Synergetic treatment of oxygen microcapsules and lenvatinib for enhanced therapy of HCC by alleviating hypoxia condition and activating anti-tumor immunity

Hypoxia is a typical characteristic of hepatocellular carcinoma(HCC), which causes tremendous obstacles to tumor treatments. Current first-line treatment may further deteriorate tumor hypoxia. For example,Lenvatinib, a receptor tyrosine kinase inhibitor(RTKI), suppresses tumor growth via blocking vascular endothelial growth factor(VEGF) signaling, and can also inhibit angiogenesis, thus limiting oxygen supply to tumor sites. Therefore, alleviating tumor microenvironment(TME) hypoxia holds great potential for enhancing the therapeutic effect of RTKI. Here, nanoparticle-stabilized oxygen microcapsules, a stable and biocompatible oxygen-loaded delivery system, are successfully prepared through interfacial polymerization of polydopamine nanoparticles. The microcapsules with a large loading capacity of oxygen in the core show excellent bioavailability and dispersity, which could effectively improve the hypoxic TME when they serve as oxygen delivery vehicles. Synergetic treatments of Lenvatinib and oxygen microcapsules could induce the transition of “cold tumor” in an immune-suppressed state to “hot tumor” in an immune-activated state by improving tumor hypoxic TME and reducing angiogenesis in HCC. It is revealed that combined treatments of oxygen microcapsules and Lenvatinib could polarize tumor-associated macrophages(TAMs) to anti-tumor M1 cells and activate T cell-mediated anti-tumor immune responses.The results suggest that synergetic therapy using oxygen microcapsules and Lenvatinib could alleviate the hypoxic TME and enhance the therapeutic performance of RTKI, demonstrating a promising anti-tumor strategy for enhanced therapy of HCC.

Oxygen microcapsules improve immune checkpoint blockade by ameliorating hypoxia condition in pancreatic ductal adenocarcinoma

Rationale:Hypoxia in tumor microenvironment(TME)represents an obstacle to the efficacy of immunotherapy for pancreatic ductal adenocarcinoma(PDAC)through several aspects such as increasing the expression of immune checkpoints or promoting fibrosis.Reversing hypoxic TME is a potential strategy to improve the validity of immune checkpoint blockade(ICB).Methods:Here,we synthesized polydopamine-nanoparticle-stabilized oxygen microcapsules with excellent stabilization,bioavailability,and biocompatibility for direct oxygen delivery into tumor sites by interfacial polymerization.Results:We observed oxygen microcapsules enhanced the oxygen concentration in the hypoxia environment and maintained the oxygen concentration for a long period both in vitro and in vivo.We found that oxygen microcapsules could significantly improve the efficiency of ICB against PDAC in vivo.Mechanismly,combined treatments using oxygen microcapsules and ICB could reduce the infiltration of tumor-associated macrophages(TAMs)and polarized pro-tumor M2 macrophages into anti-tumor M1 macrophages.In addition,combined treatments could elevate the proportion of T helper subtype 1 cells(Th1 cells)and cytotoxic T lymphocytes cells(CTLs)to mediate anti-tumor immune response in TME.Conclusion:In summary,this pre-clinical study indicated that reversing hypoxia in TME by using oxygen microcapsules was an effective strategy to improve the performances of ICB on PDAC,which holds great potential for treating PDAC in the future.