Stable Synthetic Bacteriochlorins for Photodynamic Therapy: Role of Dicyano Peripheral Groups, Central Metal Substitution (2H, Zn, Pd), and Cremophor EL Delivery

Abstract

A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)2BC and corresponding zinc chelate (NC)2BC–Zn and palladium chelate (NC)2BC–Pd were studied. Direct dilution of a solution of bacteriochlorin in an organic solvent (N,N-dimethylacetamide) into serum-containing medium was compared with the dilution of bacteriochlorin in Cremophor EL (CrEL; polyoxyethylene glycerol triricinoleate) micelles into the same medium. CrEL generally reduced aggregation (as indicated by absorption and fluorescence) and increased activity up to tenfold (depending on bacteriochlorin), although it decreased cellular uptake. The order of PDT activity against HeLa human cancer cells after 24 h incubation and illumination with 10 J cm−2 of near-infrared (NIR) light is (NC)2BC–Pd (LD50 = 25 nm) > (NC)2BC > (NC)2BC–Zn ≈ BC. Subcellular localization was determined to be in the endoplasmic reticulum, mitochondria and lysosomes, depending on the bacteriochlorin. (NC)2BC–Pd showed PDT-mediated damage to mitochondria and lysosomes, and the greatest production of hydroxyl radicals as determined using a hydroxyphenylfluorescein probe. The incorporation of cyano substituents provides an excellent motif for the enhancement of the photoactivity and photostability of bacteriochlorins as PDT photosensitizers.

Photodynamic Therapy: Current Status and Future Directions

“…Therefore, maximal penetration of light into tissues can be achieved at the so-called ‘phototherapeutic window' [101,102], which is schematically illustrated in figure 6. Among the natural pigments with strong absorption in the NIR region of the spectrum (720-850 nm) are bacteriochlorins and bacteriopurpurins [103], but they are unstable, easily photobleach, and permit limited chemical modifications [54,104]. Recently developed new synthetic strategies allowed the synthesis of artificial stable bacteriochlorins, which demonstrated improved pharmacokinetics and high PDT efficacy [52,54,95,96,105].…”

“…PSs rarely participate only in type I or type II processes; therefore, photodynamic activation usually generates a mixture of 1 O 2 and radicals [51]. Recent studies suggest that high PDT efficacy results from a synergistic action of species generated by type I and type II reactions (O 2 - ∙ , HO ∙ and 1 O 2 ) [52,53,54]. …”

“…Among the natural pigments with strong absorption in the NIR region of the spectrum (720-850 nm) are bacteriochlorins and bacteriopurpurins [103], but they are unstable, easily photobleach, and permit limited chemical modifications [54,104]. Recently developed new synthetic strategies allowed the synthesis of artificial stable bacteriochlorins, which demonstrated improved pharmacokinetics and high PDT efficacy [52,54,95,96,105]. Light with λ >850 nm, however, does not provide enough energy for excitation of 3 O 2 to 1 O 2 [100,106].…”

Mechanistic studies on versatile metal-assisted hydrogen peroxide activation processes for biomedical and environmental incentives

“…Alternatively, similar effects can be reached by incorporation of dicyano substituents into a bacteriochlorin macrocycle (Fig. 5E) [241,243]. In addition, these modifications increase the triplet quantum yield by promoting spinorbit coupling in the electronically excited orbital [232,236] due to the heavy-atom effect.…”

“…A photosensitizing drug (photosensitizer, PS) that absorbs visible or near infrared (NIR) light is administered to the organism and after a time referred to as drug-to-light interval (DLI); the target tissue is irradiated followed by the generation of singlet oxygen, oxygen centered radicals and hydrogen peroxide [230][231][232]234,236,237,[241][242][243][244][245][246][247][248][249][250][251][252][253][254][255][256][257]. They are basically responsible for three biological mechanisms that occur separately or simultaneously to make PDT an effective anti-cancer procedure: 1) vascular shutdown and consequent massive ischemic death of tumor tissue, 2) direct killing of tumor cells induced by the oxidative stress inside the cells, and 3) PDT-induced acute local and systemic inflammation activates dendritic cells that eventually stimulate T-cell activation and generate antitumor immune memory and systemic responses [227,237,258,259].…”