Hydroxylated dendrimer nanogels co-deliver drugs and cytokines for chemoimmunotherapy of glioma

Developing simple blood-brain barrier (BBB)-crossing nanoplatforms capable of overcoming the restrictions of BBB and the immunosuppressive tumor microenvironment (TME) still remains challenging. Herein, we develop a dual pH/reactive oxygen species-responsive dendrimer nanogel (DNG) platform based on generation 3 poly(amidoamine) (G3 PAMAM) dendrimers for co-delivery of the hypoxia-activated prodrug tirapazamine (TPZ) and the immunomodulatory cytokine interferon-gamma (IFN-γ). First, DNGs were synthesized by crosslinking hydroxylated G3 PAMAM dendrimers partially modified with phenylboronic acid (PBA) with dual PBA-terminated poly(ethylene glycol) <i>via</i> a reverse microemulsion method, followed by physical loading of TPZ within the DNGs and surface complexation of IFN-γ. The prepared DNGs-TPZ/IFN-γ with a size of 72.5 nm display a desired colloidal stability, and can release TPZ and IFN-γ under the TME condition to induce cancer cell death through TPZ-mediated cytotoxic radical generation and IFN-γ-induced upregulation of pro-apoptotic pathway. Moreover, the released IFN-γ is able to promote macrophage M1 polarization, dendritic cell maturation, T lymphocyte activation, and regulatory T cell suppression. Leveraging the rich hydroxyl groups and the enhanced permeability and retention effect of DNGs, the DNGs-TPZ/IFN-γ can penetrate the BBB and demonstrate potent therapeutic efficacy in an orthotopic mouse glioma model. The developed DNGs-TPZ/IFN-γ with a simple composition may be developed to co-deliver drugs and cytokines to tackle other cancer types.