Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative

Abstract

Summary Plasma lipoproteins, such as low-density lipoprotein (LDL), have been proposed to enhance the delivery of hydrophobic photosensitisers to malignant tissue since tumour cells have been shown to have increased numbers of LDL receptors. We have investigated the role of this receptor in the cellular accumulation of the photosensitiser benzoporphyrin derivative (BPD). We observed that: (1) [`4C]BPD-LDL accumulation by LDL receptor-negative fibroblast cell lines was insignificant compared with normal cell lines; (2) there was no evidence that BPD dissociated from LDL during incubation with the cells; and (3) chemical acetylation of LDL markedly decreased the uptake of ['4C]BPD-LDL. We conclude, therefore, that virtually all of the photosensitiser accumulated by the cells was due to specific binding and internalisation via the LDL receptor. Subsequent in vivo studies in M-1 (methylcholanthrene-induced rhabdomyosarcoma) tumour-bearing DBA/2J mice showed that tumour accumulation of BPD associated with native LDL was significantly (P<0.01) enhanced over that of acetyl-LDL-associated BPD. These results indicate that the LDL receptor is responsible for the accumulation of LDL-associated BPD both in vitro and in vivo. Thus, utilisation of this delivery system may provide for improvements in photodynamic therapy in clinical practice.

Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD)

“…This selectivity may be related to the increased accumulation of BPD by tumour endothelial cells with high levels of low-density lipoprotein (LDL) receptors (Allison et al, 1994) or the rapid internalization of agents bound to the LDL receptor on proliferating endothelial cells compared to quiescent endothelial cells (Fielding et al, 1979). Cells with increased phagocytotic activity, such as injured vessel wall in atherosclerotic vessels, have been shown to accumulate BPD at levels in excess of surrounding microvasculature (Allison et al, 1997) and this may play a role in tumour microvasculature as well.…”

Recent Advances in Ocular Drug Delivery Systems

“…A Phase I/II study has been conducted for 21 patients with DME unresponsive laser photocoagulation and demonstrated central macular edema measured by OCT showed a reduction from baseline exceeding 59% at 3 months after injection of RETAAC, which remained at 6 and 12 months, but significant improvement of visual acuity was not achieved. [151]. In addition, it is reported that liposomes composed of negatively charged phospholipids, such as phosphatidylglycerol, uptake into tumor cells by LDL receptor-mediated endocytosis [152].…”

Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-D-arabinofuranosylcytosine in Daudi lymphoma cells

“…The elevated number of LDL receptors expressed on tumour cells has been exploited for the delivery of lipophilic drugs. Allison et al (1994) described the tumour targetting of photosensitizers using LDL as drug carriers and van Berkel et al (1996) used a lipid emulsion mimicking lipoprotein particles loaded with a lipophilic antiviral drug for increased liver uptake.…”