Design features for optimization of tetrapyrrole macrocycles as antimicrobial and anticancer photosensitizers

• Published in: Chemical biology & drug design 2017-02, Vol.89 (2), p.192-206
• Main Authors: Martinez De Pinillos Bayona, Alejandra, Mroz, Pawel, Thunshelle, Connor, Hamblin, Michael R.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; bacteriochlorin; biodistribution; chlorin; Humans; Hydrophobic and Hydrophilic Interactions; Indoles - chemistry; Indoles - pharmacology; Light; pharmacodynamics; Photochemotherapy - methods; photodynamic therapy; photosensitizer; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; phthalocyanine; porphyrin; Tetrapyrroles - chemistry; Tetrapyrroles - pharmacology; Tissue Distribution
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12792

Photodynamic therapy (PDT) uses non‐toxic dyes called photosensitizers (PS) and harmless visible light that combine to form highly toxic reactive oxygen species that kill cells. Originally, a cancer therapy, PDT, now includes applications for infections. The most widely studied PS are tetrapyrrole macrocycles including porphyrins, chlorins, bacteriochlorins, and phthalocyanines. The present review covers the design features in PS that can work together to maximize the PDT activity for various disease targets. Photophysical and photochemical properties include the wavelength and size of the long‐wavelength absorption peak (for good light penetration into tissue), the triplet quantum yield and lifetime, and the propensity to undergo type I (electron transfer) or type II (energy transfer) photochemical mechanisms. The central metal in the tetrapyrrole macrocycle has a strong influence on the PDT activity. Hydrophobicity and charge are important factors that govern interactions with various types of cells (cancer and microbial) in vitro and the pharmacokinetics and biodistribution in vivo. Hydrophobic structures tend to be water insoluble and require a drug delivery vehicle for maximal activity. Molecular asymmetry and amphiphilicity are also important for high activity. In vivo some structures possess the ability to selectively accumulate in tumors and to localize in the tumor microvasculature producing vascular shutdown after illumination. Photodynamic therapy (PDT) uses non‐toxic dyes called photosensitizers (PS) and harmless visible light that combine to form highly toxic reactive oxygen species that kill cells. PS are often tetrapyrrole macrocycles including porphyrins, chlorins, bacteriochlorins, and phthalocyanines. We discuss drug‐design parameters including hydrophobicity, charge, molecular asymmetry that influence subcellular localization and pharmacokinetics.