DOI: https://doi.org/10.29363/nanoge.amamed.2022.007
Publication date: 22nd April 2022
The tumor microenvironment (TME) comprises non-cancerous stromal components such as the extracellular matrix (ECM), blood vessels, infiltrating immune cells, and various associated tissue-specific cells [1]. This unique environment, which emerges during tumor progression via complex interactions between host and tumorous tissue, has been proposed as a target for anti-tumor therapies [2]. Understanding the unique nature of the TME and implementing rational design by engineering biodegradable, multivalent polymeric nanocarriers (such as polypeptides [3]) may foster the development of more efficient anticancer nanotherapeutics.
Our studies demonstrated that polyglutamate-based polymers (PGA) represent excellent candidates for TME targeting due to their architectural versatility, biodegradability, and multivalency that allows the rational design of polymer-based combination therapies and the implementation of targeting strategies. We obtained PGAs through N-carboxyanhydride ring-opening polymerization (NCA-ROP) and introduced various functionalities through post-polymerization techniques to yield a set of orthogonal reactive attachment sites [4]. Following a bottom-up strategy, we obtained self-assembling star-based polypeptide architectures that formed supramolecular nanostructures with interesting properties [5], including a lymphotropic character highly suitable for nanovaccine development. This strategy, combined with adequate bioresponsive polymer-drug linker design [6] and drug selection and tumor-associated antigens or targeting moieties [7], allowed us to achieve proof-of-concept for metastatic breast cancer [6,7], melanoma, pancreatic cancer and castration-resistant prostate cancer treatment.
The rational design of polypeptide-based therapeutics, incorporating bioresponsive elements and targeting moieties for the TME, could significantly enhance their anticancer therapeutic efficiency. Adequate tropism and appropriate drug release kinetics represent crucial parameters for achieving an adequate safety:efficacy ratio and securing an adequate therapeutic window for future treatments.
This research was funded by the European Research Council (Grant ERC-CoG-2014-648831 MyNano and ERC-PoC-Polymmune), LaCaixa NanoPanTher Project (HR18-00589), Agencia Valenciana de Innovación (AVI) and the Spanish Ministry of Science and Innovation (PID2019-108806RB-I00). 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).
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