Exogenous macrophages as radionuclide delivery vectors for radiotherapy as adjuvant therapy after photochemical internalization (PCI) of solid tumours

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Photochemical internalization (PCI) is a technology for cytosolic delivery of drugs based on the principles of photodynamic therapy (PDT). PDT is a treatment that uses special drugs, called photosensitizers, along with light to kill tumour cells. The PCI technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces a release of a number of drugs. Efficacy of PCI with bleomycin has been documented in several preclinical studies and clinical trials of solid tumors. We have also observed that PDT alone causes necrosis in the tumour center. However, after PDT viable tumour cells have been observed in the peripheral zone of the tumour, while after PCI much less viable cells in the peripheral zone of the tumour can be detected. The sparing of the tumour cells in the peripheral rim is poorly understood. However, even few viable tumour cells remain they may be responsible for tumour recurrence after PCI treatment. The removal of such cells could improve the outcome of PCI. This research project is focused on the development and preclinical testing of novel targeted treatment modality used as adjuvant therapy after PCI against viable tumour cells in tumour periphery. PDT not only reduces tumour burden but also induce inflammation and the recruitment of the neutrophils and macrophages to the inflamed tumour site within a short time. The aim of this project is to kill these viable tumour cells with targeted radionuclide therapy using radiopharmaceuticals emitting alpha/beta particles delivered by exogenous macrophages.
We are going to carry out our experiments causing minimal pain and distress to the animals by monitoring them daily, by selecting experimental endpoints that precede the onset of clinical illness, by early recognition of humane endpoints, and by judicious use of anaesthetics and analgesics.
We need to study these processes in a suitable in vivo system to design and implement better therapeutic strategies of solid tumours.
The information obtained from these experiments is important part of testing of new treatment modalities. No alternative biological systems can be found to obtain such information. We are requesting 330 Hsd:Athymic Nude-Foxn1nu female mice.
Drug-based cancer treatment is frequently limited by unacceptable toxicity and the development of multidrug resistance. PCI delivers drugs in that way which is not affected by most common mechanisms of cancer drug resistance, and targeted drug delivery allows the reduction of drug doses and, consequently, toxicity. PCI is a future treatment option for cancers resistant to other therapies. However, it must be improved in order to avoid tumour recurrence.
Biodistribution of macrophages and therapeutic efficacy of PCI and new radiopharmaceuticals will be tested in mice. Three different non-invasive diagnostic methods (magnetic resonance imaging, IVIS fluorescent imaging and gamma scintigraphic imaging) in the same animal will be used to obtain the same parameters to decrease the number of animals. Numbers of mice required/group (sample size) was determined by own previous experience, earlier experiments and statistical calculations in order to achieve statistical significance.