Necrosis Avidity: A Newly Discovered Feature of Hypericin and its Preclinical Applications in Necrosis Imaging

Abstract

Hypericin has been widely studied as a potent photosensitizer for photodynamic therapy in both preclinical and clinical settings. Recently, hypericin has also been discovered to have a specific avidity for necrotic tissue. This affinity is also observed in a series of radiolabeled derivatives of hypericin, including [123I]iodohypericin, [124I]iodohypericin, and [131I]iodohypericin. Hypericin, along with other necrosis-avid contrast agents, has been investigated for use in noninvasively targeting necrotic tissues in numerous disorders. Potential clinical applications of hypericin include the identification of acute myocardial infarction, evaluation of tissue viability, assessment of therapeutic responses to treatments, and interventional procedures for solid tumors. The mechanisms of necrosis avidity in hypericin remain to be fully elucidated, although several hypotheses have been suggested. In particular, it has been proposed that the necrosis avidity of hypericin is compound specific; for instance, cholesterol, phosphatidylserine, or phosphatidylethanolamine components in the phospholipid bilayer of cellular membranes may be the major targets for its observed selectivity. Further investigations are needed to identify the specific binding moiety that is responsible for the necrosis avidity of hypericin.

Necrosis avid near infrared fluorescent cyanines for imaging cell death and their use to monitor therapeutic efficacy in mouse tumor models

“…The concept of employing tissue necrosis, as a biomarker for diagnostic and prognostic purposes of disease, is not new. With the objective to target and image necrotic tissue, already back in 1988 Epstein and colleagues developed several so called TNT antibodies [ 20 ] and more recently Ni and colleagues [ 22 , 40 , 51 , 52 ] reported on the specific necrosis avid properties of the photosensitizer Hypericin in small animals. However, both compounds were examined not just for their potential as contrast agents, but also for their possible usage in cancer treatment by coupling of Iodine-131 used for local radionuclide therapy.…”

“…Necrosis avid contrast agents (NACAs) are another class of compounds that specifically accumulate in necrotic tissue, these are categorized in porphyrin and non-porphyrin-based compounds. NACAs, such as the well-known compound hypericin, are assumed to specifically bind proteins, peptides and nucleotides that become available upon loss of cell membrane integrity [ 22 , 23 ]. However, most of these compounds have poor solubility, high tendency to aggregate, are photo-toxic and lack specificity, which are the main reasons why there are currently no clinically approved NACAs available [ 23 , 24 ].…”

Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

“…The existing necrosis imaging agents can be divided into two different groups: (non-) specific CT and MR contrast agents to enhance the natural signal and the other group consists out of mostly radiolabeled necrosis avid contrast agents (NACAs) that specifically target necrotic tissue. The latter can also be employed for therapeutic purposes, e.g., when radiolabeled with Iodine-131 [2–10, 13, 15, 23, 45–49]. It is expected that the non-specific necrosis contrast agents will fall into abeyance when compounds with high necrosis specificity become clinically available.…”

Improved therapeutic outcomes of thermal ablation on rat orthotopic liver allograft sarcoma models by radioiodinated hypericin induced necrosis targeted radiotherapy

“…Recently, hypericin has been afresh recognized due to its exceptional affinity for necrotic tissue [16–19]. Compared with some targeted drugs that just anchor to viable tumor tissues, hypericin could specifically and steadily bind to the tumor necrotic tissue with high target-to-nontarget ratios [16–19].…”

“…Recently, hypericin has been afresh recognized due to its exceptional affinity for necrotic tissue [16–19]. Compared with some targeted drugs that just anchor to viable tumor tissues, hypericin could specifically and steadily bind to the tumor necrotic tissue with high target-to-nontarget ratios [16–19]. 131 I-Hyp has also been identified as a potential therapeutic radiopharmaceutical in the field of so-called necrosis target radiotherapy compared with other previously identified specific agents [18, 19].…”