Nitroreductase-Responsive Photosensitizers for Selective Imaging and Photo-Inactivation of Intracellular Bacteria.

Intracellular Staphylococcus aureus (S. aureus), especially the methicillin resistant staphylococcus aureus (MRSA), are difficult to detect and eradicate due to the protection by the host cells. Antibacterial photodynamic therapy (aPDT) offers promise in treating intracellular bacteria, provided that selective damage to the bacteria ranther than host cells can be realized. According to the different nitroreductase (NTR) levels in mammalian cells and S. aureus, herein NTR-responsive photosensitizers (PSs) (T)CyI-NO2 were designed and synthesized. The emission and 1O2 generation of (T)CyI-NO2 are quenched by the 4-nitrobenzyl group, but can be specifically switched on by bacterial NTR. Therefore, selective imaging and photo-inactivation of intracellular S. aureus and MRSA were achieved. Our findings may pave the way for the development of more efficient and selective aPDT agents to combat intractable intracellular infections.

An Alkynyl-Dangling Ru(II) Polypyridine Complex for Targeted Antimicrobial Photodynamic Therapy.

To realize clinical application of antibacterial photodynamic therapy (aPDT), one of the most arduous challenges is how to render aPDT agents high selectivity against bacterial pathogens. In light of the fact that amino group-containing lipids are rich on the outer surfaces of Gram-positive bacteria, we herein constructed an alkynyl-dangling ruthenium(II) polypyridine complex (Ru2) to preferentially label Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) over mammalian cells via the amino-yne bio-orthogonal click reaction. Thanks to the strong singlet oxygen generation ability, Ru2 could photo-inactivate S. aureus and MRSA effectively and specifically. Phosphatidylethanolamine (PE) molecules also exist in mammalian cells but are not accessible for Ru2, leading to its poor binding/uptake and negligible cytotoxicity in the dark and upon irradiation towards mammalian cells as well as low hemolysis, all favorable for aPDT application.

A photo-degradable BODIPY-modified Ru(II) photosensitizer for safe and efficient PDT under both normoxic and hypoxic conditions.

Photodynamic therapy (PDT) is promising for cancer treatment but still suffers from some limitations. For instance, PDT based on 1O2 generation (in a type-II mechanism) is heavily dependent on high oxygen concentrations and will be significantly depressed in hypoxic tumors. In addition, the residual photosensitizers after PDT treatment may cause severe side-effects under light irradiation. To solve these problems, herein a BODIPY (boron dipyrromethene)-modified Ru(II) complex [Ru(dip)2(tpy-BODIPY)]2+ (complex 1, dip = 4,7-diphenyl-1,10-phenanthroline, tpy = 2,2':6',2''-terpyridine) was designed and synthesized. Complex 1 exhibited both high singlet oxygen quantum yield (Φ = 0.7 in CH3CN) and excellent superoxide radical (O2˙-) generation, and thus demonstrated efficient PDT activity under both normoxic and hypoxic conditions. Moreover, complex 1 is photo-degradable in water, and greatly loses its ROS generation ability after PDT treatment. These novel properties of complex 1 make it promising for efficient PDT under both normoxic and hypoxic conditions with reduced side-effects.

Biocompatible hypocrellin A-Fe(III) nanoparticles exhibiting efficient photo-activated CDT in vitro and in vivo.

Chemodynamic therapy (CDT) is novel and promising for cancer treatment, however, the potential systematic toxicity of the used nanoparticles is still a big concern. In this work the biocompatible hypocrellin A-Fe(III) nanoparticles (HA-Fe(III) NPs) were synthesized and studied. The CDT effect of HA-Fe(III) NPs in the dark is negligible but can be photo-activated upon red light irradiation, which is meaningful to realize precise CDT treatment by selective light irradiation. Moreover, HA-Fe(III) NPs can also generate O2˙-, which may be converted into H2O2 to further enhance the CDT effect. As a result, HA-Fe(III) NPs had little cytotoxicity in the dark at the concentration up to 200 µg ml-1, but exhibited efficient CDT activity upon red light irradiation under both normoxic and hypoxic conditions. The in vivo results also showed that HA-Fe(III) NPs can efficiently inhibit tumor growth upon 628 nm light irradiation.

A Ru-anthraquinone dyad with triple functions of PACT, photoredox catalysis and PDT upon red light irradiation.

Phototherapy for cancer treatment has received much attention in recent years, and compounds with multiple anticancer mechanisms upon irradiation are particularly appealing. In this work, a nitro-anthraquinone group was attached to a biq (2,2'-biquinoline) ligand based Ru(ii) complex, endowing the resultant Ru1 compound with multiple anticancer mechanisms upon 600 nm light irradiation. Ru1 can undergo biq ligand photodissociation, showing its potential as a photoactivated chemotherapy (PACT) agent. Moreover, a Ru(iii) centre and an anthraquinone anion centre may be generated upon irradiation, which can further oxidize NADH/NADPH and generate O2˙-, successfully eliciting photoredox catalysis and photodynamic therapy (PDT). Compared to the control complex Ru2 without the nitroanthraquinone group, Ru1 exhibited much enhanced photocytotoxicity towards a series of cancer cell lines and 3D multicellular spheroids upon red light irradiation.

UCNP@BSA@Ru nanoparticles with tumor-specific and NIR-triggered efficient PACT activity in vivo.

Ru(ii)-based photoactivated chemotherapy (PACT) agents are promising; however, their short wavelength absorption (generally <550 nm) and poor tumor accumulation ability limit their in vivo applications. Herein, bovine serum albumin (BSA) coated lanthanide-doped upconversion nanoparticles (NaYF4:Yb:Tm@NaYF4 (UCNPs)) were loaded with a Ru(ii) PACT agent, i.e. [Ru(dip)2(spc)]+ (dip = 4,7-diphenyl-1,10-phenanthroline; spc = 2-sulfonic acid pyridine-3-carboxylic acid). The resultant UCNP@BSA@Ru can transfer [Ru(dip)2(spc)]+ to tumor cells in vitro as well as tumor tissues in vivo highly efficiently and selectively owing to the targeting ability of BSA and the enhanced permeability and retention effect of the nanoparticles. The subsequent near infrared (NIR) light irradiation at 980 nm or visible light irradiation at 470 nm can initiate dissociation of the spc ligand, and the released Ru(ii) aqua compounds ([Ru(dip)2(H2O)2]2+) may exert a potent cytotoxicity towards a series of cancer cells but a much weaker effect on the normal IOSE80 cells. The in vivo (mouse) results showed that UCNP@BSA@Ru could inhibit tumor growth upon 980 nm irradiation more efficiently than in the dark and more efficiently than cisplatin (in the dark).