chemotherapeutics after they specifically attach to cancer cells.
使用聚合物纳米结构进行靶向给药是一个新兴的癌症研究领域，旨在更安全、高效且有效地使用化疗药物。通过可生物降解的连接子2,4-二氨基丁酸（DABA），利用叶酸功能化的两亲性交替共聚物聚（苯乙烯-alt-马来酸酐）（FA-DABA-SMA）设计了一种pH响应型主动靶向给药系统。该聚合物模板具有pH响应性，在pH 7时形成两亲性纳米结构，能够在其内部包裹疏水性药物。此外，该结构仅在中性pH下稳定，在酸性肿瘤微环境中会解体，从其核心部位原位释放药物。使用人胰腺PANC-1癌细胞和RAW-Blue™小鼠巨噬细胞报告细胞系对该给药载体进行了研究，这两种细胞系均过度表达叶酸受体。为了追踪两种细胞系的细胞摄取情况，由于姜黄素具有荧光特性和疏水性质，因此选择它作为染料和药物模拟物。对负载姜黄素的FA-DABA-SMA进行荧光显微镜观察发现，与未功能化聚合物（SMA）相比，人胰腺PANC-1癌细胞对该染料有显著的内化作用。此外，FA-DABA-SMA聚合物表现出特定于细胞的棒状缔合。如通过WST-1细胞增殖试验所表征的，空的SMA和FA-DABA-SMA对PANC-1细胞均显示出极低的毒性。这些结果清楚地表明，FA-DABA-SMA聚合物具有作为主动肿瘤靶向给药系统的潜力，能够在特异性附着于癌细胞后内化疏水性化疗药物。
