Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) is now a well-recognized modality for the treatment of cancer. While PDT has developed progressively over the last century, great advances have been observed in the field in recent years. The concept of dual selectivity of PDT agents is now widely accepted due to the relative specificity and selectivity of PDT along with the absence of harmful side effects often encountered with chemotherapy or radiotherapy. Traditionally, porphyrin-based photosensitizers have dominated the PDT field but these first generation photosensitizers have several disadvantages, with poor light absorption and cutaneous photosensitivity being the predominant side effects. As a result, the requirement for new photosensitizers, including second generation porphyrins and porphyrin derivatives as well as third generation photosensitizers has arisen, with the aim of alleviating the problems encountered with first generation porphyrins and improving the efficacy of PDT. The investigation of nonporphyrin photosensitizers for the development of novel PDT agents has been considerably less extensive than porphyrin-based compounds; however, structural modification of nonporphyrin photosensitizers has allowed for manipulation of the photochemotherapeutic properties. The aim of this review is to provide an insight into PDT photosensitizers clinically approved for application in oncology, as well as those which show significant potential in ongoing preclinical studies.

Nanodrug applications in photodynamic therapy

“…Porphyrin-based photosensitizers are also often classified as a first, second, and third generation PS. The first generation agent, hematoporphyrin (Hp) was isolated from hemoglobin during research on the nature of blood in 1841 [1,6]. Unfortunately, this first photosensitizer demonstrated several limitations which led to the investigation of newer agents called second generation photosensitizers, with better properties and lower toxic side effects ( Fig.…”

“…Unfortunately, this first photosensitizer demonstrated several limitations which led to the investigation of newer agents called second generation photosensitizers, with better properties and lower toxic side effects ( Fig. 1) [6]. Second generation photosensitizers demonstrate higher absorption in the 650-800 nm range where tissue penetration is optimal and have higher extinction coefficients of absorption in the red than first generation compounds [7].…”

“…Currently, research on this the third generation of photosensitizers is ongoing and these new drugs are characterized by conjugation to carrier molecules or prodrug-drug conversion steps, both of which specifically target the PS to the target cells, resulting in minimized accumulation in healthy tissues [8]. The development of safe and highly selective photosensitizing agents is the main topic of many ongoing research programs [6]. The development of non-porphyrin photosensitizers lacks considerably behind that of the respective porphyrin PS.…”

“…The development of non-porphyrin photosensitizers lacks considerably behind that of the respective porphyrin PS. A typical example is hypericin, a naturally occurring compound from Hypericum plants with an absorbance around 590 nm [6]. It shows high singlet oxygen production, minimal dark toxicity, and high clearance from the body, after administration [9].…”

“…To date, Photofrin ® has been approved in most countries for treatment of various cancer indications, for example, esophageal cancer, superficial bladder cancer, early and late stage lung cancers as well as malignant and non-malignant skin disease [6,12]. Porfimer sodium unfortunately has limitations for use in PDT because of its poor water solubility [7], prolonged photosensitivity (low clearance rate) and it also lacks long wavelength absorption [12].…”