Targeted photodynamic therapy via receptor mediated delivery systems

Abstract

Targeted photodynamic therapy (PDT) offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. While antibody-conjugates have received the most attention, cellular transformations offer numerous other potent targets to exploit during the delivery of photosensitizers (PSs) for PDT. Alterations in receptor expression, increased levels of specific cell surface membrane lipids and proteins as well as changes in the cellular microenvironment all occur in diseased cells. Along with other biochemical and physiological changes that occur during diseased and malignant cell transformation, these factors have been utilized in order to improve the efficacy of PDT. Attempts have been made to either increase the uptake of the dye by the target cells and tissues or to improve subcellular localization so as to deliver the dye to photosensitive sites within the cells. This review discusses various PS bioconjugates that utilize these factors and summarizes the results obtained to date.

Introduction

Traditional cancer treatments including surgery, radiation therapy and chemotherapy all result in serious side effects caused by the loss of normal cell function. This is a result of the relative indiscriminate cytotoxic properties of modern treatment modalities. Researchers have thus invoked the search for the “magic bullet”, the single underlying process that will allow for selectively targeting and destroying diseased cells while sparing their healthy functional neighbors. Despite decades of experimentation, success has been fleeting. Complicating the search is the fact that cancer is not a single entity but is a family of diseases characterized by uncontrolled proliferative growth and the unwanted spread of aberrant cells from their site of origin [1]. Each malignancy exhibits their own characteristics and each expresses their own possible target antigens. Furthermore, individual tumors are incredibly heterogeneous, where therapy that causes cell death in one subset of cells might in fact strengthen another subset.

Despite much early promise, antibody targeting has had little real success in cancer therapy [2]. There are a number of problems associated with antibody-based therapies that preclude them from being the “magic bullet” so long sought after. Among these problems are the following:

• It is remarkably difficult to achieve tumor-specific antibodies that also display high affinity.

• Clinical tumors are highly heterogeneous and do not have consistent expression of target antigens throughout their mass.

• Antibodies are large proteins and do not penetrate well into the tumor mass.

• Only a very small amount of the antibody dose (much less than 1%) actually reaches the tumor and most of that is localized to the tumor vasculature.

• Antibodies are often not internalized by the cell, leaving the cytotoxic agent to do its damage on the cell surface, away from the most sensitive sites within the cell.

• Antibody–drug conjugates will only be active against those tumor cells that express the corresponding antigen and any chemical instability in the chemical bond between the antibody and the drug could result in undesirable systemic effects.

These important disadvantages have led research towards new areas.

Photodynamic therapy (PDT) is one step towards the “magic bullet” as only those cells that are simultaneously exposed to the photosensitizing dye, molecular oxygen and light receive the cytotoxic insult [3], [4], [5]. The ability to confine activation of the photosensitizer (PS) by restricting illumination to the diseased tissue allows for a certain degree of selectivity towards these cells. Ideally, PDT holds the promise of dual selectivity with preferential tumor uptake of the PS leading to improved efficiency. To date, most first and second-generation PSs studied for PDT display only a slight preference for malignant cells, often leading to significant skin photosensitivity and high uptake by healthy cells and tissues. In order to overcome this, third-generation PSs that are actively targeted towards diseased tissue are being designed and synthesized [6]. These can be said to include targeted vehicles used to improve PS delivery along with PS–antibody conjugates. This chapter deals with other methods of targeting PSs to cancer cells, paying particular attention to non-antibody based protein carriers and protein/receptor systems. Several of these targeting methodologies offer the added advantage of trafficking the PS across the cellular plasma membrane, resulting in intracellular accumulation of the dye. Such intracellular accumulation may allow for targeting of photosensitive intracellular sites, thus improve photodynamic efficiency.