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Protease-Stable Polycationic Photosensitizer Conjugates between Polyethyleneimine and Chlorin(e6) for Broad-Spectrum Antimicrobial Photoinactivation

George P. Tegos,^1,2 Masahiro Anbe,^1,3 Changming Yang,^1,2 Tatiana N. Demidova,^1,4 Minahil Satti,^1,5 Pawel Mroz,^1,2 Sumbul Janjua,^1,5 Faten Gad,^1,2, and Michael R. Hamblin^1,2,6*

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts,¹ Department of Dermatology, Harvard Medical School, Boston, Massachusetts,² Department of Materials Science and Engineering, Graduate School of Engineering, University of Tokyo, Tokyo, Japan,³ Graduate Program in Cell Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts,⁴ Aga Khan Medical School, Karachi, Pakistan,⁵ Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts⁶

Received 10 October 2005/ Returned for modification 8 December 2005/ Accepted 31 January 2006

We previously showed that covalent conjugates between poly-L-lysine and chlorin(e6) were efficient photosensitizers (PS) of both gram-positive and gram-negative bacteria. The polycationic molecular constructs increased binding and penetration of the PS into impermeable gram-negative cells. We have now prepared a novel set of second-generation polycationic conjugates between chlorin(e6) and three molecular forms of polyethyleneimine (PEI): a small linear, a small cross-linked, and a large cross-linked molecule. The conjugates were characterized by high-pressure liquid chromatography and tested for their ability to kill a panel of pathogenic microorganisms, the gram-positive Staphylococcus aureus and Streptococcus pyogenes, the gram-negative Escherichia coli and Pseudomonas aeruginosa, and the yeast Candida albicans, after exposure to low levels of red light. The large cross-linked molecule efficiently killed all organisms, while the linear conjugate killed gram-positive bacteria and C. albicans. The small cross-linked conjugate was the least efficient antimicrobial PS and its remarkably low activity could not be explained by reduced photochemical quantum yield or reduced cellular uptake. In contrast to polylysine conjugates, the PEI conjugates were resistant to degradation by proteases such as trypsin that hydrolyze lysine-lysine peptide bonds, The advantage of protease stability combined with the ready availability of PEI suggests these molecules may be superior to polylysine-PS conjugates for photodynamic therapy of localized infections.

Deceased.

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