Uchegbu, Ijeoma; (1994) Some aspects of the niosomal delivery of doxorubicin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Vesicular drug delivery systems prepared from two types of non-ionic surfactants, cholesterol and other additives were studied and characterized with regard to their physicochemical and biological properties. Sorbitan ester (Span) niosomes containing doxorubicin showed an inverse correlation between mean vesicle size and surfactant hydrophilic lipophilic balance (HLB) number (r = -0.92). The remote loading method (exploiting transmembrane proton gradients) was used to increase the encapsulation efficiency of doxorubicin niosomes. Encapsulation efficiency of Span surfactant niosomes increased with increasing mean niosome size, except with Span 80 niosomes which gave lower than expected values. Span 60 niosomes in female NMRI mice bearing the MAC 15A tumour were fairly stable in vivo, with 90% of plasma doxorubicin being niosome associated (determined by a gel filtration technique) 4h after dosing and 50% niosome associated 24h after dosing. Plasma area under the time level curve (AUC) was increased 6 fold by encapsulation of the drug. Doxorubicin levels in all tissues, except the heart, were also increased. The AUC tumour to heart ratio was increased from 0.27 to 0.36. Hexadecyl-diglycerol ether (C₁₆G₂) niosomes containing doxorubicin, when compared to the free drug, doubled the area under the plasma level time curve (plasma AUC), following intraperitoneal injection, but resulted in an inflammatory response in the lung of male AKR mice. This response was however not seen when empty niosomes were administered intraperitoneally, doxorubicin niosomes were administered intravenously or with doxorubicin solution, by any route. In vivo C₁₆G₂ niosomes were equiactive with doxorubicin solution, against a subcutaneously implanted MAC 13A tumour whereas Span 60 niosomes doubled the activity of doxorubicin against a subcutaneously implanted MAC 15A tumour. In vitro doxorubicin niosomes reduced the IC₅₀, slightly against a resistant variant of a human ovarian cancer cell line. Large (12-60μm) disc shaped structures formed from C₁₆G₂ were found to be an intermediate structure in the Solulan C24-mediated C₁₆G₂ vesicle to micelle transition and were termed discomes. These structures were able to encapsulate and retain 45% of an aqueous marker (5-(6)-carboxyfluorescein) after 24h at room temperature. From the above, there appears to be a future for niosomal drug delivery systems in the field of drug targeting.

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