Synthesis and evaluation of cationic bacteriochlorin amphiphiles with effective in vitro photodynamic activity against cancer cells at low nanomolar concentration

Abstract

Bacteriochlorins are attractive candidates as photosensitizers for photodynamic therapy (PDT) due to their intense absorption in the near-infrared (NIR) region of the spectrum where light transmission through tissue is maximal. Many naturally occurring bacteriochlorins are inherently unstable due to adventitious atmospheric oxidation. A de novo synthesis affords bacteriochlorins that contain a geminal dimethyl group in each reduced pyrrole ring to increase stability against oxidation. Here, three new synthetic bacteriochlorins, each bearing a single side-chain containing one or two positive charges, were investigated for their in vitro PDT activity against HeLa human cancer cells. All bacteriochlorins were active at low nanomolar concentration when activated with NIR light; those bearing a single positive charge exhibited faster uptake and higher activity. The bacteriochlorins were localized in mitochondria, lysosomes and endoplasmic reticulum as shown by organelle specific fluorescent probes. Cell death was via apoptosis as shown by cell morphology and nuclear condensation. Taken together, the results show the importance of appropriate peripheral groups about a photosensitizer for effective PDT applications.

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

“…Cationic amphiphilic porphyrin-based PSs obtained completely by synthesis are mostly meso-substituted porphyrins with different symmetry patterns, free or in complex with metal (Caminos et al 2006;Lazzeri and Durantini 2003). There are somewhat fewer examples of different cationic amphiphilic phthalocyanines, mostly metalated with zinc(II) (Dummin et al 1997;Kussovski et al 2009), but also with other metals such as silicon (Allen et al 2001;Mantareva et al 2013), then synthetic chlorins (Costa et al 2012a), bacteriochlorins (Sharma et al 2013;Yakubovskaya et al 2014) and isobacteriochlorins (Mesquita et al 2014). The great advantage of phthalocyanines, chlorins and (iso)bacteriochlorins as PSs is better absorption of red light, which facilitates treatments of deeper infections and deep-seated tumours, but some of the frequent drawbacks often associated with these compounds include a propensity for aggregation and insufficient solubility in water (Mantareva et al 2013;Sharma et al 2013).…”

Stable synthetic mono-substituted cationic bacteriochlorins mediate selective broad-spectrum photoinactivation of drug-resistant pathogens at nanomolar concentrations

“…The bacteriochlorins were designed and synthesized as described by Sharma et al [14]. BC37 and BC39 each bears a single quaternized ammonium group and hence is monocationic.…”

“…1) were synthesized and tested for PDT-mediated killing of human cancer cells [14]. These compounds exhibited exceptional activity, with substantial cancer cell killing at concentrations as low as 6 nM excited with modest fluences of light (5 J/cm 2 ) after 24-h incubation.…”

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

“…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].…”