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Mechanical Targeting as an Integrative Approach for Personalized Nanomedicine

Periodic Reporting for period 2 - MTrix (Mechanical Targeting as an Integrative Approach for Personalized Nanomedicine)

Reporting period: 2019-06-01 to 2020-11-30

Cancer chemotherapies often have poor selectivity, thus causing severe side effects due to undesired systemic exposure. Targeting of drug action is an important goal as it reduces non-desired side effects, allowing the use of higher doses that can potentially provide more effective cure. Present research largely focuses on allocating highly specific molecules as targets of cancer therapy. However, the enormous heterogeneity and dynamic nature of tumors makes it extremely challenging to identify universal target molecules. In the novel approach proposed here we hypothesize that mechanical based interactions between drug carriers and cells can largely promote drug targeting and selectivity. In many cancers, it is well-established that the flexibility and deformability of the cells are correlated with their metastatic potential. We therefore hypothesize that cancer cells, but not normal cells, would be able to engulf and uptake particles whose internalization requires massive shape change. This notion motivated our vision of a “Mechanical targeting” (MT) method, in which intrinsic deformability of cells will control the specificity of drug carrier uptake. The rationale of the proposed study is that by considering physical parameters of cells, the mechanical properties of drug delivery systems (DDS) can be tuned to achieve selective uptake. We thus propose to develop tools for the rational design of DDS for personalized nanomedicine that will apply simple tests performed on a patient’s own cells for optimized treatments.
A major progress of our work is that we have identified a Triangular Correlation (TrC) between cancer aggressiveness, cell uptake capability and cell deformability (submitted recently to a high level journal after revision). An important consequence of this correlation is that differential particle uptake capacity can be considered in rational design of selective drug delivery systems. Cell uptake assessments can provide a simple, robust and accurate diagnostic method and add mechanical knowledge to the existing clinical tools. Moreover, finding specific cell uptake features may provide a mean to rationally design individual drug carriers with higher specificity. We found that the uptake of inert sub-micron and micro-beads was massively higher in cancer cells compared with non-cancerous cells. Moreover, cells with a higher malignancy potential had greater uptake capacity. We further sorted two types of human cancer cells into four sub-populations, solely based on their phagocytic capacity. The more phagocytic subpopulations showed elevated phenotypes of cancer aggressiveness ex vivo and in vivo. The uptake potential was found to be an imprinted feature preserved genetically and enriched over the sorting cycles. Importantly, enhanced phagocytic ability and elevated aggressiveness phenotypes were correlated with greater cell deformability, providing the mechanical link of the TrC. A computational model supported the notion that the uptake capacity can be a marker for malignancy mediated by cell mechanics. In addition we have successfully developed a microfluidic device for the formation of rigid nano and micro particles of varying size, and we are in the process of developing a microfluidic based platform for controlling also the particle rigidity.
We succeed to fabricate 3D printed molds for PDMS replica microfluidics devices in geometries and designs that are not possible using the traditional method in soft lithography. Moreover, we are producing stand-alone 3D printed microfluidic devices such as a gradient chip without the requirement of PDMS fabrication. It is expected that in the future we will further extend our abilities of precise and efficient fabrication of particles with controlled physical parameters. This will allow for additional uptake experiments using a large matrix of particles. In accordance with our encouraging results thus far, we predict to find also that particles that require massive cell deformation for their internalization will be specifically taken by cancer cells rather than normal ones, and that the uptake will further increase with the metastatic level of the cells. Importantly, our next experiments will include inert particles with controlled rigidity, where we predict that tuning particle elasticity will result in elevated specificity and high uptake by cancer cells. A detailed computer model will allow predicting what particles would be optimal for treatment, and we hope this could be used in the future as a platform in precision medicine.
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