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Recent Advances of Nanotechnologies for Cancer Immunotherapy Treatment
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
siRNA can be delivered using polymeric nanoparticles to silence an immunoinhibitory molecule and subsequently boost the antitumor immune response. For example, CD73 (ecto-5ʹ-nucleotidase), which is overexpressed in tumor and immune cells, catalyzes the production of adenosine from AMP. Adenosine binds to the A2A adenosine receptors (A2AR) at the surface of T cells, resulting in decreased T-cell proliferation, reduced production of costimulatory cytokines such as IFN-γ and TNF-α, suppressed NK cell activity, and impaired secretion of cytolytic molecules such as perforin and FasL. In tumor cells, CD73 is involved in tumor neovascularization, metastasis, and invasion [304]. Jadidi-Niaragh et al. [305] loaded CD73 siRNA into chitosan nanoparticles (~100 nm) through ionic gelation using tripolyphosphate (TPP). Following i.v. administration to 4T1 breast cancer-bearing mice, the nanoparticles accumulated in the tumor, causing CD73 downregulation in tumor-associated immune cells, including DCs, Treg, and MDSCs. This led to the reduction of inhibitory cytokine IL-10 and increased secretion of immunostimulatory cytokines (IL-17 and IFN-γ). Subsequently, the growth of the primary tumor was thus decreased with reduced lung metastases, while free siRNA and saline-treated mice showed no efficacy. In cancer cells, over-activation of STAT3 is correlated with increased secretion of immunosuppressive factors such as IL-10 and VEGF [306,307], which inhibit activation of DCs and suppress the immune response against tumors [308,309]. Luo et al. [310] prepared a polyplex formulation containing poly(ethylene glycol)-b-poly(llysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) and poly I:C (a TLR 3 agonist immunoadjuvant), which was then mixed with OVA and an siRNA against STAT3. S.c administration of the polyplex (~142 nm) to C57BL/6J mice bearing B16 OVA tumor resulted in significant uptake by DCs in the draining lymph node. STAT3 level in the DCs was reduced, leading to increased expression of CD40 and CD86. This treatment also decreased the number of immunosuppressive cells in the lymph node, including Treg and MDSCs, resulting in enhanced antitumor efficacy compared to the formulation without siRNA. It was shown that the polyplex was mostly taken up through the lipid raft mechanism rather than the clathrin-mediated endocytosis and, therefore, could result in an increased cytosolic delivery [311–313]. Although cationic polymeric micelles exhibited increased interaction with negatively charged siRNA and were effective in cytosolic delivery to DC, the positively charged surface displayed poor colloidal stability in physiological fluids and cellular selectivity. Other studies associated with the development of siRNA polymeric nanoparticles for downregulation of various immunosuppressors are summarized in [90].
Insights of ethyl acetate fraction from Vassobia breviflora in multidrug-resistant bacteria and cancer cells: from biological to therapeutic
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Altevir Rossato Viana, Nathieli Bianchin Bottari, Daniel Santos, Marissa Bolson Serafin, Bruna Garlet Rossato, Rafael Noal Moresco, Katianne Wolf, Aline Ourique, Rosmari Hörner, Érico Marlon de Moraes Flores, Maria Rosa Chitolina Schetinger, Bruno Stefanello Vizzotto, Luciana Maria Fontanari Krause
In this study V. breviflora increased NTPDase activity when ATP was used as a substrate. It became evident that during cell apoptosis, high levels of extracellular ATP are released. The enzymatic activity of CD39 and CD73 is, therefore, able to modulate the duration and magnitude of purinergic signaling through the ATP-CD39-CD73-Ado cascade, as CD39 hydrolyzes extracellular ATP to AMP and CD73 dephosphorylates AMP to Ado, a critical regulator in both innate immune systems response mechanisms and adaptive immune response, where CD39 acts as a limiting enzyme for this cascade. The lower expression of these ectonucleotidases involved in the catabolism of ADP and AMP is considered a signal of nucleoside and nucleoside modulation.