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Lipoprotein delivery of benzoporphyrin derivative : a photosensitizer for photodynamic therapy

University of British Columbia

Photodynamic Therapy (PDT) involves the systemic administration of a light activated drug combined with the precise delivery of light to produce a selective cytotoxic reaction. Benzoporphyrin derivative (BPD) has been shown to be a potent photosensitizer both in vitro and in vivo and is therefore a good candidate for PDT. Since BPD is administered systemically, it is important to know the factors which affect its biodistribution. In this thesis, the in vitro and in vivo distribution of BPD in plasma was examined and the majority of BPD was recovered with the plasma lipoproteins. Association of other photosensitizers with plasma lipoproteins has been show to increase accumulation in tumours and enhance tumour cell damage upon light activation. Based on this information, we hypothesized that association of BPD with lipoproteins, before administration, would increase the accumulation of the photosensitizer in neoplastic tissue and therefore enhance the efficacy of PDT. The effect of precomplexing BPD with purified lipoproteins on the biodistribution of the drug in vivo was studied in tumour bearing mice. Low density lipoprotein (LDL) or high density lipoprotein (HDL) associated BPD accumulated in tumour tissue in greater amounts than aqueous BPD. The association of BPD with either LDL or HDL increased tumour cell killing in vitro and the efficacy of in vivo photosensitization. In particular, LDL-BPD mixtures led to enhanced tumour eradication compared to BPD administered in aqueous solution or unfractionated plasma. These results suggest that the association of BPD with lipoproteins can have a profound effect on the eradication of tumours in vivo. In an attempt to define the mechanism by which LDL enhanced the delivery of BPD to tumours, we performed in vitro accumulation experiments using ¹⁴C-labelled BPD LDL mixtures on human fibroblast cell lines. LDL receptor-mediated internalization of LDL-BPD complexes, as well as LDL receptor facilitated diffusion mechanisms, were involved in cellular accumulation of the drug and, therefore, may be partially responsible for the enhanced efficacy of PDT in the presence of LDL. The results of these studies suggest that lipid based formulations should be designed to deliver photosensitzers preferentially to the LDL fraction of plasma.

Thesis/Dissertation

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2008-12-12

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http://hdl.handle.net/2429/2878

Microbiology and Immunology

University of British Columbia

UBCV

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