Vascular and Cellular Targeting for Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) involves the combination of photosensitizers (PS) with light as a treatment, and has been an established medical practice for about 10 years. Current primary applications of PDT are age-related macular degeneration (AMD) and several types of cancer and precancer. Tumor vasculature and parenchyma cells are both potential targets of PDT damage. The preference of vascular versus cellular targeting is highly dependent upon the relative distribution of photosensitizers in each compartment, which is governed by the photosensitizer pharmacokinetic properties and can be effectively manipulated by the photosensitizer drug administration and light illumination interval (drug-light interval) during PDT treatment, or by the modification of photosensitizer molecular structure. PDT using shorter PS-light intervals mainly targets tumor vasculature by confining photosensitizer localization within blood vessels, whereas if the sensitizer has a reasonably long pharmacokinetic lifetime, then PDT at longer PS-light intervals can induce more tumor cellular damage, because the photosensitizer has then distributed into the tumor cellular compartment. This passive targeting mechanism is regulated by the innate photosensitizer physicochemical properties. In addition to the passive targeting approach, active targeting of various tumor endothelial and cellular markers has been studied extensively. The tumor cellular markers that have been explored for active photodynamic targeting are mainly tumor surface markers, including growth factor receptors, low-density lipoprotein (LDL) receptors, transferrin receptors, folic acid receptors, glucose transporters, integrin receptors, and insulin receptors. In addition to tumor surface proteins, nuclear receptors are targeted, as well. A limited number of studies have been performed to actively target tumor endothelial markers (ED-B domain of fibronectin, VEGF receptor-2, and neuropilin-1). Intracellular targeting is a challenge due to the difficulty in achieving sufficient penetration into the target cell, but significant progress has been made in this area. In this review, we summarize current studies of vascular and cellular targeting of PDT after more than 30 years of intensive efforts.

Porphyrin-based cationic amphiphilic photosensitisers as potential anticancer, antimicrobial and immunosuppressive agents

“…2 Basic structure of porphyrin and the most common porphyrintype photosensistisers mechanisms of PDT depends not only on the nature of the PS but also on the choice of the drug light interval (DLI), which is the period between the time of drug administration and the time of irradiation. In the case of direct tumour cell targeting, the DLI is usually much longer than in the case of vascular targeting, to allow PS accumulation in the tumor cells (Chen et al 2006). The PDT that preferentially targets blood vessels is known as vascular-targeted photodynamic (VTP) therapy.…”

The role of photodynamic therapy (PDT) physics

“…Some photosensitizers may act as vascular agents at short times after injection and at high fluence rates, where only the vasculature is sufficiently oxygenated, and produce direct cell kill at low fluence rates and long times after injection. 72 An additional level of complexity arises from the fact that the response to PDT is not confined to the cells where the singlet oxygen is deposited but can involve physiological 73 and immunological 74,75 responses as well.…”

“…One strategy to accomplish this is to optimize the timing the administration of light to coincide with the desired distribution of the photosensitizer. 72 This approach has been used to target vasculature by applying light while the photosensitizer is in circulation, for the treatment of AMD using Vertepofin and the prostate using Tookad. 12 In cases where the rate of production of singlet oxygen is limited by the vascular resupply of oxygen, changes in the light fluence rate can change the distribution of deposited singlet oxygen, with higher fluence rates leading to preferential targeting of vascular-adjacent tissue.…”

Photodynamic therapy in the treatment of prostate cancer

“…Eradykacja ta może być wynikiem bezpośredniego działania fotosensybilizatora na komórki tkanki nowotworowej i/lub na komórki jej naczyń, co prowadzi do jej śmierci wskutek zahamowania angiogenezy oraz wstrzymania dowozu tlenu i substancji odżywczych. Działanie PDT związane jest również z indukowaniem komórkowej i humoralnej odpowiedzi immunologicznej, poprzez mobilizację neutrofilów oraz indukowanie cytokin prozapalnych w tkance nowotworu [8]. Obecnie PDT jest coraz szerzej wykorzystywana w leczeniu chorób nowotworowych, i coraz częściej także nienowotworowych, takich jak zwyrodnienie plamki wzrokowej czy infekcje bakteryjne [6].…”