Nov 23, 2005
Nanocarrier suits eye disease treatment
Researchers from the University of Tokyo, Osaka Prefecture University and Santen Pharmaceutical, all in Japan, have tested a nanocarrier loaded with a novel dendritic photosensitizer for use in photodynamic therapy. They found that dendrimer porphyrin encapsulated in a polyion-complex micelle was suitable for treating the eye disease exudative age-related macular degeneration.
Photodynamic therapy works by irradiating a photosensitizer with laser light, causing it to form highly reactive oxygen species. These destroy the target tissue by a process of oxidation.
"Photodynamic therapy is a promising approach for the treatment of several diseases such as solid tumours and ophthalmic diseases," Nobuhiro Nishiyama of the University of Tokyo told nanotechweb.org. "However, most photosensitizers (e.g. porphyrin, phthalocyanine) easily form aggregates due to their hydrophobic structure and large π-conjugation domains, resulting in their self-quenching, which significantly decreases the quantum yield of singlet oxygen production. Also, there are no appropriate carriers for such very hydrophobic compounds."
According to the researchers, the dendrimer porphyrin consists of a central porphyrin molecule "surrounded by the third generation of poly(benzyl ether) dendrons". This prevents the porphyrin molecules from aggregating and also enables incorporation of the dendrimer porphyrin into a polyion-complex micelle through interaction of its 32 negative charges with positively charged poly(ethylene glycol)-block-poly(L-lysine). The micelle acts as a supramolecular nanocarrier for the photosensitizer.
"The dendrimeric framework of dendrimer porphyrin sterically prevents the interaction (self-quenching) of the core photosensitizer even at extremely high concentrations," said Nishiyama. "Therefore, incorporation of dendrimer porphyrin into drug carriers does not reduce the efficiency of singlet oxygen production. This is a new biomedical application of dendrimers. Our approach fully uses [the dendrimer's] unique structure."
The researchers found that incorporating the dendrimer porphyrin into a micelle increased its toxicity under irradiation in vitro by a factor of 280. They attributed this result to efficient production of singlet oxygen from the micelle. Neither the dendrimer porphyrin or dendrimer porphyrin-loaded micelle was toxic under dark conditions.
Studies in rat eyes revealed that the micelles accumulated selectively at choroidal neovascularization sites, i.e. where new blood vessels were growing in the choroid, a membrane that contains pigment cells. Subsequent photodynamic therapy caused occlusion (or blocking-up) of the choroidal neovascularization sites. Significantly, the occlusion effect was long-lasting and the treatment did not cause skin phototoxicity. Photodynamic therapy using dendrimer porphyrin that wasn't encapsulated in a micelle did not affect the choroidal neovascularization sites.
"In clinical situations, recurrence of choroidal neovascularization is the most serious problem in the treatment of age-related macular degeneration, and most patients require repeated treatments every three months," said Nishiyama. "Our system may decrease the possibilities of such recurrence of choroidal neovascularization."
So far, the team has studied polymeric micelles as nanocarriers for drug and gene delivery, and has demonstrated their utility in cancer-targeted therapy. "Indeed, polymeric micelles incorporating anticancer drugs are currently being studied in a phase II clinical trial in Japan," said Nishiyama.
The researchers reported their work in Nano Letters.
About the author
Liz Kalaugher is editor of nanotechweb.org.