Amphotericin B-albumin conjugates: Synthesis, toxicity and anti-fungal activity.

Gurudevan, Sneha; Francis, Arul Prakash; Jayakrishnan, A

Gurudevan, Sneha; Francis, Arul Prakash; Jayakrishnan, A.

Afiliación

Gurudevan S; Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India.
Francis AP; Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India.
Jayakrishnan A; Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India. Electronic address: ajk@iitm.ac.in.

Eur J Pharm Sci ; 115: 167-174, 2018 Mar 30.

Article en En | MEDLINE | ID: mdl-29325755

RESUMEN

Amphotericin B (AmB), a hydrophobic drug with negligible aqueous solubility was conjugated to bovine serum albumin (BSA) via amide bond coupling to give 6 to 8â¯wt% drug payload. The resulting conjugate was characterized using SDS-PAGE and UV-visible, FTIR and CD spectroscopy. The conjugate was water-soluble to the extent of 150â¯mg/ml, was non-toxic to HEK 293â¯T cells at a concentration of 500â¯µg/ml (equivalent to ~30â¯µg AmB) and showed hemolysis of <5% at 200â¯µg/ml (equivalent to ~12â¯µg AmB) against human erythrocytes in vitro. In vitro release studies at 37â¯°C demonstrated steady release of AmB up to 20% from the conjugate with little burst effect in phosphate buffered saline whereas thrice the amount was released in human plasma in 72â¯h. AmBisome® used as a reference showed a very similar release profile in plasma. The conjugate exhibited potential anti-fungal activity against yeast strains such as C. albicans, C. neoformans and C. parapsilosis with the minimum inhibitory concentration (MIC) equivalent to AmB ranging from 0.7 to 1.1â¯µg/ml while AmBisome® and AmB alone showed the MIC between 0.78 and 1.5 and 0.53-0.78â¯µg/ml respectively. Although AmB has been conjugated to various natural and synthetic polymers to improve its solubility and reduce its toxicity, the results obtained in this study using the model protein BSA as a carrier point to the possibility of taking this pro-drug approach to human clinical use using human serum albumin (HSA) as the carrier, since HSA has emerged as a versatile drug carrier for treating diabetes and cancer and improving the pharmacokinetic profile of many drugs with US FDA approving HSA as a drug carrier for the anti-cancer drug paclitaxel (Abraxane®) for human use.

Asunto(s)

Anfotericina B/farmacología; Antifúngicos/farmacología; Albúmina Sérica Bovina/farmacología; Albúmina Sérica Humana/farmacología; Levaduras/efectos de los fármacos; Anfotericina B/efectos adversos; Anfotericina B/química; Antifúngicos/efectos adversos; Antifúngicos/química; Línea Celular; Portadores de Fármacos/química; Eritrocitos/efectos de los fármacos; Células HEK293; Hemólisis/efectos de los fármacos; Humanos; Pruebas de Sensibilidad Microbiana/métodos; Paclitaxel/farmacología; Albúmina Sérica Bovina/efectos adversos; Albúmina Sérica Bovina/química; Albúmina Sérica Humana/efectos adversos; Albúmina Sérica Humana/química; Solubilidad/efectos de los fármacos

Palabras clave

Albumin; Amphotericin B; Anti-fungal; Hemolysis; Pro-drug

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Levaduras / Albúmina Sérica Bovina / Anfotericina B / Albúmina Sérica Humana / Antifúngicos Límite: Humans Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2018 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos

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