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MyNano Report Summary

Project ID: 648831
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - MyNano (Towards the design of Personalised Polymer-based Combination Nanomedicines for Advanced Stage Breast Cancer Patients)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

Research on anticancer therapies has provided little progress towards improved survival rates for patients with metastatic disease. The intrinsic advantages of nanomedicines and, in particular polymer conjugates, can be optimised to rationally design targeted combination therapies, a concept that I (Mario Jesus Vicent) pioneered that allows enhanced therapeutic efficiency. Early clinical trials involving polymer conjugates demonstrated activity in chemotherapy refractory patients and reduced drug-related toxicity. However, there is growing concern about patient variability regarding tumor patho-physiology that underlies successful therapeutic outcomes. Specific biomarkers are required to select those patients most likely to show heightened clinical response to these therapies.
The objective of MyNano is to engineer polymer-based combination therapies designed to treat metastatic breast cancer in a patient personalised manner. Therefore, novel multicomponent polymer conjugates with precise control over size, shape, solution conformation, multifunctionality and bioresponsiveness are being obtained while in parallel their structure-activity relationships to underlying proposed mechanisms of action in clinically relevant models are being studied. Crosslinked star-shaped polyglutamates obtained by controlled polymerisation and self-assembly strategies have been obtained and used as carriers. Primary breast cancer patient tissue will be used to generate in vitro cell and in vivo models representing different clinical molecular subtypes. MyNano will also investigate new combination strategies using current treatments together with inhibitors of tumor-derived exosome release pathways, a phenomenon related to metastasis and resistance mechanisms. The aim is to provide a novel methodological approach that would allow by reiterative design to optimise the design of the next generation nanoconjugates for the treatment of specific metastatic cancer clinical subtypes. MyNano will be a breakthrough as it introduces a paradigm shift in the strategy to design nanomedicines in areas of unmet clinical need.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the first 18 months, the chemistry part of MyNano has been devoted to “WP1.1 Synthesis/Physicochemical Characterization – Star PGAs, Block co-polymer unimers” related to the synthesis of novel carriers based on BTA cores and star-shaped polyglutamates, a task which has been accomplished. In this regard, due to the success obtained in the development of star-shaped polymers with different BTA initiators, and the initial failures in di-block copolymer synthesis and self-assembly, this latter part has been abandoned, and the star-shaped approach have been pushed forward. Indeed, this success has been translated into a recent patent (REF. PCT/EP2016/067554) and a submitted manuscript under the title “Capturing extraordinary soft-assembled homocharged polypeptides to approach nanocarriers design”.

The second task “WP1.1: Synthesis/Physicochemical Characterization - Nanoconstructs by bottom-up approach” has also been addressed at this point, where selected candidates have emerged. Those candidates, after proper characterization, have been effectively labelled for in vitro and in vivo analysis.

Finally, the task “WP1.3. Synthesis of polymer-based combination conjugates/Linking chemistry” is also an ongoing task. We have been able to develop effective biodegradable linking chemistry (carbamates, hydrazones, disulphides, etc.) and a manuscript describing hydrazone linkers and an interesting drug combination is already in preparation. Combination conjugates with selected drugs from the high throughput-screening platform are currently also ongoing to optimise adequate drug release kinetics. Task “WP2.1 Synthesis/Physicochemical Characterization - Candidates Physicochemical characterization, Descriptors” is being developed alongside the other tasks.

During this period, the biological part of the project has been focused on the in vitro experiments in the different cell models, devoted to “WP1.2. Selection of drug combinations”. This included the characterization of four breast cell lines for the screening platform: including their Cathepsin B activity, intracellular pH, as well as oestrogen, progesterone, Her2 receptors, glutathione, and exosomes levels. High throughput screening of drug combinations was also performed by measuring their ability to promote cell death (MTS assays) and their influence on exosome release. This task is still ongoing, past its deadline, due, in part, to the inclusion of previously uncontemplated drug combinations. Furthermore, the preliminary experiments of task “WP2.2. Accurate SAR. Physico-chemical descriptors and Biomarker Identification in representative BC cell models,” have also been performed regarding polymer-candidates toxicity, immunogenicity, and cellular uptake. In vivo studies have been already started within this period, as biodistributions and pharmacokinetic studies of the first polymeric candidates after Cy5.5 labelling have been already addressed in athymic nude mice to improve the in vivo visualization using IVIS® Spectrum. These studies have shed light on the great potential of our first candidates in metastatic cancer treatment since lymph node-specific accumulation has been found. Finally, towards “WP3.1. MDA-MB-231.Fluc2.C19 in vivo model”, optimization steps have been carried out during this period, where the choice of an appropriate animal strain has represented an ongoing concern, however we note that the model is now fully established and also the strategies to monitor metastasis progression by IVIS® Spectrum as well as positron emission tomography (PET).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The design of our new BTA initiated star-shaped polymers and the patent/manuscript associated can be viewed as progress beyond the state of the art and we hope the advanced characteristics that these polymers constructs exhibit will allow us to effectively target primary tumor, target lymph nodes, and inhibit metastasis. This could provide a revolution in the treatment of various forms of breast cancer and we hope our upcoming in vitro and in vivo work and the associated amalgamation of the biological and chemical arms of the project will synergise to create a truly effective treatment option. To this end, we believe that the inclusion of the study of exosomes also has the potential to have impact towards the ultimate aim of treating metastatic breast cancer.
Furthermore, our systematic outlook, with deep analysis and understanding of conjugate structure-activity relationships with biological environment, will promote the market translation of these anti-cancer agents and will advance our understanding of the molecular basis of life-threating diseases such as metastatic breast cancer. We believe the MyNano project will contribute enormously towards personalised medicine of metastatic breast cancer.
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