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Hydrogel-nanoparticle patches as prophylactic scaffold agents for in vivo local gene/drug delivery in colorectal cancer tumours

Final Report Summary - CANCERHYDROGELPATCH (Hydrogel-nanoparticle patches as prophylactic scaffold agents for in vivo local gene/drug delivery in colorectal cancer tumours.)

Cancer is among the major causes of mortality in the developed world, and the worldwide incidence continues to increase. It is here that Nanotechnology can make a difference. In reality, the outstanding advancements made in Medicine and Biomedical Engineering over the last decade is somewhat due to the fundamental improvements made in Nanotechnology. The National Cancer Institute envisions that over the next years, Nanotechnology will result in significant advances in early detection, molecular imaging, targeted and multifunctional therapeutics, prevention and control of cancer.

In the last years, Dr. João Conde and colleagues developed several smart platforms to tackle cancer from all sides. From the development of nanoparticles and scaffolds able to overcome drug resistance by detecting and silencing a specific multidrug resistance protein (Conde et al. PNAS 2015) to gene-, chemo-, photo- and immuno-therapy nanoparticles able to target and inhibit, with outstanding efficiencies, the progression of breast (Conde et al. Nature Materials 2015; Avital & Conde et al. Nature Communications 2016), gastric (Bao & Conde et al. Scientific Reports 2015), lung (Conde et al. Advanced Functional Materials 2015; Conde et al. Nanoscale 2015) or colon cancer (Conde et al. J. Controlled Release 2014; Conde et al. Nature Materials 2016), Conde et al. were able to develop novel and essential tools in Nanotechnology and Nanomedicine that lead to cancer regression and increased survival.

As Marie Curie fellow, Dr. João Conde provided strong evidence for the development of pioneer platforms for treating cancer locally using hydrogel patches.
The majority of the conventional treatments for cancer are the systemic administration of chemotherapeutic drugs, which are rapidly cleared from the blood stream and accumulate non-specifically in kidneys, spleen, liver and lymph nodes, producing a strong immunogenicity and toxicity. Local application of cargo-containing vehicle at the target site might be the method of choice for multitude of pathologies as it allows for the delivery of higher ‘effective’ dose while enhancing therapeutic molecules stability, minimizing side-effects and clearance. In fact, a local therapeutic vehicle opens up new vistas for effective neoadjuvant therapy, to treat non-resectable tumors, or for washout procedure following tumor resection to prevent recurrence.

In the last 36 months during the Marie Curie Grant, Dr. João Conde has obtained significant results in the development of a new class of smart injectable, biocompatible and biodegradable hydrogels based on dendrimers and dextrans. These hydrogels are highly biocompatible. Additionally, they provide facile encapsulation of drugs and genes without affecting their activity and may serve as depots for the delivery of these therapeutic payloads.

Dr. João Conde have shown that dendrimer:dextran adhesive hydrogels are able to sense and differentially react with the disease microenvironment (e.g. can sense the tissue microenvironment by detecting the expression of specific genes related with multidrug resistance, Conde et al. PNAS 2015), potentiating targeted drug release and uptake in certain disease settings. These hydrogels also prove to be incredible useful for re-programing the primary tumor using gene-regulating RNA molecules to prevent metastasis in a breast cancer mouse model (Avital & Conde et al. Nature Communications 2016) or for miRNA delivery by using the self-assembly of a triple-helix forming RNA structure that lead to nearly 90% levels of tumor shrinkage two weeks post-gel implantation (Conde et al. Nature Materials 2015). Taken one step-forward, these hydrogels were also optimized and developed as prophylactic patches able to perform gene, chemo and phototherapy in a triple-combination approach to achieve complete tumor resection when applied to non-resected tumors and to the absence of tumor recurrence when applied following tumor resection (Conde et al. Nature Materials 2016). This study also identifies the molecular and genetic pathways triggered in response to the three therapeutic modalities − gene-, chemo-, photo-therapy − by tumor gene expression profiling in treated mice.

Taken together the studies developed in the Marie Curie Project reported by Conde et al., hydrogels are excellent candidates for a successful strategy of the proposed project and represent a rational treatment strategy following a comprehensive scrutiny of the tumor microenvironment and host response to different therapeutic modalities.