Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553695
Title: A novel solubilisation technique based on poly(y-glutamic acid) for the delivery of amphotericin B and anticancer agents
Author: Dinh, Tan
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2011
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Abstract:
Improving the water solubility of hydrophobic drugs still remains one of the foremost important issues in the formulation of a drug. This thesis describes a novel complexation method based on biodegradable poly(y- glutamic acid) (PGA) for the effective solubilisation and delivery of the hydrophobic antifungal drug amphotericin B. Poly(y-glutamic acid) is a biosynthetic polymer derived from Bacillus anthracis and is known to be biocompatible and non-toxic towards humans and the environment; the sodium salt of which is highly water soluble. The preparation of an amphotericin B complex comprises of three steps: (i) initially the molecular weight reduction of PGA from 1500 kDa to 30-110 kDa by alkaline hydrolysis followed by (ii) hydrophobisation of PGA by activation with N-hydroxysuccinimide and then (iii) the complexation of amphotericin B with PGA to produce a highly water soluble PGA/amphotericin B complex. The complex shows attenuated toxicity compared with traditional amphotericin B deoxycholate (Fungizone®) and comparable to the liposomal amphotericin B formulation (Ambisome®). The complex retains its broad-spectrum antifungal activity against Candida sp. In comparison to amphotericin B deoxycholate, the AmB complexes show a marked reduction in the pro-inflammatory response which is thought to be responsible for infusion-related adverse effects. The complex shows enhanced uptake by macrophage which may further contribute towards the lower toxicity of the complex. In vivo studies demonstrate that AmB complexes to be more effective compared with Fungizone® with the complex constructed from the high molecular weight PGA the most efficacious. Analyses by DSC and XRPD show that the complex is amorphous in nature although it proves to be stable for more than 6 months at 4°C and more than two months at 37°C. Finally, water solubility of chemotherapeutic agents such as SN-38, etoposide and resveratrol could also be improved using the same concept.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.553695  DOI: Not available
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