Immunomodulatory Effects Associated with Cladribine Treatment

Cladribine is a synthetic deoxyadenosine analogue with demonstrated efficacy in patients with relapsing-remitting multiple sclerosis (MS). The main mechanism of action described for cladribine is the induction of a cytotoxic effect on lymphocytes, leading to a long-term depletion of peripheral T and B cells. Besides lymphocyte toxicity, the mode of action may include immunomodulatory mechanisms affecting other cells of the immune system. In order to induce its beneficial effects, cladribine is phosphorylated inside the cell by deoxycytidine kinase (DCK) to its active form. However, the mechanism of action of cladribine may also include immunomodulatory pathways independent of DCK activation. This in vitro study was designed to explore the impact of cladribine on peripheral blood mononuclear cells (PBMC) subsets, and to assess whether the immunomodulatory mechanisms induced by cladribine depend on the activation of the molecule. To this end, we obtained PBMCs from healthy donors and MS patients and performed proliferation, apoptosis and activation assays with clinically relevant concentrations of cladribine in DCK-dependent and -independent conditions. We also evaluated the effect of cladribine on myeloid lineage-derived cells, monocytes and dendritic cells (DCs). Cladribine decreased proliferation and increased apoptosis of lymphocyte subsets after prodrug activation via DCK. In contrast, cladribine induced a decrease in immune cell activation through both DCK-dependent and -independent pathways (not requiring prodrug activation). Regarding monocytes and DCs, cladribine induced cytotoxicity and impaired the activation of classical monocytes, but had no effect on DC maturation. Taken together, these data indicate that cladribine, in addition to its cytotoxic function, can mediate immunomodulation in different immune cell populations, by regulating their proliferation, maturation and activation.

Photothermal and photodynamic photoactivation of nanomaterials-based prodrugs are two key methods for NIR light-mediated photoactivation

New research focuses on nanomaterials-based prodrugs (NLNPs) activation techniques, mechanisms, and bioapplications. Photothermal and photodynamic photoactivation of nanomaterials-based prodrugs are being explored as two key methods for NIR light-mediated photoactivation. Four common applications of NLNPs in cancer treatment have been completed, but the clinical translation is more complicated. Large-scale manufacturing of high-quality NLNps is critical for valid prodrug activation and delivering the intended therapeutic effect. NILNPs with higher therapeutic efficacy, superior biosafety, and stability are predicted to be developed as a result of future research.