Jingquan Zhao

For photodynamic therapy (PDT) treatment of microvascular diseases, drugs are delivered via blood circulation and the targets are vasculature endothelial cells, for which the contradictory requirements of hydrophilicity and lipophilicity of the drugs have been achieved by liposome preparations. Herein, it is demonstrated that the drug delivery and target affinity are achieved by a single chemical compound, hypocrellin B (HB) derivative 6 selected from three novel aminoalkanesulfonic acid HB derivatives, 5–7. 6 exhibits a much higher PDT activity (IC₅₀ = 22 nM) on human gastric carcinoma BGC823 cells than HB, while it has no cellular toxicity in the dark. On the basis of estimation of the clinically required concentration according to relative PDT activity and clinical criteria, it can be predicted that 6 is directly deliverable to and PDT effective on target cells. The enhanced red absorption and superhigh photoactivity suggest that 6 is more powerful for PDT of tumors than HB.

Water‐soluble derivatives of hypocrellins can be safely delivered in blood plasma but lose their photodynamic activity in vivo due to poor cell uptake, while hydrophobic derivatives retaining their activity may aggregate in the blood plasma and block vascular networks. Considering both drug delivery and biological activity, surfactant‐like hypocrellin B (HB) derivatives, sodium 12‐2‐HB‐aminododecanoate (SAHB) and sodium 11,11′‐5,8‐HB‐dimercaptoundecanoate (DMHB), were first designed and then synthesized in the current work. Both SAHB and DMHB were photoactive, generating free radicals and reactive oxygen species, as confirmed by EPR and chemical measurements. Most importantly, DMHB was not only readily soluble, allowing preparation of an intravenous injection solution at a clinically acceptable concentration, but it was also more photodynamic therapy (PDT) active to human breast carcinoma MCF‐7 cells than its parent HB under irradiation. The photodynamic activity was exactly identical to the ¹O₂ quantum yield and was not reduced by the improved water solubility, suggesting an independent hydrophilicity or lipophilicity. To our knowledge, this is a new strategy that possesses general significance for converting hydrophobic photosensitizers into clinically usable PDT drugs.

Photodynamic therapy (PDT) is a versatile methodology to treat various diseases but the drugs (photosensitizers) specifically aimed at individual character of diseases are urgently needed. Among those, the perilenoquinoid photosensitizers were thought of low PDT effectiveness to solid tumors due to low absorption on the “photodynamic window” but may be specially suitable for PDT to some microvascular diseases, such as age-related macular degeneration (AMD) and port wine stains (PWS), as well as other superficial diseases. Two strategies were discussed to convert the photosensitizers into clinically acceptable drugs in consideration of the drug-delivery and biological activity.

Elsinochrome A (EA) possesses the highest singlet-oxygen quantum yield (0.98) amongst the perilenoquinoid pigments and may be suitable as a phototherapeutic drug. However, there have been virtually no studies into its medicinal applications. Based on the analysis of chemical derivatives of hypocrellins (the same family as EA), 5-(3-mercapto-1-propanesulfonic acid)-substituted elsinochrome A (MPEA) with an amphiphilicity was designed and synthesized by considering drug delivery and biological activity requirements. MPEA possesses a water solubility of 5.1 mg mL⁻¹, which is just sufficient to enable dissolution at a clinically acceptable concentration, while its partition coefficient (n-octanol/phosphate buffered saline) of 7 guarantees affinity to biological targets. MPEA could photogenerate semiquinone anion radicals and reactive oxygen species, especially singlet oxygen, at a yield of 0.73, which approaches that for hypocrellin B. Biological tests confirmed that the photodynamic activity of MPEA was as high as 60% of that of its parent EA, which is significantly higher than that of most other photosensitizers.

Monomerization and trimerization of photosystem I (PSI) in cyanobacteria are reversible to response to light switched off and on, which leads to “energy spillover” to regulate excitation of the two photosystems in balance. Considering that PSI is a trans-membrane protein embedded in thylakoid membranes, the monomerization or trimerization must involve a movement of PSI in the membranes. In this work, the mobility of PSI was demonstrated by dependence of the monomerization and trimerization on temperature for intact Spirulina platensis cells undergoing a light-to-dark or a dark-to-light transition. Based on the characteristic absorbance of monomers and trimmers, it confirms that both monomerization and trimerization are temperature-sensitive. The relative populations of the monomers and trimmers are invariable above the phase transition temperature (T _PT) while directly proportional to temperature below T _PT. On the other hand, the rate to reach the equilibrium population is proportional to temperature above T _PT but invariable below T _PT. The PSI mobility and the temperature-dependent population are contrary to those of plastoquinone (PQ) molecules because PSI is a trans-membrane protein while PQ molecules are small diffusive electron carriers in thylakoid membranes as well as their distinctive sizes and environments. The less monomerization of PSI but the invariable time constant at lower temperature below T _PT may be due to that accumulation of the reduced PQ molecules results in decrease of the stromal-side H⁺ concentration which is a driving force of PSI monomerization.