The delivery of drugs to selected lesions can be enhanced by preparation of targeted macromolecular conjugates. Although photodynamic therapy (PDT) has dual selectivity due to control of light delivery and to some extent selective photosensitizer (PS) accumulation in tumors, additional targeted selectivity of PS accumulation in tumors is desirable. This may be accomplished by taking advantage of characteristics of tumor biology (e.g. increased vascular permeability) and/or cell type specific targeting by ligand-receptor recognition. In this review I will discuss five applications of this technology. Conjugates of PS with monoclonal antibodies that recognize tumor-associated antigens can be used for increasing the specificity of PS delivery to various tumor types, but we have shown that the molecular charge together with the administration route is of great importance in determining the amount of PS in the tumor, its selectivity compared to normal tissue, and the efficacy of the treatment. Other receptors that are over-expressed on tumor cells compared to normal cells such as the low-density lipoprotein receptor and the transferrin receptor can be used as targets for delivering PS attached to their ligands thus obtaining cell-type specificity. By preparing polymer-PS conjugates that differ in molecular weight, overall charge, hydrophobicity and degree of aggregation it is possible to vary the pharmacokinetics, biodistribution, tumor-targeting and phototoxic efficacy of the PS and by rationally designing these parameters it may be possible to substantially increase the overall therapeutic benefit.
Macrophages and monocytes express a scavenger-receptor that is a high-capacity route for delivering molecules into endocytic compartments in a cell-type specific manner. We have shown that by attaching PS to scavenger-receptor ligands it is possible to get three logs of selective cell killing. The capability to selectively kill macrophages may have applications in treating cancer, atherosclerosis, arthritis, inflammatory conditions and various infections. Another highly selective PS targeting technology is able to kill bacteria in localized infections without harming host tissue. This involves attaching the PS to polycationic peptides that are able to permeabilize the outer membrane barriers typical of Gram (-) bacteria, and because mammalian cells take up these macromolecules by the time-dependent process of endocytosis, this allows a high degree or temporal selectivity. We have demonstrated the PDT-mediated killing of bacteria infecting wounds in live mice for the first time. We were able to destroy >99% of the bacteria (Pseudomonas aeruginosa) without harming the wound healing, and the mice were saved from an otherwise lethal infection that would have to led to death from sepsis.
These examples of the use of rationally designed PS-conjugates illustrate a new approach to optimizing PDT and may allow PDT to be applied in hitherto unexplored diseases.
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