New Derivatives of Bacteriopurpurin with Thiolated Au (I) Complexes: Dual Darkand Light Activated Antitumor Potency

Abstract

Background:: Conventional antitumor Photosensitizers (PS) are normally low toxic in the dark whereas light activation triggers massive cell death (photodynamic therapy, PDT). Objective:: To expand the therapeutic potential of PS to dual potency cytocidal agents, taking advantage of the use of bacteriopurpurin for a deeper tissue penetration of light, and suitability of the tetrapyrrolic macrocycle for chemical modifications at its periphery. Methods:: Conjugation of a pro-oxidant thiolate Au (I) moiety to the bacteriopurpurin core and evaluation of cytotoxicity in cell culture and in vivo. Results:: New water-soluble derivatives showed micromolar cytotoxicity for cultured human tumor cell lines in the dark, including the subline with an altered drug response due to p53 inactivation. Cellular PDT with the selected conjugate, thiolate Au (I)-dipropoxybacteriopurpurinimide (compound 6) with two triphenylphosphine Au fragments, triggered rapid (within minutes) cell death. Damage to the plasma membrane (necrosis) was a hallmark of cell death by compound 6 both in the dark and upon light activation. Furthermore, one single i.v. injection of compound 6 caused retardation of transplanted syngeneic tumors at the tolerable dose. Illumination of tumors that accumulated compound 6 significantly synergized with the effect of 6 in the dark. Conclusion:: Complexes of virtually non-toxic, photoactivatable bacteriopurpurin with the gold-containing organic moiety are considered the dual potency antitumor agents, tentatively applicable for intractable tumors.

The First Selenoanhydride in the Series of Chlorophyll a Derivatives, Its Stability and Photoinduced Cytotoxicity

“…One of the promising approaches in the development of new PS involves their chemical design based on molecules of known pigments, namely, by replacing oxygen, nitrogen, and sulfur atoms in the exocycles of purpurin, cycloimide, and thioanhydride with a selenium atom. Since our research team has accumulated extensive experience in the chemical modification of porphyrins and their hydrogenated analogs [ 37 , 38 , 39 , 40 ], it seems interesting to create a selenoanhydride exocycle annulated with the main macrocycle to obtain new photosensitizers of chlorin series. As shown previously, a thioanhydride exocycle created in a chlorin molecule results in new physicochemical and spectral properties appearing in the pigment [ 41 , 42 , 43 , 44 , 45 , 46 , 47 ].…”

“…Earlier, our research group obtained derivatives of natural chlorins containing various heterocycles, annulated with the main macrocycle, as photosensitizers for photodynamic therapy of cancer [ 37 , 38 , 39 , 40 ].…”

Advances in photosensitizer-related design for photodynamic therapy

“…Elena et al have introduced a photosensitizers system which was derivatives of bacteriopurpurin with thiolated Au(I) complexes, to realize a deep-seated tumor therapy program that can be activated by light ( Fig. 4 ) [25] . Photosensitive systems that introduce metal ions can also be combined with chemotherapy and photothermal therapy (PTT) to enhance therapy [26] .…”

“… Material Characteristic Model Radiation source Ref. Bi 2 S 3 @Bi Z-scheme Regulation of electron energy level, and achieved high conversion efficiency – 808 nm laser irradiation [20] Se/N—CDs Bind RNA selectively, RNA then acted as a carrier to transport photosensitizer to the nucleus of tumor cell 4T1 tumor mice LED irradiation (550 nm( [22] Ru II -Pt IV polypyridine Au(I) complexes Combined with chemotherapy and PTT to improve the effectiveness of cancer treatment Drug resistant cancers 480 and 595 nm light [24] – 800 nm laser irradiation [25] MnFe 2 O 4 Cr 2 Fe 6 O 12 Metal compounds of Mn and Cr are made to NCs and the release of chemotherapeutic drug was pH-dependent Michigan cancer foundation-7, breast cancer cells UV light [27] g-C 3 N 4 & PEG This nanoplatform could produce oxygen via water splitting, and turn oxygen into ROS under light. It also improved biocompatibility due to the PEG modification A-431 tumors blue light [29] CuS Does no produce ROS, but can be used as an excellent carrier of photosensitizer to achieve the combination of PTT and PDT L929 normal fibroblast cells and HeLa cells 808 nm laser irradiation [30] Iridium (III) complex Self-assembled by electrostatic force with HA to form a spherical nanostructure called Irpy-HA, which is highly stable (keep its nanostructure at least 30 d).…”

Targeted Photosensitizers With Photoinduced Antitumor Activity Based on Natural Chlorins

“…In this work, chlorophyll a and bacteriochlorophyll a derivatives were used as a platform for the creation of the abovementioned PSs, to which a PSMA ligand was attached for targeted delivery to prostate cancer cells [1]; 3rd domain of alpha-fetoprotein for delivery to cells of various tumor lines and complexes of gold (I) and tin (IV) for target-oriented intracellular delivery of pigments [2]. All the proposed targeted drugs of the chlorin series exhibited photoinduced antitumor activity, which exceeded the cytotoxicity of chlorins without the introduced vector molecules.…”