Transfer of Knowledge
 
WP1First key objective – the synthesis of a NIRF dye conjugated to a peptide that is targeted towards the tumour.
Secondments

TAG > UMG-GOE
GAMMA > LUMC
LUMC > GAMMA
UMG-GOE > PERC
ARA > UMG-GOE
Provided Knowledge

GAMMA: handling of mini camera system prototypes for the optimization of image acquisition of 177Lu and 111In.
LUMC: expertise in small animal optical imaging and intraoperative image-guided surgery.
ARA: development and testing of the (ZW800-1-cRGD-TCO) construct
TAG: To determine that the inverse-electron-demand Diels-Alder (inv-DA) reaction can improve tumour radioimmunoimaging by using TCO click chemistry.
UMG-GOE: expertise in validating NIRF probes in vitro and preclinically.

Concrete example of knowledge return:
a) LUMC and UMG-GOE will benefit from knowledge derived from using a targeted probe for many carcinomas in different surgical situations,
b) TAG will benefit from having a new target for its proprietary TCO click-tag chemistry.

WP2Second key objective – to deliver a novel clinical optoacoustic handheld camera to detect the fluorescence probe.
Secondments

TUM > RAY
RAY > TUM
LUMC > ITHERA
ITHERA > LUMC
AMOLF > ITHERA
LUMC > ITHERA
PERC > UMG-GOE
PERC > TUM
RAY > LUMC
LUMC > MKT
AMOLF > MKT
RAY > UMG-GOE
LUMC > MKT
PERC > UMG-GOE
Provided Knowledge

TUM: expertise in development of preclinical and clinical handheld optoacoustic (MSOT) and fluorescence imaging systems for intraoperative image-guided surgery.
LUMC: expertise in small animal optical imaging and surgery.
RAY: expertise in optical technology and algorithms to support the optimization of the MSOT detector design for handheld use. Integration of micro-fibre illuminators and light-guiding micro-elements into the instrument.
ITHERA: expertise in MSOT technology for the development of the intraoperative MSOT prototype (smaller transducer array geometry, miniaturized imaging probes)
AMOLF: expertise in MSI analysis in order to profile proteins at the tumour-healthy tissue interface. Sections of tumour margins will be prepared from animals and studied longitudinally.
UMG-GOE: Expertise in real-time histopathological examination of tissues and development of biological models
PERC: preparing the xenotransplant cancer models and cell lines.
MKT: preparation of optical biopsies facilitated by optical fibres to visualise deep lying and difficult tissues giving information at the subcellular and cellular levels of an anesthetised small animal.

Concrete examples of knowledge return:
a) Knowledge of various strategies for labelling of cells in order to image under different modalities. This will mean that PERC can make a larger repertoire of different kits to the market,
b) The TUM researcher will be trained in the development and quality control aspects of in vivo assays but will also assist in the training of the two less experienced researchers from an academic environment recruited by PERC.

WP3Third key objective: to validate the probe/target combination across the subcellular, cellular, endoscopic and macroscopic levels with state-of-art technologies, both in vivo and in vitro, in conjunction with the optoacoustic camera system.
Secondments

MKT > AMOLF
AMOLF > MKT
PERC > UMG-GOE
UMG-GOE > PERC
LUMC > MKT
MKT > LUMC
TUM > PERC
PERC > TUM
TUM > RAY
UMG-GOE > PERC
PERC > TUM
UMG-GOE > TAG
UMG-GOE > ARA
ARA > UMG-GOE
UMG-GOE>GAMMA
LUMC > GAMMA
GAMMA > TUM
RAY > UMG-GOE (M24)
PERC > TUM (M24)
LUMC > GAMMA
ARA > UMG-GOE
TUM > PERC
Provided Knowledge

MKT: expertise in proprietary fibred microprobes to support the validation of the (ZW-800-1-cRGD-TCO) construct that is bound in-vivo by use of confocal laser endomicroscopy.
AMOLF: expertise in MSI of biological surfaces to study the binding of the cRGD peptide to its target.
PERC: expertise in in-vitro bioassay development in the characterisation of the binding specificity and sensitivity of (ZW800-1-cRGD-TCO) construct.
UMG-GOE: expertise in high resolution CT, SPECT and non invasive optical imaging and advanced fluorescence microscopy to support the macroscopic visualisation of the (ZW800-1-cRGD-TCO) construct within the tumour margin. Preclinical in-vitro and in-vivo validation of the probe for image-guided surgery.
TUM: expertise in high-resolution in vivo microscopic-macroscopic MSOT analysis to determine the minimum tumour margin distance.
RAY: development of new software algorithms for MSOT.
TAG: expertise in click chemistry and expertise to develop and evaluate 177Lu/111In-labelled DOTA-tetrazine probes for coupling to the TCO click-tag.
ARA: Expertise in in-vitro bioassays for correlating resection margin distances with relapse
LUMC: expertise in optical technology to support the visualisation of the (ZW800-1-cRGD-TCO) construct within the tumour margin during surgery at different tumour margin distances.

Concrete examples of knowledge return:
a) MKT will benefit from being able to map out aberrant pathways by cross referencing MSI and in vivo data,
b) LUMC will benefit from being able to image in vivo T-cells and especially in relation to their immunotherapy programs of cancer vaccines,
c) GAMMA will benefit from the knowledge of camera systems used for fluorescence imaging and how the process can be used for hybrid probes on integrated fluorescence/radionuclide detection systems.

WP4Fourth key objective: to develop the probe further by conjugating a radionuclide entity to the click-tag molecule for postoperative radiotherapy.
Secondments

TECO > AMOLF
GAMMA > LUMC
LUMC > GAMMA
TECO > LUMC
LUMC > TECO
UMG-GOE > MKT
TAG > UMG-GOE
Provided Knowledge

UMG-GOE: expertise in small animal tumour models in combination with optical and SPECT imaging.
TECO: radionuclide and PET/SPECT expertise.
GAMMA - expertise in digital autoradiography systems for tissue slice imaging to support postoperative radiotherapy studies.
LUMC: expertise in small animal imaging and surgery to support: a) whole-body radionuclide distribution studies and b) analysis of the molecular signature of the tumour margin and its surrounding area.
TAG: chemistry expertise to develop and evaluate 177Lu/111In-labelled DOTA-tetrazine probes for coupling to the TCO tag.

Concrete example of knowledge return:
a) TAG will benefit from new information of pharmacokinetics of hybrid probes in the context of having the click-tag,
b) LUMC and UMG-GOE will benefit from being able to utilise postoperative molecular radiotherapy as standard-of-care,
c) MKT will benefit from having a new application for its Cellvizio LAB system to support further sales of its systems and d) in the near future, we expect an increased examination of combination treatment strategies, where molecular radiotherapy in current conventional cancer treatment may be further defined within nuclear medicine.