Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity

Abstract

Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to target tumors. Selective therapies can be established by focusing on distinctive intracellular (receptors, apoptotic pathways, multidrug resistance system, nitric oxide-mediated stress) and environmental (glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity.

Keywords: Breast cancer; Photodynamic therapy; Synergism; Treatment combination; Tumor microenvironment.

Figure 1

Photodynamic therapy (PDT) combined with tumor microenvironment intervention on breast cancer. PDT is one of the alternative methods for breast cancer treatment and involves: (1) administration of a photosensitizer (PS), which is internalized into either tumor cells or surrounding vasculature; (2) local irradiation at a wavelength corresponding to the absorbance peak of the PS; and (3) light activation of the PS, which promotes cell death mainly by apoptosis. Because of the benefits of improving PDT outcome, researchers have developed strategies to target the vasculature surrounding breast tumor cells by conjugating the PS with endothelial cell (EC)-specific ligands. Immunoactivation of dendritic cells using CpG increases phagocytosis of PDT-killed tumor cells and leads to their maturation and activation, thereby promoting an antitumor immune response. Regarding abiotic environmental factors, it was shown that photodynamic therapy sensitivity is reduced in glucose-deprived cells, and that a lower extracellular pH leads to increased PS uptake, reinforcing the photodynamic response.