Acid-Activatable Transmorphic Peptide-Based Nanomaterials for Photodynamic Therapy

Inspired by the dynamic morphology control of molecular assemblies in biological systems, we have developed pH-responsive transformable peptide-based nanoparticles for photodynamic therapy (PDT) with prolonged tumor retention times. The self-assembled peptide–porphyrin nanoparticles transformed into nanofibers when exposed to the acidic tumor microenvironment, which was mainly driven by enhanced intermolecular hydrogen bond formation between the protonated molecules. The nanoparticle transformation into fibrils improved their singlet oxygen generation ability and enabled high accumulation and long-term retention at tumor sites. Strong fluorescent signals of these nanomaterials were detected in tumor tissue up to 7 days after administration. Moreover, the peptide assemblies exhibited excellent anti-tumor efficacy via PDT in vivo. This in situ fibrillar transformation strategy could be utilized to design effective stimuli-responsive biomaterials for long-term imaging and therapy.     

Oligolysine‐Conjugated Zinc(II) Phthalocyanines as Efficient Photosensitizers for Antimicrobial Photodynamic Therapy

A series of zinc(II) phthalocyanines conjugated with an oligolysine chain (n=2, 4, and 8) were synthesized and characterized by using various spectroscopic methods. As shown by using UV/Vis and fluorescence spectroscopic methods, these compounds were nonaggregated in N,N‐dimethylformamide, and gave a weak fluorescence emission and high singlet oxygen quantum yield (Φ_Δ=0.86–0.89) as a result of their di‐α‐substitution. They became slightly aggregated in water with 0.05 % Cremophor EL, but they could still generate singlet oxygen effectively. The antimicrobial photodynamic activities of these compounds were then examined against various bacterial strains, including the Gram‐positive methicillin‐sensitive Staphylococcus aureus ATCC 25923 and methicillin‐resistant Staphylococcus aureus ATCC BAA‐43, and the Gram‐negative Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853. Generally, the dyes were much more potent toward the Gram‐positive bacteria. Only 15 to 90 nM of these photosensitizers was required to induce a 4 log reduction in the cell viability of the strains. For Escherichia coli, the photocytotoxicity increased with the length of the oligolysine chain. The octalysine derivative showed the highest potency with a 4 log reduction concentration of 0.8 μM . Pseudomonas aeruginosa was most resistant to the photodynamic treatment. The potency of the tetralysine derivative toward a series of clinical strains of Staphylococcus aureus was also examined and found to be comparable with that toward the nonclinical counterparts. Moreover, the efficacy of these compounds in photodynamic inactivation of viruses was also examined. They were highly photocytotoxic against the enveloped viruses influenza A virus (H1N1) and herpes simplex virus type 1 (HSV1), but exhibited no significant cytotoxicity against the nonenveloped viruses adenovirus type 3 (Ad3) or coxsackievirus (Cox B1). The octalysine derivative also showed the highest potency with an IC₅₀ value of 0.05 nM for the two enveloped viruses.     

Synthesis of Lactosylated Piperazinyl Porphyrins and Their Biological Activity

The aim of this work is to synthesize of a new family of lactosylated piperazinly porphyrins, in which the galactoside piperazine moieties are linked to the tetra‐ and mono‐phenyl rings of tetraphenylporphyrin (TPP). 5,10,15,20‐Tetrakis[4‐(4‐lactobionylpiperazin‐1‐yl)phenyl]porphyrin (TLPP) and 5‐mono[4‐(4‐lactobionylpiperazin‐1‐yl)phenyl]‐10,15,20‐triphenylporphyrin (MLPP) have been synthesized. A detailed ¹H NMR study gave their complete structural elucidation. The UV‐Visible, mass spectra and elemental analysis are also presented. The biological activity on cancer cells and the pharmacokinetics have also been evaluated, showing a better biological activity, a very high liver to skin ratio and short retention time in tissues. It was suggested that such novel lactosylated piperazinly porphyrins, as potential hepatocyte‐selective targeting drugs, exhibit a promising activity in photodynamic therapy (PDT).     

Effect of Polyacrylamide and Dextran-Polyacrylamide Graft Polymers on Absorption and Fluorescence Spectra of Hematoporphyrin

Absorption and fluorescence spectra of hematoporphyrin (HP) solutions in distilled water and in the presence of polyacrylamide and three dextran-graft-polyacrylamide branched polymers are studied. HP is shown to interact with the studied polymers leading to the destruction of HP aggregates, which is positive for the use of porphyrin as a photosensitizer in the photodynamic therapy. For the concentrations of the polymers of 0.001%, the studied polymers demonstrated a similar impact on HP.     

Synthesis and Biological Evaluation of a Library of Glycoporphyrin Compounds

A library of glycosylated porphyrins (glycoporphyrins) was prepared and the compounds were evaluated for their photodynamic therapy (PDT) activity against the oesophageal squamous‐cell carcinoma cell line OE21 in vitro. A synthetic methodology was developed to allow incorporation of biologically active carbohydrates, including the histo‐blood‐group antigen trisaccharide Lewis^X, onto the porphyrin backbone. The effect of the carbohydrate group and substitution pattern on the PDT activity, cell uptake and subcellular localisation of the glycoporphyrin compounds is reported.     

Exploiting a Bacterial Drug‐Resistance Mechanism: A Light‐Activated Construct for the Destruction of MRSA

A cunning and dangerous plan foiled! An enzyme‐specific molecular construct exploits the overexpression of β‐lactamase in several drug‐resistant bacteria. Specific photodynamic toxicity was detected towards β‐lactam‐resistant methicillin‐resistant Staphylococcus aureus (MRSA), whereby the usual mechanism for antibiotic resistance (cleavage of the β‐lactam ring) releases the phototoxic component from the prodrug (see picture; Q=quencher).

     

Two‐Photon Absorption and the Design of Two‐Photon Dyes

Two photons are better than one : This principle applies to a wide range of applications, ranging from engineering to physiology. Recent advances in our understanding of the phenomenon of two‐photon absorption (see picture) and in the design of two‐photon dyes are rapidly increasing the scope of this field.

     

Photodynamic Activity of C70 Caged within Surface‐Cross‐Linked Liposomes

[70]Fullerene (C₇₀) encapsulated into a surface‐cross‐linked liposome, a so‐called cerasome, was prepared by an exchange reaction incorporating C₇₀?γ‐cyclodextrin complexes into lipid membranes. Fullerene exchange in a cerasome‐incorporated C₇₀ (CIC₇₀), as well as in a lipid‐membrane‐incorporated C₇₀ (LMIC₇₀), was completed within 1 min with stirring at 25 °C. CIC₇₀ was more resistant to lysis than LMIC₇₀ towards lysing agents such as surfactants. Furthermore, the photodynamic activity of CIC₇₀ in HeLa cells was similar to that of LMIC₇₀, indicating that C₇₀ can act as a photosensitizing drug (PS) without release from cerasome membranes. Thus, in contrast with general drug‐delivery systems (DDSs), which require the drug to be released from the interior of liposomes, carriers for PSs for use in photodynamic therapy (PDT) do not necessarily need to release the drug. These results indicate that DDSs with high morphological stability can increase the residence time in blood and achieves tumor‐selective drug delivery by the enhanced permeability and retention (EPR) effect.