Nanomedicine - Immune System Interactions: Limitations and Opportunities for the Treatment of Cancer.

Nanoparticles interact with immune cells in many different ways. These interactions are crucially important for determining nanoparticles' ability to be used for cancer therapy. Traditionally, strategies such as PEGylation have been employed to reduce (the kinetics of) nanoparticle uptake by immune cells, to endow them with long circulation properties, and to enable them to exploit the Enhanced Permeability and Retention (EPR) effect to accumulate in tumors. More recently, with immunotherapy becoming an increasingly important cornerstone in the clinical management of cancer, ever more research efforts in academia and industry are focusing on specifically targeting immune cells with nanoparticles. In this chapter, we describe the barriers and opportunities of immune cell targeting with nanoparticles, and we discuss how nanoparticle-based drug delivery to specific immune cell populations in tumors as well as in secondary myeloid and lymphoid organs (such as bone marrow, lymph nodes, and spleen) can be leveraged to boost the efficacy of cancer immunotherapy.

Drugless nanoparticles tune-up an array of intertwined pathways contributing to immune checkpoint signaling and metabolic reprogramming in triple-negative breast cancer.

Metabolic reprogramming 'Warburg effect' and immune checkpoint signaling are immunosuppressive hallmarks of triple-negative breast cancer (TNBC) contributing to the limited clinical applicability of immunotherapy. Biomaterials arise as novel tools for immunomodulation of the tumor microenvironment that can be used alongside conventional immunotherapeutics. Chitosan and lecithin are examples of versatile biomaterials with interesting immunomodulatory properties. In this study, we aimed at investigation of the role of carefully designed hybrid nanoparticles (NPs) on common mediators of both programmed death ligand 1 (PD-L1) expression and glycolytic metabolism. Hybrid lecithin-chitosan NPs were prepared and characterized. Their intracellular concentration, localization and effect on the viability of MDA-MB-231 cells were assessed. Glycolytic metabolism was quantified by measuring glucose consumption, adenosine triphosphate (ATP) generation, lactate production and extracellular acidification. Nitric oxide production was quantified using Greiss reagent. Gene expression of inducible nitric oxide synthase (iNOS), phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB or Akt), mammalian target of rapamycin (mTOR), hypoxia-inducible factor 1α(HIF-1α) and PD-L1 was quantified by quantitative reverse transcription polymerase chain reaction (q-RT-PCR). Chitosan, lecithin and the NPs-formulated forms have been shown to influence the 'Warburg effect' and immune checkpoint signaling of TNBC cells differently. The composition of the hybrid systems dictated their subcellular localization and hence the positive or negative impact on the immunosuppressive characteristics of TNBC cells. Carefully engineered hybrid lecithin-chitosan NPs could convert the immune-suppressive microenvironment of TNBC to an immune-active microenvironment via reduction of PD-L1 expression and reversal of the Warburg effect.