Polypeptides are already playing a major role on a number of different relevant areas such as nanomedicine. The physico-chemical parameters of a polypeptide-conjugate, and hence its biological performance, are defined by an intricate interplay of multiple structural factors. Structural complexity also represents a unique opportunity, since small changes at the structural level might endow nanomedicines with outstanding and unexpected biological performance. We have overcome the main classical limitations for the synthesis of defined polypeptides using precise controlled reactions followed by an adequate characterization yielding to well-defined polypeptidic architectures by NCA polymerization techniques. In addition, post-polymerization techniques allow us the introduction of a variety of functionalities yielding a set of orthogonal reactive attachment sides. Using these techniques and following a bottom-up strategy we have been able to obtain star-based polypeptide architectures with the capacity to self-assemble yielding supramolecular nanostructures of different size and shape with interesting properties. This strategy revealed a lack of toxicity, an enhanced in vitro cell internalization rate and significantly greater half-life in vivo together with a significant lymph node accumulation for specific cases. In order to target metastatic processes, we used pH-responsive linkers that can promote the specific release of the drug from the polymeric backbone within the tumor microenvironment (TME). This, together with an optimal drug(s) loading allowed significant reduction on primary tumor growth and lung metastasis (∼90%) in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. With adequate derivatisation (targeting LRP-1 receptor) polyglutamate-based conjugates showed the capability to bypass the blood-brain barrier (BBB). Feature of high interest not only for the treatment of brain metastatis but also to design a strategy for neurodegenerative disorders.

Polypeptide-based conjugates as versatile therapeutics as single agents or in combination therapy

2019 Fall National Meeting

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