bobstar 2008-09-20 11:04
Nanoparticles speed PDT drug delivery
Sep 16, 2008
A technique that speeds the delivery of light-sensitizing drugs for photodynamic therapy (PDT) from days to hours has been reported by researchers at Case Western Reserve University (Cleveland, OH). PDT - an alternative to conventional cancer treatments - involves the injection of a photosensitizing agent that's transported to the tumour via the circulatory system. Upon irradiation of the tumour with an appropriate wavelength of light, the agent produces reactive oxygen species that kill the malignant cells.
PDT provides the opportunity for highly targeted tumour damage and has been used to treat diseases including skin, lung and head-and-neck cancers. However, one major drawback to date has been the efficiency of the drug delivery process. Typically, patients must wait a few days after injection for the photosensitizer to be transported to and accumulate in the tumour site. During this time, they must avoid exposure to sunlight and other bright lights.
The longer the drug resides outside of the tumour site, the greater the risk of undesirable side-effects. Furthermore, the significant waiting period intrudes on patients seeking to live a "normal" lifestyle. These limitations are ameliorated with speedier photosensitizer transport to the tumour site.
Case Western graduate student Yu Cheng and colleagues devised such a delivery system for the photosensitizing drug Pc 4 (a phthalocyanine compound) using nanoparticles as carriers (J. Am. Chem. Soc. 130 10643).
Secure delivery
In the past, photosensitizers have been injected in pure form. However, safe and efficient in vivo transport of the drug to the tumour is not a trivial process. Unprotected in their pure form, the photosensitizers are attacked and removed from circulation by phagocytic cells produced by the immune system. This reduces drug yield at the location where it is needed: the tumour site. Furthermore, unadulterated Pc 4 is insoluble in aqueous physiologic conditions - a pretty fundamental drawback for drug delivery.
The key to overcoming these limitations is to incorporate the drug onto a water-soluble carrier that is not a target for phagocytes. The researchers did just this - using 5 nm-diameter gold nanoparticles covered with coils of polyethylene glycol (PEG) ligands. When attached to molecules of Pc 4, the resultant particles act as both carrier and protector for the photosensitizer.
Transport of the conjugate nanoparticle was tested in tumour-bearing mice by examining the Pc 4 fluorescence. Fluorescence images were taken of control mice receiving Pc 4 alone and of mice receiving Pc 4 attached to the PEG-coated nanoparticles. Pc 4 was observed in the diseased area within minutes. Two hours post-injection, a dramatic difference was seen: while no drug was observed anywhere in the body (tumour included) in the pure Pc 4 case, strong uptake was noted in the composite delivery scheme.
Fluorescence images of the nanoparticle-delivered photosensitizer revealed the release of Pc 4 from its carrier and its accumulation at the tumour site. This occurs as a result of leaky vasculature around the tumour assisting uptake, and a lack of effective lympatic drainage preventing Pc 4 losses.
Treatment of the mice using a 672 nm diode laser resulted in no side-effects. The tumours became necrotic within one week of treatment and then began to shrink, demonstrating treatment efficacy.
"The system is very modular, we can change the size and shape of the gold-core nanoparticles and we can change the functionality of the PEG ligands," explained co-author Clemens Burda. "This should lead to optimization of the drug targeting and therapy. If our research is successful, other researchers might adapt this drug delivery system to other diseases and applications."
Studies in humans are some time away. Although the separate components are already approved, the composite particles still require approval from the US Food and Drug Administration.