Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells.

in ACS nano by Yamin Peng, Mengsi Zhan, Andrii Karpus, Yu Zou, Serge Mignani, Jean-Pierre Majoral, Xiangyang Shi, Mingwu Shen

TLDR

  • The study develops a special kind of medicine called nanomedicine to help fight a type of brain tumor called glioma. The nanomedicine is made of a special kind of protein called phosphorus dendrimer (AK128) and an antibody called programmed cell death protein 1 antibody (aPD1). The nanomedicine is also covered with a special kind of cell called M1-type macrophage cell membranes (M1m) to help it get into the brain and work better. The study finds that the nanomedicine with M1m camouflage works better than the nanomedicine without M1m camouflage, as it can get into the brain and work better. The study also finds that the nanomedicine with aPD1 works better than the nanomedicine without aPD1, as it can help the immune system fight the tumor better. The study's findings suggest that the nanomedicine could be a good way to fight glioma and further research is needed to see if it works well in people.

Abstract

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having αand βintegrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Overview

  • The study aims to develop a nanomedicine formulation for enhanced immunotherapy of orthotopic glioma using phosphorus dendrimer (AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) camouflaged with M1-type macrophage cell membranes (M1m).
  • The study uses a simple composition of AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm, which possess good stability and cytocompatibility. The NCs are able to penetrate the blood-brain barrier and codeliver both AK128 and aPD1 to the orthotopic glioma with prolonged blood circulation time. The study tests the immunomodulatory activity of AK128 and the immune checkpoint blockade (ICB) enabled by aPD1 to promote tumor cell apoptosis and decrease the tumor distribution of regulatory T cells for improved glioma immunotherapy. The study's hypothesis is that the developed nanomedicine formulation will achieve multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, including the NCs with and without M1m camouflage, the NCs with and without aPD1, and the NCs with and without AK128. The study finds that the NCs with M1m camouflage have enhanced immunotherapy efficacy compared to the NCs without M1m camouflage, as they are able to penetrate the blood-brain barrier and codeliver both AK128 and aPD1 to the orthotopic glioma with prolonged blood circulation time. The study also finds that the NCs with aPD1 have enhanced immune checkpoint blockade (ICB) compared to the NCs without aPD1, as they are able to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and decreasing the tumor distribution of regulatory T cells. The study's findings support the hypothesis that the developed nanomedicine formulation will achieve multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they provide an effective strategy for enhanced immunotherapy of orthotopic glioma. The study's limitations include the need for further studies to evaluate the long-term efficacy and safety of the developed nanomedicine formulation. Future research directions could include the exploration of the use of the developed nanomedicine formulation for other types of cancer and the optimization of the formulation's composition and dosage for improved efficacy. The study's findings suggest that the developed nanomedicine formulation could be a promising tool for cancer immunotherapy, and further research is needed to fully realize its potential.
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