Hierarchically porous, and Cu- and Zn-containing \u03b3-AlOOH mesostrands as adjuvants for cancer immunotherapy

Xia Li,Sherif A Ei-Safty,Xiupeng Wang,Akiyoshi Taniguchi,Atsuo Ito,Mohamed A Shenashen

doi:10.1038/s41598-017-12446-9

Abstract

Alum is the only licensed adjuvant by Food and Drug Administration of USA used in many human vaccines and has excellent safety record in clinical applications. However, alum hardly induces T helper 1 (Th1) immune responses that are required for anti-tumor immunity. In the present study, we fabricated hierarchical copper- and zinc- buds dressing γ-AlOOH mesostrands (Cu- and Zn-AMSs) with randomly wrinkled morphology, mesoscale void- or cave-like pockets, high-exposed surface coverage sites, and positive charge streams in saline. We confirmed that Cu- and Zn-AMSs promoted intracellular uptake of model cancer antigen (ovalbumin, OVA) by THP-1-differentiated macrophage-like cells in vitro. Moreover, Cu- and Zn-AMSs enhanced maturation and cytokine release of bone marrow dendritic cells in vitro. In vivo study demonstrated that Cu- and Zn-AMSs markedly induced anti-tumor-immunity and enhanced CD4+ and CD8+ T cell populations in splenocytes of mice. These findings demonstrated that hierarchical copper- and zinc- buds dressing γ-AlOOH mesostrands, which are oriented in randomly wrinkled matrice, are suitable platforms as novel adjuvants for cancer immunotherapy.

Highlights

Cancer immunotherapy has greatly increased its clinical benefit, because it is able to remove inhibitory pathways or enhance stimulatory pathways in the immune system to eradicate cancer cells[1,2,3,4,5,6]
The wide-angle X-ray diffraction peaks of all the samples were indexed without difficulty as the orthorhombic γ-AlOOH with lattice parameters of a = 3.691 Å, b = 12.24 Å, and c = 2.859 Å (JCPDS no. 21-1307)
There is no obvious difference between the pristine AlOOH mesostrands (AMS), Figure 2. (A) Wide-angle X-ray diffraction (WAXRD) and (B) N2 sorption isotherms and pore structure parameters of hierarchical AMSs (a), Cu-AMSs (b) and Zn-AMSs (c). (C–E) Transmission electron microscopy (TEM) images (C), high-magnification TEM (HRTEM) image (D), and electron diffraction (E) of AMSs. (F,G) TEM images of CuAMSs (F) and Zn-AMSs (G), respectively. (H) OVA adsorption onto different AMSs samples. (I) Zeta potential of OVA and hierarchical AMSs, Cu-AMSs and Zn-AMSs

Summary

Introduction

Cancer immunotherapy has greatly increased its clinical benefit, because it is able to remove inhibitory pathways or enhance stimulatory pathways in the immune system to eradicate cancer cells[1,2,3,4,5,6]. Example, interleukin (IL)-12–aluminum adjuvant complex can enhance Th1 immune response, and this action can be further augmented with coexistence of IL-1818,19. In another case, α-Al2O3 nanoparticles enhanced antigen cross-presentation, activated OT-I CD8+ T cells and significantly improved antitumor immune response[20]. Clinical use of IL-12 and α-Al2O3 nanoparticles would be challenging due to potential toxicity, high-cost associated with the former and poor degradability associated with the latter, these examples motivated us to alter chemistry and structure of alum adjuvant to strengthen Th1 immune response and to enhance its adjuvanticity in anti-tumor immunity. Zinc deficiency may result in reduced activity of thymus and thymic hormones, phagocytosis, T-helper cell numbers, natural killer cell activity, antibody production and cell-mediated immunity, and shift of Th1 cell balance toward Th2 cells[34,35]

Methods

Results

Conclusion