Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins
Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins
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DOI：
10.1080/10717540903101655
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发表时间：
2009-10-01
期刊：
影响因子：
6
通讯作者：
Montaldo, P. G.
中科院分区：
文献类型：
--
作者：
Orienti, I.;Zuccari, G.;Montaldo, P. G.
本研究涉及一系列两亲性糊精的制备及其作为芬维A胺、紫杉醇、依托泊苷和喜树碱等抗肿瘤疏水性药物络合剂的评价。两亲性糊精是通过低分子量糊精(平均分子量1670，平均聚合度9.33葡萄糖单体)与烃链以每摩尔葡萄糖单体约0.1摩尔烃链的取代度缀合而获得的，如通过H-1-NMR谱证实的。该缀合物在水中高度可溶，并溶解形成具有疏水内核的纳米聚集体，能够通过络合容纳疏水药物。络合提高疏水性药物的水溶性；使用芬维A胺获得了最好的结果。采用三种不同的方法制备芬维A胺固体复合物：捏合法、共溶法和共沉淀法。捏合方法使复合物具有最佳的功能特性。对固体样品的热重分析表明，共轭糊精和固体复合物在高达 300 摄氏度的温度下均具有显着的热稳定性。在差示扫描量热法中，两亲性糊精和复合药物之间没有观察到显着差异，表明客体分子以无定形状态存在于固体基质中。粒度分析证实了复合物对于肠胃外给药的尺寸适用性。此外，所有分析的复合物均在体外观察到药物持续释放。关于生物学效应，络合的芬维A胺对HTLA-230神经母细胞瘤细胞系的细胞毒性始终高于游离药物，表明络合增加了药物的生物利用度。这些发现综合起来表明，这些可生物降解的自组装糊精缀合物可被视为疏水性药物，特别是芬维A胺的新的潜在络合剂，以增加药物溶解度、生物利用度，从而提高治疗效果。
This study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by H-1-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three differents approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300 degrees C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential complexing agents for hydrophobic drugs and, in particular, for fenretinide, to increase drug solubility, bioavailability, and thus therapeutic efficacy.