Highlights d Tumor-secreted CXCR1 and CXCR2 ligands induce extrusion of NETs d NETs protect tumor cells from CTL and NK cytotoxicity in 3D cultures d Inhibition of NETosis sensitizes tumors to PD-1+CTLA-4 dual checkpoint blockade d NETs impair contact of immune cytotoxic cells with tumor cells in living mice Authors

Polydopamine (PD) is a synthetic melanin analogue of growing importance in the field of biomedicine, especially with respect to cancer research, due, in part, to its biocompatibility.

No abstract

Polydopamine has acquired great relevance in the field of nanomedicine due to its physicochemical properties. Previously, it has been reported that nanoparticles synthetized from this polymer are able to decrease the viability of breast and colon tumor cells. In addition, it is well known that the size of therapeutic particles plays an essential role in their effect. As a consequence, the influence of this parameter on the cytotoxicity of polydopamine nanoparticles was studied in this work. For this purpose, polydopamine nanoparticles with three different diameters (115, 200 and 420 nm) were synthetized and characterized. Their effect on the viability of distinct sorts of human carcinomas (breast, colon, liver and lung) and stromal cells was investigated, as well as the possible mechanisms that could be responsible for such cytotoxicity. Moreover, polydopamine nanoparticles were also loaded with doxorubicin and the therapeutic action of the resulting nanosystem was analyzed. As a result, it was demonstrated that a smaller nanoparticle size is related to a more enhanced antiproliferative activity, which may be a consequence of polydopamine’s affinity for iron ions. Smaller nanoparticles would be able to adsorb more lysosomal Fe3+ and, when they are loaded with doxorubicin, a synergistic effect can be achieved.

HER2 overexpression, which occurs in a fifth of diagnosed breast cancers as well as in other types of solid tumors, has been traditionally linked to greater aggressiveness. Nevertheless, the clinical introduction of trastuzumab has helped to improve HER2-positive patients’ outcomes. As a consequence, nanotechnology has taken advantage of the beneficial effects of the administration of this antibody and has employed it to develop HER2-targeting nanomedicines with promising therapeutic activity and limited toxicity. In this review, the molecular pathways that could be responsible for trastuzumab antitumor activity will be briefly summarized. In addition, since the conjugation strategies that are followed to develop targeting nanomedicines are essential to maintaining their efficacy and tolerability, the ones most employed to decorate drug-loaded nanoparticles and liposomes with trastuzumab will be discussed here. Thus, the advantages and disadvantages of performing this trastuzumab conjugation through adsorption or covalent bindings (through carbodiimide, maleimide, and click-chemistry) will be described, and several examples of targeting nanovehicles developed following these strategies will be commented on. Moreover, conjugation methods employed to synthesized trastuzumab-based antibody drug conjugates (ADCs), among which T-DM1 is well known, will be also examined. Finally, although trastuzumab-decorated nanoparticles and liposomes and trastuzumab-based ADCs have proven to have better selectivity and efficacy than loaded drugs, trastuzumab administration is sometimes related to side toxicities and the apparition of resistances. For this reason also, this review focuses at last on the important role that newer antibodies and peptides are acquiring these days in the development of HER2-targeting nanomedicines.