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Novel precision technological platforms to promote non-invasive early diagnosis, eradication and prevention of cancer relapse: proof of concept in the bladder carcinoma.

Periodic Reporting for period 2 - EDIT (Novel precision technological platforms to promote non-invasive early diagnosis, eradicationand prevention of cancer relapse: proof of concept in the bladder carcinoma.)

Reporting period: 2019-10-01 to 2021-03-31

The unmet clinical needs in the management of bladder cancer (BCa) are the prevention of tumor onset/relapse/progression, and therapy of the aggressive bladder carcinoma in situ (Cis).
EDIT will exploit the structural and mechanical properties of the bladder extracellular matrix (ECM) as a unique biomarker of the early onset/progression/relapse of carcinoma, through engineered gold nanorods (GNRs) used as intravesical photoacoustic antennas targeted at the neoplastic ECM and consequently generating an ad hoc visualization platform. GNRs will be utilized as heat-releasing effectors for targeted cancer photothermal therapy. EDIT is designed to detect pre-neoplastic area and eradication of local areas at few cells resolution.
Objectives of EDIT are:
1) Early prognosis based on the recognition of fibrillary collagen rich matrix, providing novel functionalized nanoparticles to be employed as intravesical source of ultrasound through photoacoustic effect.
2) Early eradication will exploit the locally delivered nanoparticles able to thermal ablating Cis cells upon near-infrared laser irradiation.
3) Novel biomarkers that identify pre-conditioning of the ECM, and new ligands for expanding the armamentarium for targeted delivery of GNRs.
EDIT pursues the development of novel technological platforms for the early detection of neoplastic modifications and early treatment of bladder cancer. Steps toward the delivery of targeted therapy is searching for makers of neoplastic modifications associated to non-muscle invasive bladder carcinoma. EDIT has identified markers that are shared between human and preclinical models of non-muscle invasive bladder carcinoma, as well a protocol for measuring the mechanical properties of the tissue. Being a hollow organ, any treatment instilled into the bladder is going to be localized to the bottom of the organ; EDIT has identified a non-invasive strategy for distributing the intravesical therapy on the entire urothelium. Ongoing studies are aimed to demonstrate the selective localization of the targeted therapy, showing the recognition of small bladder lesions irrespectively of their localization.
Nanostructures play a key role in the field of cancer treatment, acting as contrast agents for diagnostics and as therapeutic factors. The project developed metallic Gold Nanorods labelled with different active agents, tested by photoacoustic techniques for the diagnostics, and laser beams for the therapeutic exploitation, since they can act as “nanoheater” for thermoablation of cancerous cells. Two systems are created, GNRs@Chit-Dec and GNRs@Chit-Lig, by chemical conjugation with, respectively, ECM decoys and cyclic peptides with different integrin selectivity (Lig). A large evaluation of the systems has been performed in terms of stability, diagnostic performances, binding ability and attitude to detection and photo-thermal ablation.
3D model of the mouse bladder based on MRI scans was prepared. Using this model, the treatment using gold nanorods-assisted photothermal therapy (GNR-PTT) for cases where the tumour is located at different sections of the bladder, instead of the surface closest to the skin surface, was investigated. The treatment using GNR-PTT for cases when the thickness of the skin surface above the bladder becomes very large was simulated. This analysis showed that the method of externally irradiating the bladder tumour in the case of human patients is not feasible.
Imaging platforms by mathematical models were also developed: a method to automatically identify pixels from photoacoustic imaging with different tissue characteristics was developed and implemented. Different classification methods were tested to find the best performing models for datasets grouped by time since the treatment. The software has been tested and refined based on 56 orthotopic datasets. There is already drafted a validation protocol, where validation activities will start during the 3rd reporting period.
Strategies for the identification of pre-neoplastic regions, based on the early detection of modified tissue properties, in particular stiffness and ultrastructure were designed, based on molecules with high affinity and specificity to the fibrillary collagen conjugated to the GNRs. Ultrastructural characterization showed that modification of the stroma and of the mechanical property occurs at an earlier stage of tumor invasion.
Early diagnosis was demonstrated in the preclinical model of orthotopic bladder cancer. In the preclinical model several experimental conditions were optimized in order i) to avoid reshaping of targeted gold nanorods under pulsed laser light and ii) to avoid settling of the gold nanorods to the bottom of the bladder. In the preclinical model the optimized strategy allowed the use of photoacousting imaging for the early detection of bladder cancer, 3-5 days before the tumor was visible by ultrasound imaging. This strategy allowed early detection of bladder cancer in every region of the bladder and it was reproducible in 1 year time frame using different batches of targeted gold nanorods.
The consortium published 13 papers in peer reviewed journals with open access and participated in 15 conferences workshops and seminars
EDIT will pursue a three-fold transformational impact on Technology, Society and Economy.
Technology: EDIT will develop and provide radical innovation and impact in the management of solid tumors with a proof of concept in BCa by providing a new clinical platform based on a sophisticated imaging-guided-therapy. Increased spatial resolution and efficacy of therapy through non-invasive approach will offer unmet prognostic, diagnostic and therapeutic opportunities against BCa.
Society: Considering that increased stiffness of ECM is also shared by tumors at breast, colon and prostate the novel and non-invasive approach of the EDIT platform could also be applied in these clinical and therapeutic applications, as well as visualization of deep anatomical targets or delicate organs such as brain, having a profound impact on the diagnosis, localized surgery and thermo-ablation of different malignancies.
Economic: By improving diagnosis and treatment the outcomes of EDIT will reduce the costs of the BCa management. Structural and mechanical modification of the ECM is a common denominator of different solid tumors; broading the range of EDIT applications will further contribute to the spread and lower costs of the technology, and increasing indirect jobs in the relevant industries, academies and in parallel in the indirect jobs.
The generated know-how will have deep impact at the society level and in related scientific fields, fostering i) combinatoric chemistry for engineering of nanoparticles adapting to specific microenvironments, ii) bladder cancer research, iii) mathematical modelling and iv) development of visualization algorithms.
EDIT project concept