Ravichandran Vasanthan, Kesavan Venkitasamy, Cojean Sandrine, Loiseau Philippe M, Jayakrishnan A
Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India.
Chimiotherapie antiparasitaire, UMR 8076 CNRS BioCIS, Faculte de Pharmacie, Universite Paris-Sud, Rue Jean-Baptiste Clement, F-92296, Chatenay-Malabry, France.
Curr Drug Deliv. 2018;15(7):1028-1037. doi: 10.2174/1567201815666180503122829.
Amphotericin B (AmB), a polyene antibiotic used for the treatment of fungal and leishmanial infections is virtually insoluble in water and exhibits severe toxicity. AmB has been conjugated to various soluble polymers for improving its solubility and reducing its toxicity. Conjugating AmB to a polysorbate surfactant such as polyoxyethylene sorbitan monolaurate (Tween 20), was examined to improve its solubility and reduce its toxicity.
AmB was coupled to Tween 20 via carbamate linkage at 15 and 30 wt% concentrations in high yield by activating the hydroxyl groups of the surfactant using p- nitrophenyl chloroformate. The conjugates were characterized by using 1H NMR, IR, UV and HPLC analysis and were examined for their toxicity, and anti-fungal and anti-leishmanial activities in vitro.
Tween-AmB conjugates were soluble to the extent of 10 mg/mL in water, showed improved critical micelle concentration in comparison with AmB, exhibited negligible hemolytic potential even at a concentration of 1000 µM and were not toxic against human embryonic kidney cell line (HEK293T) at similar concentrations. The conjugates showed potent anti-fungal activity against Candida albicans, Candida parapsilosis and Cryptococcus neoformans and anti-leishmanial activity against intramacrophage amastigotes of Leishmania donovani.
Tween 20 is a surfactant approved by the US FDA as an additive in food and pharmaceutical preparations. Synthesis of drug conjugates with surfactants such as Tween-20 could open up new opportunities to improve the solubility of many drugs, reduce their toxicity and could possibly target the brain as polysorbates known to facilitate nanoparticulate systems to cross the blood-brain barrier.
两性霉素B（AmB）是一种用于治疗真菌和利什曼原虫感染的多烯抗生素，几乎不溶于水且具有严重毒性。AmB已与各种可溶性聚合物偶联，以提高其溶解度并降低其毒性。研究了将AmB与聚山梨酯表面活性剂如聚氧乙烯脱水山梨醇单月桂酸酯（吐温20）偶联，以提高其溶解度并降低其毒性。
通过使用对硝基苯基氯甲酸酯活化表面活性剂的羟基，以15%和30%（重量）的浓度高产率地通过氨基甲酸酯键将AmB与吐温20偶联。通过1H NMR、IR、UV和HPLC分析对缀合物进行表征，并检测其毒性以及体外抗真菌和抗利什曼原虫活性。
吐温-AmB缀合物在水中的溶解度可达10 mg/mL，与AmB相比，临界胶束浓度有所提高，即使在1000 μM的浓度下溶血潜力也可忽略不计，并且在相似浓度下对人胚肾细胞系（HEK293T）无毒。该缀合物对白色念珠菌、近平滑念珠菌和新型隐球菌显示出强效抗真菌活性，对杜氏利什曼原虫的巨噬细胞内无鞭毛体显示出抗利什曼原虫活性。
吐温20是美国食品药品监督管理局批准的可用于食品和药物制剂的添加剂。与吐温20等表面活性剂合成药物缀合物可为提高许多药物的溶解度、降低其毒性开辟新机会，并且由于已知聚山梨酯可促进纳米颗粒系统穿过血脑屏障，可能还能靶向脑部。
