Harris, Debra Leigh; (2007) A homopolymer complex of amphotericin B for the pharmacological treatment and immunotherapy of leishmaniasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There is an urgent need for a safe, low cost, tropical climate stable and simply reconstituted replacement for amphotericin B (AmB) to treat leishmaniasis in resource poor countries. This thesis describes a stable, highly water-soluble and homogeneous non-covalently bound complex of AmB with a defined narrow molecular weight distribution polymer, poly(methacrylic acid sodium salt) (PMAA-Na). PMAA-Na was derived from an active ester homopolymer precursor. This polymer is biocompatible, cost effective and is widely used as an excipient in several consumer healthcare products. The complex has attenuated toxicity compared to traditional clinical grade AmB. The complex is effective against Leishmania promastigotes and amastigotes in vitro, and in a validated murine model of acute visceral leishmaniasis. It also retains its broad-spectrum anti-fungal activity against Cryptococcus neoformans and Candida sp. The complex is stable for 12 months during cold storage (4°C) and also for at least 4 weeks at 37°C. In addition, we have found that PMAA-Na and the complex provoke a pro-inflammatory immune response in tissue-derived cells but not in blood derived cells. This means that infusion-related adverse effects can be avoided, until the complex is preferably distributed to inflamed tissues. Following incubation with tissue-derived cells, both PMAA-Na and the complex induced the release of endogenous pro-inflammatory chemokines, and the Th1 cytokines IL-12 and IFN-γ. This could potentially initiate a local Th1 immunomodulatory response, promotion of the recruitment of immature dendritic cells and CD4+ T cells, and activation of macrophages as well as the generation of effector CD8+ T cell responses. Thus it is possible to develop a new, stable and cost effective pharmacological treatment for leishmaniasis with synergistic immunotherapy contained in a single drug.

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