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Novel Nanoparticulate Photosensitizers for Daylight-driven Activation

Abstract

Innovative Hybrid Nanoparticles Generating Singlet-Oxygen for Efficient Photodynamic Therapy (PDT):
These two novel types of nanomaterials and efficient daylight-activated photocatalysts are activated by blue, green, and even red light.
They exhibit high photostability and excellent uptake into cells, while the systemic toxicity is low. The concept offers new approaches to the treatment of near-surface tumors as well as for inter- or post-surgery killing of individual remaining cancer cells.

Background

Photocatalysts are highly relevant for a wide range of applications, such as selective oxidation (e.g. in organic synthesis), photocatalytic degradation of organic mole­cules and germs (e.g. for water purification), or photo­dynamic therapy (e.g. for tumor therapy). Especially, daylight-activated photocatalysts are highly promising due to the ubiquitious availability of daylight and its less harmful interaction with tissue.

Problem

In general, two classes of photosensitizers are widely discussed: molecular photosensitizers (most often por­phyrine-based), and inorganic nanoparticles, including various metal oxides (e.g. TiO2, ZnO, BiVO4, Ag3PO4). Molecular photosensitizers are also often encapsulated in an inorganic matrix (e.g. SiO2, Fe2O3). These types of photosensitizers exhibit specific disadvantages, such as the presence of harmful and/or expensive metals, low photostability, limited cell uptake, high systemic toxicity, heavy agglomeration under physiological conditions due to strong hydrophobic interaction (e.g. porphyrins) or low colloidal stability (e.g. nanoparticles). Inorganic oxide nanoparticles often suffer from UV-light activation, having a limited penetration depth and being harmful to cells and tissue.
All in a nutshell, there is still a strong need for agents with further optimized photophysical characteristics and depth of light penetration.

Solution

At the Karlsruher Institut für Technologie (KIT) novel inor­ganic-organic hybrid nanoparticles (IOH-NPs) such as La43+ [TPPS4]34- and Gd43+ [AlPCS4]34- (AlPCS4: alu­minium(III) chlorido phthalocyanine tetrasulfonate; TPPS4: tetraphenylporphine sulfonate) as well as inorganic nano­particles such as β-SnWO4 and β-SnMoO4 were devel­oped.
They can be activated by blue to green and even red light. Both systems were also successfully tested in vitro (e.g. HepG2, HeLa cells) and in vivo (e.g. mice, zebrafish). Gd43+[AlPCS4]34- (in suspension) significantly outperforms the clinically approved H4AlPCS4 (in solution) in terms of photostability, 1O2 generation, phototoxic effect in cells as well as suppression of microcapillary networks and vas­cular cord formation.
Due to the fluorescence of AlPCS4 and the magnetism of Gd3+, Gd43+[AlPCS4]34- is suitable for multimodal imaging, including optical imaging/OI and magnetic resonance imaging/MRI.
β-SnWO4 and β-MoWO4 are especially characterized by excellent phtostability. In contrast to the IOH-NPs, β-SnWO4 and β-MoWO4 are activated by blue light, which means a smaller penetration depth into the tissue.

Phototoxic effect of ß-SnWO4 nanoparticles: Photos of HepG2 cells before and after exposure to daylight (top), MTT assays with HepG2 cells after cultivation with nanoparticles with storage in darkness, acute Phototoxicity after 2 h and low long-term toxicity after 72 h.
Phototoxic effect of ß-SnWO4 nanoparticles: Photos of HepG2 cells before and after exposure to daylight (top), MTT assays with HepG2 cells after cultivation with nanoparticles with storage in darkness, acute Phototoxicity after 2 h and low long-term toxicity after 72 h.
Schematic illustration of Gd43+[AlPCS4]34- IOH-NPs with photochemical 1O2 production and phototoxicity under red-light illumination of the nanoparticles (green bars) in comparision to the clinically approved H4AlPCS4 (black bars).

Advantages

for β-SnWO4 and β-MoWO

  • Activated by blue light
  • High chemical stability
  • Excellent photostability

for IOH-NPs

  • Strong 1O2 production upon green or red-light irradiation with quantum yields similar to the conventional molecules in solution
  • Contentof photocatalytic active porphyrins/phthalocyanine >80%
  • Gd43+[AlPCS4]34- with LD50 < 5x10-6 M
  • Excellent cell membrane permeability
  • High biocompatibility
  • Low systemic toxicity
  • Lower threshold for approval
  • No inhibition of endothelial cell alignment and cord formation in darkness
  • Multimodal imaging possible
  • Simple, straightforward aqueous synthesis of the IOH-NPs

Application

Here, we present two concepts and novel types of nano­materials as efficient daylight-activated photocatalysts that are activated by blue, green, and even red light. The photocatalysts exhibit high photostability and excellent uptake into cells. Whereas they show high phototoxicity the systemic toxicity is low. Aiming at medicine, specific interest can be related not only to the treatment of near-surface tumors but also to inter- or post-surgery killing of individual cancer cells remaining after extraction of the solid primary tumor.

Find out more

1)     Saline Hybrid Nanoparticles with Phthalocyanine and Tetraphenylporphine Anions Showing Efficient Sin­glet-Oxygen Production and Photocatalysis; Chem. Commun. 2018, 54, 1245–1248.

2)     Gd43+ [AlPCS4]34- Nanoagent Generating 1O2 for Photo­dynamic Therapy; Adv. Funct. Mater. 2018.
doi.org/10.1002/adfm.201801074

3)     Tin Tungstate Nanoparticles: A Photosensitizer for Photodynamic Tumor Therapy.
ACS Nano. 2016 Mar 22; 10(3):3149-5, Epub 2016 Feb 25.
doi: 10.1021/acsnano.5b03060

4)     In-vitro Fluorescence and Phototoxicity of ß-SnWO4 Nanoparticles, Chem. Commun. 2014, 50, 6600–6603

Exposé
Contact
Dr. Frank Schlotter
TLB GmbH
Ettlinger Straße 25
76137 Karlsruhe | Germany
Phone +49 721-79004-0
schlotter(at)tlb.de | www.tlb.de
Development Status
Late basic research / TRL2
Patent Situation
DE 502011006460.8 und DE 502012002803.5 granted
FR (EP 2614037 B1 und EP 2680968 B1) granted
GB (EP 2614037 A1 und EP 2680968 B1) granted
EP 2 680 968 B1 und EP 2614037 A1 granted
Reference ID
10/107TLB
Service
TLB GmbH manages inventions until they are marketable and offers companies opportunities for license and col­laboration agreements.