Evidence for a major role of plasma lipoproteins as hematoporphyrin carriers in vivo

Jori, Giulio; Beltramini, Mariano; Reddi, Elena; Salvato, Benedetto; Pagnan, Antonio; Ziron, L; Tomio, L.; Tsanov, Tsanko

doi:10.1016/0304-3835(84)90025-9

Cited by 193 publications

(73 citation statements)

References 11 publications

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“…In subsequent experiments in tumour-bearing mice, administration of BPD premixed with LDL resulted in enhanced delivery to tumours and increased photosensitisation when compared with BPD administered in aqueous solution . Similar studies by other groups have demonstrated that the association of haematoporphyrin, haematoporphyrin derivative and Photofrin with LDL can lead to enhanced delivery to tumours in mice (Jori et al, 1984;Candide et al, 1986). In light of these reports and our evidence that LDL association enhances delivery of BPD to tumour tissue, we hypothesised that receptor-mediated endocytosis of BPD-LDL complexes might be an important mechanism in the selective accumulation of this photosensitiser in tumour tissue.…”

supporting

confidence: 77%

“…In vivo studies have demonstrated that the association of several different photosensitisers with LDL can enhance their delivery to malignant tissues (Jori et al, 1984;Zhou et al, 1988;Maziere et al, 1991). Results of in vivo studies on the distribution, elimination and cytotoxic effects of photosensitisers in experimental tumours have been explained by eluding to the mechanism of LDL receptor-mediated endocytosis of photosensitisers, without experimental confirmation of the process (Kessel, 1986;Maziere et al, 1990;Allison et al, 1991;Richter et al, 1991).…”

Section: '4c]bpd-ldl Accumulation By Cultured M-j Tumour Cellsmentioning

confidence: 99%

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

Allison

Ph²,

Levy³

1994

Br J Cancer

152

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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.

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supporting

confidence: 77%

Section: '4c]bpd-ldl Accumulation By Cultured M-j Tumour Cellsmentioning

confidence: 99%

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

Allison

Ph²,

Levy³

1994

Br J Cancer

152

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“…As already mentioned, sufficiently hydrophobic PS can be readily incorporated into lipoproteins such as LDL and highdensity lipoproteins (HDL), 63,75 with the receptors for the former being more abundant in cancerous cells than in surrounding normal tissues. 54,[76][77][78] Experiments with PS preincorporated into lipoproteins have shown that simple incorporation into LDL provides for effective photodynamic action.…”

Section: Internalizable Ligand-photosensitizer Complexes and Their Sumentioning

confidence: 99%

Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency

Jans²,

2000

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IntroductionPhotodynamic therapy (PDT) is a relatively new cytotoxic treatment, predominantly used in anticancer approaches, that depends on the retention of photosensitizers (PS) in tumour cells and their activation within the tumour through irradiation with light of the appropriate wavelength. Photoactivated PS generate reactive oxygen species (singlet oxygen, 1 O 2 , and free radicals, such as ·OH, HO· 2 and ·O 2 -) which are able to damage cellular structures, meaning that PDT is particularly attractive as an alternative means to kill drug-and radioresistant tumour cells.1,2 Normal cells, however, are also able to accumulate PS and be damaged by them, so that prolonged skin photosensitization, light-sensitivity of the eye and other side-effects have proved to be severe limitations of PDT. When photoactivated, PS inflict damage on many types of biomolecules without any specificity, their action being mediated largely via the reactive oxygen species mentioned, none of which travel more than several tens of nanometers before reacting with a biomolecule. Keeping in mind that cell dimensions are of the order of micrometres or tens of micrometres, it is clear that the intracellular action of PS is restricted to the site of their subcellular location and the surrounding radius of not more than 40 nm.3-5 That uneven intracellular distribution of PS can lead to differences in toxicity has been shown using laser microbeam irradiation. 6In contrast to cell membranes and other cytoplasmic organelles, the cell nucleus 7-9 is known to be a very sensitive target for reactive oxygen species. In order to reduce the dose of PS administered to patients and hence minimize the harmful side-effects of PDT, new approaches have been devised to increase the effectiveness of tumour-cell killing through targeted delivery of PS to hypersensitive subcellular sites. These approaches are the focus of the present review. Subcellular distribution of photosensitizersInsomuch as most mammalian cells span tens of micrometres, it is clear that PS efficiency will depend not only on the relative distribution of PS between the tumour and surrounding tissues and between malignant and normal cells, but also on the intracellular distribution of the PS. Furthermore, membranes divide the interior of the eucaryotic cell into compartments that differ markedly in their sensitivity to reactions induced by PS-generated reactive oxygen species, in the ability of damaged molecules to be replaced/recycled and in the extent to which such damage affects cell viability and/or the capability of the cell to divide. It is noteworthy that preferential PS accumulation in tumours is itself not a guarantee of selective photoinduced tumour damage and successful PDT. In experiments on rats with gliosarcoma 9L, 10 for example, it has been found that despite a 13-fold higher accumulation of the PS Photofrin in the tumour compared with Summary Photodynamic therapy (PDT) is a novel treatment, used mainly for anticancer therapy, that depends on the retention of photosensitizer...

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“…Better methods of localization in which sensitizers are combined with carriers that recognize the target tissue may therefore be useful in certain instances in order to increase the selective accumulation of the PS within the tumour (Jori, 1990;Hasan, 1992;Hamblin and Newman, 1994). Such delivery systems include monoclonal antibodies (MAbs) (Mew et al, 1983;Oseroff et al, 1986;Jiang et al, 1991), liposomes (Jori, 1990;Jori and Reddi, 1990), low-density lipoproteins (LDLs) (Mosley et al, 1981;Jori et al, 1984;SchmidtErfurth et al, 1994) and microspheres (Bachor et al,199 la). MAbs exhibit the highest selectivity, but their uptake by the target tissue is limited by vascular barrier problems and rapid clearance by the reticuloendothelial system.…”

mentioning

confidence: 99%

“…For this study, we selected covalent conjugates of an endogenous delivery system, human LDL, which is known to possess high-affinity receptors on certain neoplastic and proliferating cells at significantly increased numbers (Gal et al, 1981;Vitols et al, 1985). A number of investigators have demonstrated that photosensitizers mixed non-covalently with LDL before administration showed enhanced photodynamic activity compared with the administration of the photosensitizer alone (Mosley et al, 1981;Jori, 1984Jori, , 1990Jori et al, 1990;Maziere et al, 1990;Schmidt-Erfurth et al, 1994). However, covalently linked LDL-PS conjugates have rarely been used in PDT.…”

mentioning

confidence: 99%

Photodynamic targeting of human retinoblastoma cells using covalent low-density lipoprotein conjugates

Schmidt-Erfurth

Diddens²,

Birngruber³

et al. 1997

Br J Cancer

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Evidence for a major role of plasma lipoproteins as hematoporphyrin carriers in vivo

Cited by 193 publications

References 11 publications

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

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

Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency

Photodynamic targeting of human retinoblastoma cells using covalent low-density lipoprotein conjugates

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