Validation of a nanoparticle-based protocol for treating cancer with the combination of chemotherapy and photodynamic therapy.
Due to Covid-restrictions, in particular for our collaborator in Italy, the project has been postponed. We therefore wish to prolong the project time. There is no change of the project plan.
1. The overall aim of this project is to validate a protocol for treating cancers by the use of a novel nanoformulation to allow the combination of chemotherapy and photodynamic therapy (PDT) in tumor models. Therefore, a chemodrug and a light-activable drug (photosensitizer) will be administered to animals using nanoparticles (NPs) made of biocompatible polymers as delivery vehicle. The therapeutic nanoformulation to be tested in human tumor (derived from HeLa cells) xenografted mice, contains three essential components: 1) the chemotherapeutic; 2) the light-activable drug; 3) an external layer of a polymer acting as targeting agent for tumor-receptor positive cancer cells. To find the optimal conditions and timing of irradiation, since no information are available about biodistribution and pharmacokinetics of our nanoformulation after i.v. injection in live animals, preliminary experiment will be dedicated to properly study photosensitizer accumulation. Afterwards, tumor treatment will be performed and the tumor growth followed up. The effects on tumor growth induced by both drugs encapsulated in NPs will be compared with those produced by the drug administered without NPs. It will be relevant to test also intra-tumoral delivery of NPs and drugs, as well as to perform some control experiments in which the animals will not subjected to PDT treatment (dark controls). To extend the principle of this tumor treatment strategy also toward drug-resistant cancer cells, a tumor model established from chemo-resistant HeLa cells (HeLa-R) is included and a murine tumor model (CT26) for evaluation of thymic immune system responses.
2. Based on experience from several other FOTS experiments, short-term small to moderate adverse effects on the animals are expected. For a minority of the animals, i.e. those who will receive the highest photochemical doses, we expect small ulcerations in light-exposed areas due to local inflammatory reactions. Our experience is that proper wound healing is relatively fast.
3. The project should be of great scientific and societal value. There is a high need for development of more effective tumor therapeutic strategies for the different types of solid cancers, and the combination of chemotherapy with PDT using NPs as drug delivery vehicles appears promising. We sincerely believe that this anti-tumor, nano-based therapy can be transferred to other types of cancer.
4. We plan to use maximum 165 mice
5. The 3R-requirements are followed by building on a number of previous experiences which indicate that 8 mice per group are sufficient to obtain statistically significant data. To be able to study the overall effects of combination therapy, and in order to better simulate the patient conditions experiments in an animal model are necessary. The animals will be placed under anaesthesia during the drug/light treatment and become carefully monitored during and after treatment.
1. The overall aim of this project is to validate a protocol for treating cancers by the use of a novel nanoformulation to allow the combination of chemotherapy and photodynamic therapy (PDT) in tumor models. Therefore, a chemodrug and a light-activable drug (photosensitizer) will be administered to animals using nanoparticles (NPs) made of biocompatible polymers as delivery vehicle. The therapeutic nanoformulation to be tested in human tumor (derived from HeLa cells) xenografted mice, contains three essential components: 1) the chemotherapeutic; 2) the light-activable drug; 3) an external layer of a polymer acting as targeting agent for tumor-receptor positive cancer cells. To find the optimal conditions and timing of irradiation, since no information are available about biodistribution and pharmacokinetics of our nanoformulation after i.v. injection in live animals, preliminary experiment will be dedicated to properly study photosensitizer accumulation. Afterwards, tumor treatment will be performed and the tumor growth followed up. The effects on tumor growth induced by both drugs encapsulated in NPs will be compared with those produced by the drug administered without NPs. It will be relevant to test also intra-tumoral delivery of NPs and drugs, as well as to perform some control experiments in which the animals will not subjected to PDT treatment (dark controls). To extend the principle of this tumor treatment strategy also toward drug-resistant cancer cells, a tumor model established from chemo-resistant HeLa cells (HeLa-R) is included and a murine tumor model (CT26) for evaluation of thymic immune system responses.
2. Based on experience from several other FOTS experiments, short-term small to moderate adverse effects on the animals are expected. For a minority of the animals, i.e. those who will receive the highest photochemical doses, we expect small ulcerations in light-exposed areas due to local inflammatory reactions. Our experience is that proper wound healing is relatively fast.
3. The project should be of great scientific and societal value. There is a high need for development of more effective tumor therapeutic strategies for the different types of solid cancers, and the combination of chemotherapy with PDT using NPs as drug delivery vehicles appears promising. We sincerely believe that this anti-tumor, nano-based therapy can be transferred to other types of cancer.
4. We plan to use maximum 165 mice
5. The 3R-requirements are followed by building on a number of previous experiences which indicate that 8 mice per group are sufficient to obtain statistically significant data. To be able to study the overall effects of combination therapy, and in order to better simulate the patient conditions experiments in an animal model are necessary. The animals will be placed under anaesthesia during the drug/light treatment and become carefully monitored during and after treatment.