Mozar Fitya Syarifa, Chowdhury Ezharul Hoque
Advanced Engineering Platform (AEP) and Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Malaysia.
Pharmaceutics. 2017 Jun 7;9(2):21. doi: 10.3390/pharmaceutics9020021.
pH sensitive nanoparticles of carbonate apatite (CA) have been proven to be effective delivery vehicles for DNA, siRNAs and proteins. More recently, conventional anti-cancer drugs, such as doxorubicin, methotrexate and cyclophosphamide have been successfully incorporated into CA for intracellular delivery to breast cancer cells. However, physical and chemical properties of drug molecules appeared to affect their interactions with CA, with hydrophillic drug so far exhibiting better binding affinity and cellular uptakes compared to hydrophobic drugs. In this study, anastrozole, a non-steroidal aromatase inhibitor which is largely hydrophobic, and gemcitabine, a hydrophilic nucleoside inhibitor were used as solubility models of chemotherapy drug. Aggregation tendency of poorly soluble drugs resulting in larger particle-drug complex size might be the main factor hindering their delivery effectiveness. For the first time, surface modification of CA with poly(ethylene glycol) (PEG) has shown promising result to drastically reduce anastrozole- loaded CA particle size, from approximately 1000 to 500 nm based on zeta sizer analysis. Besides PEG, a cell specific ligand, in this case fibronectin, was attached to the particles in order to facilitate receptor mediated endocytosis based on fibronectin-integrin interaction. High-performance liquid chromatography (HPLC) was performed to measure uptake of the drugs by breast cancer cells, revealing that surface modification increased the drug uptake, especially for the hydrophobic drug, compared to the uncoated particles and the free drug. In vitro chemosensitivity assay and in vivo tumor regression study also showed that coated apatite/drug nanoparticle complexes presented higher cytotoxicity and tumor regression effects than uncoated apatite/drug nanoparticles and free drugs, indicating that surface modification successfully created optimum particles size with the consequence of more effective uptake along with favorable pharmacokinetics of the particles.
已证实碳酸磷灰石（CA）的pH敏感纳米颗粒是用于DNA、小干扰RNA（siRNA）和蛋白质的有效递送载体。最近，传统抗癌药物，如阿霉素、甲氨蝶呤和环磷酰胺已成功被载入CA中，用于向乳腺癌细胞进行细胞内递送。然而，药物分子的物理和化学性质似乎会影响它们与CA的相互作用，与疏水性药物相比，亲水性药物迄今表现出更好的结合亲和力和细胞摄取率。在本研究中，将阿那曲唑（一种疏水性很强的非甾体芳香酶抑制剂）和吉西他滨（一种亲水性核苷抑制剂）用作化疗药物的溶解性模型。难溶性药物的聚集倾向导致更大的颗粒 - 药物复合物尺寸，这可能是阻碍其递送效果的主要因素。首次用聚乙二醇（PEG）对CA进行表面修饰已显示出有前景的结果，基于zeta粒度分析仪分析，载有阿那曲唑的CA粒径从约1000 nm大幅减小至500 nm。除了PEG，还将一种细胞特异性配体（在本研究中为纤连蛋白）附着到颗粒上，以便基于纤连蛋白 - 整合素相互作用促进受体介导的内吞作用。采用高效液相色谱法（HPLC）来测定乳腺癌细胞对药物的摄取情况，结果显示与未包被颗粒和游离药物相比，表面修饰提高了药物摄取，尤其是对于疏水性药物。体外化学敏感性测定和体内肿瘤消退研究还表明，包被的磷灰石/药物纳米颗粒复合物比未包被的磷灰石/药物纳米颗粒和游离药物呈现出更高的细胞毒性和肿瘤消退效果，这表明表面修饰成功创造了最佳粒径，从而实现了更有效的摄取以及颗粒良好的药代动力学。
