Nanoparticles (NPs) are promising drug delivery systems (DDS) for identifying and treating cancer. Active targeting NPs can be generated by conjugation with ligands that bind overexpressed or mutant cell surface receptors on target cells that are poorly or not even expressed on normal cells. Receptor-mediated endocytosis of the NPs occurs and the drug is released inside the cell or in the surrounding tissue due to the bystander effect. Antibodies are the most frequently used ligands to actively target tumor cells. In this context, antibody-based therapies have been extensively used in HER2+ breast cancer. However, some patients inherently display resistance and in advanced stages, almost all eventually progress. Functionalized NPs through conjugation with antibodies appear to be a promising strategy to optimize targeted therapies due to properties related to biocompatibility, suitable delivery control and efficiency of functionalization. This review is focused on the different strategies to conjugate antibodies into polymeric NPs. Recent antibody conjugation approaches applied to the improvement of breast cancer therapy are highlighted in this review.

Breast cancer is the most common invasive tumor in women and the second leading cause of cancer-related death. Nanomedicine raises high expectations for millions of patients as it can provide better, more efficient, and affordable healthcare, and it has the potential to develop novel therapeutics for the treatment of solid tumors. In this regard, targeted therapies can be encapsulated into nanocarriers, and these nanovehicles are guided to the tumors through conjugation with antibodies—the so-called antibody-conjugated nanoparticles (ACNPs). ACNPs can preserve the chemical structure of drugs, deliver them in a controlled manner, and reduce toxicity. As certain breast cancer subtypes and indications have limited therapeutic options, this field provides hope for the future treatment of patients with difficult to treat breast cancers. In this review, we discuss the application of ACNPs for the treatment of this disease. Given the fact that ACNPs have shown clinical activity in this clinical setting, special emphasis on the role of the nanovehicles and their translation to the clinic is placed on the revision.

Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile. Antibody conjugated nanoparticles (ACNPs) using PROTACs have not been designed and evaluated. In this pioneer approach, the commercial MZ1 PROTAC was encapsulated into the FDA-approved polymeric nanoparticles. The nanoparticles were conjugated with trastuzumab to guide the delivery of MZ1 to breast tumoral cells that overexpress HER2. These ACNPs were characterized by means of size, polydispersity index, and Z-potential. Morphology of the nanoparticles, along with stability and release studies, completed the characterization. MZ1-loaded ACNPs showed a significant cytotoxic effect maintaining its mechanism of action and improving its therapeutic properties.

Purpose: The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumour cells for stripping tumours of the protection conferred by the microenvironment. Methods: A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumour cells was performed. We focused on the study of molecules that mediate the communication between both compartments and that entail fibroblast's activation and the alteration of the sensitivity to chemotherapy. We identified targets for the blocking of the tumor-stroma interaction. Finally, we tested, in vivo, the blockade of the tumor-stroma interaction in orthotopic models derived from patients and in models of acquired resistance to oxaliplatin. Results: IL-1b/TGFb1 are the triggers for fibroblasts recruitment and conversion into carcinoma-associated fibroblasts (CAFs) in colorectal cancer. CAFs then secrete proinflammatory factors that alter sensitivity in tumour cells, activating JAK/STAT and PI3KCA/AKT pathways. Blocking such crosstalk with a neutralising IL-1b-antibody and a TGFBR1-inhibitor is relieved by the TAK1-mediated activation of the non-canonical TGFb pathway, which induces a change in the cytokine/chemokine repertoire that maintains a sustained activation of AKT in tumour cells. TAK1 plus TGFBR1-inhibition blocks IL-1b/TGFb1-mediated fibroblast activation, decreasing the secretion of proinflammatory cytokines. In turn, tumour cells became more sensitive to chemotherapy. In vivo, the combination of a TAK1-inhibitor plus TGFBR1-inhibitor reduced the metastatic capacity of tumour cells and the recruitment of fibroblasts. Conclusion: Our findings provide a translational rationale for the inhibition of TAK1 and TGFBR1 to remove the chemoprotection conferred by CAFs.

Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

The p38MAPK signalling pathway was initially described as a stress response mechanism. In fact, during previous decades, it was considered a pathway with little interest in oncology especially in comparison with other MAPKs such as ERK1/2, known to be target of oncogenes like Ras. However, their involvement in apoptotic cell death phenomena makes this signalling pathway more attractive for many cancer research laboratories. This apoptotic role allows to establish a link between p38MAPK and regular chemotherapeutic agents such as Cisplatin or base analogues (Cytarabine, Gemcitabine or 5-Fluorouracil) which are currently used in hospitals across the world. In fact, and more recently, p38MAPK has also been connected with targeted therapies like tyrosine kinase inhibitors (vg. Imatinib, Sorafenib) and, to a lesser extent, with monoclonal antibodies. In addition, the oncogenic or tumour suppressor potential of this signalling pathway has aroused the interest of the scientific community in evaluating p38MAPK as a novel target for cancer therapy. In this review, we will summarize the role of p38MAPK in chemotherapy as well as the potential that p38MAPK inhibition can bring to cancer therapy. All the evidences suggest that p38MAPK could be a double-edged sword and that the search for the most appropriate candidate patients depending on their pathology and treatment will lead to a more rational use of this new therapeutic tool.