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Mechanical Targeting as an Integrative Approach for Personalized Nanomedicine

Periodic Reporting for period 4 - MTrix (Mechanical Targeting as an Integrative Approach for Personalized Nanomedicine)

Reporting period: 2022-06-01 to 2023-05-31

Cancer requires precise drug delivery for effective treatment. Targeted drug delivery, achieved by concentrating medications at the tumor site, can enhance treatment efficiency while minimizing side effects. Biodegradable nanoparticles loaded with drugs offer an effective method for localized treatment. These nanoparticles are typically guided by surface molecules that bind to specific proteins near tumors. However, the dynamic nature of tumors limits the efficacy of this molecular targeting.
In the MTrix project, we propose an innovative approach. By harnessing mechanical interactions between drug carriers and cells, we can enhance drug targeting without relying on surface-affinity molecules. Many cancers have deformable cells, which forms the basis of our hypothesis. We suggest designing drug vehicles that exclusively interact with these deformable malignant cells, requiring shape changes for internalization. Our "Mechanical Targeting" method has been validated through a novel physical model, demonstrating how cell deformability governs drug carrier absorption.
Our theoretical model's experimental validation shows how particle characteristics and cell deformability affect particle uptake by cancer cells. We've introduced the groundbreaking "Triangular Correlation," linking cancer malignancy, cell deformability, and phagocytosis (Sci Adv. 2019). This correlation offers a tool for designing drug delivery systems, potentially enabling personalized nanomedicine. This approach could use tests on a patient's cells to tailor treatment strategies. MTrix improves specific and selective drug delivery, reducing chemotherapy toxicity, enhancing effectiveness, and impacting oncology healthcare burden.
The main issue we addressed in this project is to study whether there is an association between cell biomechanics and cell functions that are relevant for oncology. For the first time we have established a Triangular Correlation (TrC) between cancer aggressiveness, cell uptake capability and cell deformability (Sci Adv 2020). The impact of finding this correlation is the fact that we can design particles with specific physical properties that can selectively taken up by aggressive cancer cells and not low malignant ones. This uptake capacity becomes a lead consideration for rational design of selective drug delivery systems. We have established a detailed theoretical model that can predict which properties should be included in drug carrier in order to maximize targeting to cancer cells, and at the same type consider practical clinical consideration of human physiology. One of the important conclusions were that in some cases we can use for example very flexible particles instead of very big ones, and still achieve the same value of cell uptake. Flexible particles often serve as a more practical vehicle for drugs. Another important basic finding was the identification of genetic and epigenetic patterns that were unique for the more “phagocytic” cancer cells. The phagocytic subsets of cells were generated by selection with FACS sorter over several sorting cycles. These findings suggest that tendency of phagocytosis. As well as deformability of cells, are imprinted properties that are preserved over generation. The overall outcomes of the project open up new directions in rational drug delivery based on physical parameters that can potentially have impact beyond oncology. From the technological perspective, an important breakthrough was done in the field of microfluidic fabrications using 3D printing. This technology enables versatile designs of biocompatible organ on chip platforms, a tool that is currently the basis of start-up company named Pre-Cure, aiming to provide a tool for precision therapy in cancer.
We have provided couple of notions and advances beyond the stat of the art in the field. First, we have established for the first time the concept of mechanical targeting for drug delivery in cancer, and this can be further expended to a novel concept of using barcoded particles for predictive diagnostics (the core of my current effort). Another novel advance is the establishment of a physical model that can predict chance for particle uptake based on cell stiffness. This can have a huge impact in the field of drug delivery. Finally, our novel technology for 3D printed microfluidics open up new possibilities in the field of organ on a chip, and a basis for start-up company that was recently started (pre-cure). Overall, our project yielded many publications and patients and many of the technologies will be further elaborated in order to be translated clinically.
Figure 1: Cancer skin cells present an enhanced uptake compared with non-cancer skin cells, and the
Figure 2: The more metastatic are the cells, the higher is their micro-particle uptake. (A-B) Primar