PAMAM dendrimers as carrier systems for PDT drugs

Photodynamic therapy (PDT) is a treatment modality for small localized tumours accessible to light. Its principle is based on the photodynamic effect: light absorbed by a given molecule (the sensitizer) produces an excited state molecule which then transfers its energy of excitation to molecular oxygen, resulting in the production of cytotoxic species. One of them is molecular oxygen in its first excited electronic state, the so-called singlet oxygen (1O2). There is common agreement that 1O2 is the key agent in PDT. This therapeutic modality has a clinical reality since several photosensitizers obtained an approval for the treatment of various types of cancer. One major problem of photodynamic therapy is the moderate selectivity of the photosensitizer to the cancer cells, which requires the use of high photosensitizer concentrations in clinical protocols, causing serious side effects. To overcome these problems, the use of vectors for passive tumour targeting of PS was considered. Such passive targeting exploits the so called EPR effect (enhanced permeability and retention). These vectors on one hand are not filtered out by the kidneys if they are big enough and therefore remain circulating in the blood stream for a long time. On the other hand they can leave the circulation system only at the highly leaky blood vessels which are found in most rapidly growing solid tumors. Although also limited by a certain heterogeneity, the EPR effect represents a more universal and cost-effective treatment approach for solid tumors [1]. Today the basic research in PDT is mainly focused on the development of carrier systems for targeting of tumor tissue, e.g. see review [2]. The Nancy group was particularly interested in the vectorization by photosensitizer loaded liposomes. Our work [3-5] and those of other teams [6,7] showed that despite some interesting pharmacokinetic properties (best ratio tumour/normal tissue, faster clearance) overall photodynamic efficacy had little or no improvement. Ongoing work in the laboratory shows that the photosensitizer is rapidly leached from the liposome before it reaches its target. Moreover, it exists within the liposome an extremely important local concentration which can be detrimental to the photodynamic efficiency. Vectors allowing both to avoid the fast release of relevant molecules and their high local concentration have emerged in recent years, these are dendrimers. The Berlin group already has some experience with DAB dendrimers as carriers for the photosensitizer pheophorbide a [8-10]. This research showed the principal possible use of such molecules as carrier systems for PDT drugs. Finally their use could not be introduced into pharmaceutical clinical studies due to their very low photostability [8]. However the experience in investigation of the photophysical properties and photosensitizing activity in vitro of photosensitizer-DAB dendrimer systems will be useful for this project. Dendrimers are regular hyperbranched macromolecules a few nanometers in diameter (2-10 nm) and which may have on their surface different functional groups. Because of their low cytotoxicity and their solubility in water polyamidoamines or “PAMAM”-dendrimers appear as a very attractive class of biocompatible nanovectors for drug targeting in cells and tissues [11- 13]. Thanks to the many functional groups on the periphery of the dendrimer, it is easy to graft therapeutic molecules such as photosensitizers, stealth elements (polyethylene glycol), or targeting moieties (aptamers, antibodies, etc…) while controlling the size and lipophilicity of the carrier. All this will allow monitoring and optimizing cellular uptake, biodistribution and pharmacokinetics of the molecule of interest.
Photodynamic therapy (PDT) is a treatment modality for small localized tumours accessible to light. Its principle is based on the photodynamic effect: light absorbed by a given molecule (the sensitizer) produces an excited state molecule which then transfers its energy of excitation to molecular oxygen, resulting in the production of cytotoxic species. One of them is molecular oxygen in its first excited electronic state, the so-called singlet oxygen (1O2). There is common agreement that 1O2 is the key agent in PDT. This therapeutic modality has a clinical reality since several photosensitizers obtained an approval for the treatment of various types of cancer. One major problem of photodynamic therapy is the moderate selectivity of the photosensitizer to the cancer cells, which requires the use of high photosensitizer concentrations in clinical protocols, causing serious side effects. To overcome these problems, the use of vectors for passive tumour targeting of PS was considered. Such passive targeting exploits the so called EPR effect (enhanced permeability and retention). These vectors on one hand are not filtered out by the kidneys if they are big enough and therefore remain circulating in the blood stream for a long time. On the other hand they can leave the circulation system only at the highly leaky blood vessels which are found in most rapidly growing solid tumors. Although also limited by a certain heterogeneity, the EPR effect represents a more universal and cost-effective treatment approach for solid tumors [1]. Today the basic research in PDT is mainly focused on the development of carrier systems for targeting of tumor tissue, e.g. see review [2]. The Nancy group was particularly interested in the vectorization by photosensitizer loaded liposomes. Our work [3-5] and those of other teams [6,7] showed that despite some interesting pharmacokinetic properties (best ratio tumour/normal tissue, faster clearance) overall photodynamic efficacy had little or no improvement. Ongoing work in the laboratory shows that the photosensitizer is rapidly leached from the liposome before it reaches its target. Moreover, it exists within the liposome an extremely important local concentration which can be detrimental to the photodynamic efficiency. Vectors allowing both to avoid the fast release of relevant molecules and their high local concentration have emerged in recent years, these are dendrimers. The Berlin group already has some experience with DAB dendrimers as carriers for the photosensitizer pheophorbide a [8-10]. This research showed the principal possible use of such molecules as carrier systems for PDT drugs. Finally their use could not be introduced into pharmaceutical clinical studies due to their very low photostability [8]. However the experience in investigation of the photophysical properties and photosensitizing activity in vitro of photosensitizer-DAB dendrimer systems will be useful for this project. Dendrimers are regular hyperbranched macromolecules a few nanometers in diameter (2-10 nm) and which may have on their surface different functional groups. Because of their low cytotoxicity and their solubility in water polyamidoamines or “PAMAM”-dendrimers appear as a very attractive class of biocompatible nanovectors for drug targeting in cells and tissues [11- 13]. Thanks to the many functional groups on the periphery of the dendrimer, it is easy to graft therapeutic molecules such as photosensitizers, stealth elements (polyethylene glycol), or targeting moieties (aptamers, antibodies, etc…) while controlling the size and lipophilicity of the carrier. All this will allow monitoring and optimizing cellular uptake, biodistribution and pharmacokinetics of the molecule of interest.