The distribution of porphyrins with different tumour localising ability among human plasma proteins

Abstract

and 2University of Leeds, UK.Summary The distribution among the main fractions of human plasma lipoproteins of a number of porphyrins with different tumour localising ability has been determined by means of ultracentrifugation. A main trend is that the fraction of the dyes that are bound to low density lipoprotein (LDL) increases, and the fraction bound to HSA decreases with decreasing polarity of the dyes. An asymmetric charge distribution, such as in TPPS2a, favours LDL-binding more than expected on the basis of lipophilicity. No correlation between the known tumour localising ability of the drugs tested in the present work and their relative affinity for LDL was found. One of the best tumour localisers reported in the literature, TPPS4, hardly binds to LDL, while Hp and Pp, which are commonly considered inefficient tumour localisers, do have a significant affinity for LDL. On the other hand, the LDL binding capacity for a drug is suggested to be a good index for cellular uptake. Such an index does not necessarily imply that the actual uptake occurs by the LDL pathway.

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

“…These investigators concluded that a non-specific LDL-Photofrin II uptake was involved in addition to the LDL receptor-mediated pathway. They later proposed that non-specific exchange of porphyrins between LDL and the plasma membrane occurs (Maziere et al, 1990 (Jori, 1989;Kongshaug et al, 1989). Thus, the nature of the association of BPD and Photofrin II with LDL may differ, especially since Photofrin II consists of an aggregated mixture of compounds (Dougherty et al, 1987;Kessel et al, 1987), most of which are not highly hydrophobic.…”

Binding of porphyrin to human serum albumin. Structure–activity relationships

“…As a drug carrier, a protein may aid in the selective delivery of porphyrins to a tumour region and, as suggested for the lipoproteins, may facilitate drug access into the cell via receptor mechanisms (Jori et al, 1984;Reyftmann et al, 1984;Kessel, 1986a, Beltramini et al, 1987Kongshaug et al, 1989). On the other hand, the same carrier may cause a decrease in the amount of porphyrin available for PDT, by its rapid removal from the circulation.…”

“…The affinity of serum albumin and serum lipoproteins for porphyrins (Muller-Eberhard & Morgan, 1975;Morgan et al, 1980;Lamola et al, 1981 ;Reddi et al, 1981;Smith & Neuschatz, 1983;Grossweiner & Goyal, 1984;Jori et al, 1984;Reyftmann et al, 1984;Moan et al, 1985;Kessel, 1986a;Beltramini et al, 1987;Rotenberg et al, 1987;Kongshaug et al, 1989) indicates a role for these proteins as endogenous carriers of porphyrins administered for PDT (Kessel, 1985;Pottier & Truscott, 1986;Potter et al, 1987;Manyak et al, 1988). As a drug carrier, a protein may aid in the selective delivery of porphyrins to a tumour region and, as suggested for the lipoproteins, may facilitate drug access into the cell via receptor mechanisms (Jori et al, 1984;Reyftmann et al, 1984;Kessel, 1986a, Beltramini et al, 1987Kongshaug et al, 1989).…”

Strategies for optimizing the delivery to tumors of macrocyclic photosensitizers used in photodynamic therapy (PDT)

“…The pharmacokinetics and biodistribution studies conducted with PSs having different chemical structures and physical properties indicated that the extent and rate of PS accumulation in the tumor and the clearance from the body depends on several factors whose relative importance may vary considering different PSs of the families mentioned above [21,33]. It is, however, believed that, following intravenous administration, hydrophobic PSs are in general bound and transported in the bloodstream by lipoproteins, and low-density lipoproteins (LDL) are particularly important since they enhance specific accumulation in the cancer cells via LDL receptor-mediated endocytosis [34][35][36]. In fact it has been shown that many types of cancer cells overexpress LDL receptors to satisfy their need of cholesterol for the synthesis of membranes [37].…”