In the photodynamic therapy of cancer, research has focused on the influence of lipoproteins (particularly the low-density lipoprotein, LDL) on the fate and transport of the porphyrin mixture. We have studied the interaction between LDL and a series of well-defined tetraphenylporphinesulfonates, TPPS-1, TPPS-2A, and TPPS-4. Compounds with at least two unsulfonated phenyl groups were found to associate with LDL (TPPS-1 and TPPS-2A), whereas sulfonation of all four rings abolished lipoprotein binding. As shown with agarose gel electrophoresis, association of doubly charged TPPS-2A molecules with LDL strongly influences LDL's charge. Because a change in charge may alter LDL's biological behavior, the effect of increasing amounts of TPPS-2A molecules per LDL on its biological reactivity was examined. In vitro studies with Hep G2 cells indicated that up to 250 molecules of TPPS-2A per LDL left LDL receptor recognition unchanged. In vivo studies on the fate of 125I-LDL-TPPS-2A particles in rats showed that complexes with molar ratios up to 1:100 were processed like native LDL. It is concluded that tetraphenylporphines of a partial hydrophilic-hydrophobic nature are most optimal for spontaneous association with lipoproteins. These porphyrin structures will utilize lipoproteins as biological transport vehicles whereby up to 100 molecules per lipoprotein particle will not change the biological behavior of the particles so that LDL receptor-dependent uptake by tumor cells under these conditions is warranted.