Lymph Node Delivery Strategy Enables the Activation of Cytotoxic T Lymphocytes and Natural Killer Cells to Augment Cancer Immunotherapy

Abstract

Lymph nodes are the main sites for immune activation and surveillance. Effective delivery of immunomodulators into lymph nodes to trigger antitumor immunity is essential for cancer treatment. Here, we propose a lymph node delivery strategy to modulate the immune response by activating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells simultaneously. Novel pH/redox dual-sensitive micelles were prepared using poly­(l-histidine)-poly­(ethylene glycol) (PLH-PEG) as a skeleton, which can effectively deliver immunomodulators to the lymph nodes due to their suitable particle size. At 48 h after subcutaneous injection, the accumulation efficiency in lymph nodes increased 8.12-fold compared with the control group. Subsequently, Trp2/CpG-coloaded pH/redox dual-sensitive micelles (Trp2/CpG-NPs) acted on antigen-presenting cells, fully promoting CTL activation through dendritic cell antigen cross-presentation and macrophage repolarization. IL-15-loaded pH/redox dual-sensitive micelles (IL-15-NPs) were developed to activate the killing effect of NK cells by interacting with IL-15 receptors. In the tumor-bearing mice model, this lymph node delivery strategy showed significant antitumor efficiency and the tumor inhibition rate reached 93.76%. Meanwhile, the infiltration of CTLs and NK cells in tumor tissues increased, and the immunosuppressive microenvironment was relieved by the repolarization of macrophages from M2-type to M1-type. Overall, this study highlighted the potential of the lymph node delivery strategy for cancer immunotherapy.

Nanomaterial‐Boosted Tumor Immunotherapy Through Natural Killer Cells

“…In another work, IL-15 was loaded within the micelles with pH/redox responsiveness for activating the killing activity of NK cells toward B16-F10 tumors through interacting with the IL-15 receptor. [67] Numerous nanocarriers and combination therapies have been used to improve the potential biosafety issues of IL-2 and enhance the infiltration of NK cells in tumors, thereby enhancing the efficacy of immunotherapy. [68] Recently, Song et al synthesized erythrocyte membrane-coated nanogels (NR PþI ) composed of hydroxypropyl-β-cyclodextrin acrylate and two chitosan derivatives with opposite charge to co-encapsulate paclitaxel (PTX) and IL-2.…”

“…In another work, IL‐15 was loaded within the micelles with pH/redox responsiveness for activating the killing activity of NK cells toward B16‐F10 tumors through interacting with the IL‐15 receptor. [ 67 ]…”

Locoregional Lymphatic Delivery Systems Using Nanoparticles and Hydrogels for Anticancer Immunotherapy

“…Drugs with functional groups that can participate in a chemical reaction can be conjugated to various drug delivery systems, including iron oxide NPs, quantum dots, graphene oxide, liposomes, micelles, etc. [109][110][111][112][113]. Examples include conjugations of CpG and siStat3 to linkers on the quantum dots (~150 nm) via a disulfide bond [109], amide conjugations of antigen peptides to lipids to enable hydrophobic interactions with oleic acids on iron oxide NPs (30-45 nm) [110], amide conjugations of antigen peptides to PEG-(poly(maleic anhydride-alt-1-octadecene)) loaded on graphene oxide (20-30 nm) via hydrophobic interactions [111], conjugations of antigen peptides to lipids comprising liposomes (~23 nm) via an amide bond [112], and conjugations of antigen peptides to poly(L-histidine)-poly(ethylene glycol) micelles (~60 nm) via a disulfide bond [113], ultimately leading to a high accumulation of immunomodulatory drugs in the LNs, followed by efficient antitumor immunotherapy.…”

PTD4 Peptide Increases Neural Viability in an In Vitro Model of Acute Ischemic Stroke

“…Neural cultures were exposed to each peptide for 20 h, after which time their viability was assessed using a conventional spectrofluorimetric CellTiter-Blue ® (CTB) assay (Figure 4) [63].The CTB assay was selected to replace a standard MTT agent. Although MTT was shown to perform excellent effectiveness in stable cell lines [64], several reports demonstrated its ill-disposed accuracy in the assessment of drug-dose response in cell lines Neural cultures were exposed to each peptide for 20 h, after which time their viability was assessed using a conventional spectrofluorimetric CellTiter-Blue ® (CTB) assay (Figure 4) [63].The CTB assay was selected to replace a standard MTT agent. Although MTT was shown to perform excellent effectiveness in stable cell lines [64], several reports demonstrated its ill-disposed accuracy in the assessment of drug-dose response in cell lines [65,66] and neuron-astroglia cultures [67].…”