Versatile Polypeptide-based Nanoconjugates as single agents and in Combination Therapy

Abstract:  Polypeptides are already playing a major role on a number of different relevant areas such as nanomedicine [1]. The physico-chemical parameters of a polypeptide-conjugate, and hence its biological performance, are defined by an intricate interplay of multiple structural factors. This highlights the need for detailed structure-activity relationship studies to develop the hierarchical strategies of polypeptide conjugate design. However, structural complexity also represents a unique opportunity, since small changes at the structural level might endow nanomedicines with outstanding and unexpected biological performance [2].

  In our group, 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[3]. In addition, post-polymerization techniques allow us the introduction of a variety of functionalities yielding a set of orthogonal reactive attachment sides[4]. 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 with interesting properties5. This strategy together with an adequate polymer-drug linker design6 enabled in vitro and in vivo evaluation, revealing a lack of toxicity, an enhanced in vitro cell internalization rate and significantly greater terminal and accumulation half-life in vivo together with a significant lymph node accumulation[5]. These results allow us to envisage these systems as promising nanocarriers for therapeutic or diagnostic applications, especially in anti-cancer treatments including lymph node metastasis and cancer immunotherapy. Proof of Concept for metastatic breast cancer6 and for immunotherapy design in melanoma will be also shown as well as the use of this self-assembled architectures in applications such as neurodegenerative disorders, spinal cord injury or acute kidney injury.

 

References

1. a) Duro-Castano A., Conejos-Sánchez I., Vicent M.J. Polymers 2014, 6, 515-551; b) Duro-Castaño A,Movellan J, Vicent MJ Biomater. Sci., 2015,3, 1321-1334

2. Zagorodko O., Arroyo-Crespo, J.J., Nebot, V.J., and Vicent, M.J.Macromolecular Bioscience 2017, 17, 1600316-n/a.

3. a) Duro-Castano A., England, R.M., Razola, D., Romero, E., Oteo-Vives, M., Morcillo, M.A., and Vicent, M.J. Molecular Pharmaceutics 2015, 12, 3639-3649; b) Conejos-Sánchez I. Duro-Castano, A., Birke, A., Barz, M., and Vicent, M.J. Polymer chemistry 2013, 4, 3182-3186.

4. Barz M., Duro-Castano A., Vicent M.J. Polymer Chemistry 2013, 4, 2989-2994

5. Duro-Casaño Nebot, V. J., Niño-Pariente, A., Armiñán, A., Arroyo-Crespo, J. J., Paul, A., Feiner-Gracia, N., Albertazzi, L. and Vicent, M. J. Advanced Materials 2017, doi. 10.1002/adma.201702888

6. a) Arroyo-Crespo, J.J, Armiñán A., Charbonnier D:, Balzano-Nogueira L., Huertas-López F., Martí C., Tarazona S., Forteza J., Conesa A., Vicent M.J. Biomaterials 2018, 186, 8-21; b) Arroyo‐Crespo, J.J., Deladriere, C. et al.  Adv. Func. Mat. 2018. 28(22): p. 1800931

 

Acknowledgments

Spanish Ministry of Economy and Competitiveness (SAF2016-80427-R) and the European Research Council (Grant ERC-CoG-2014-648831 MyNano, Grant ERC-PoC-2018-825798 Polymmune) and AVI (project INNVAL10/19/047 and Marató TV3 for financial support. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with FEDER funds (PO FEDER of Comunitat Valenciana 2014-2020).