Advances in nanomedicines for lymphatic imaging and therapy

Abstract

Lymph nodes play a pivotal role in tumor progression as key components of the lymphatic system. However, the unique physiological structure of lymph nodes has traditionally constrained the drug delivery efficiency. Excitingly, nanomedicines have shown tremendous advantages in lymph node-specific delivery, enabling distinct recognition and diagnosis of lymph nodes, and hence laying the foundation for efficient tumor therapies. In this review, we comprehensively discuss the key factors affecting the specific enrichment of nanomedicines in lymph nodes, and systematically summarize nanomedicines for precise lymph node drug delivery and therapeutic application, including the lymphatic diagnosis and treatment nanodrugs and lymph node specific imaging and identification system. Notably, we delve into the critical challenges and considerations currently facing lymphatic nanomedicines, and futher propose effective strategies to address these issues. This review encapsulates recent findings, clinical applications, and future prospects for designing effective nanocarriers for lymphatic system targeting, with potential implications for improving cancer treatment strategies.

Keywords: Diagnosis; Lymph node; Nanomedicine; Specific delivery; Therapy.

Fig. 1

A schematic represents the application of lymph node-specific nanomedicine (upper panel), design strategies (middle panel) and optimization strategies (below panel). Upper panel shows the schematic of the main application of lymph node-specific nanoparticles, including lymph node diagnosis and drug delivery and enhanced image recognition. And the mode of administration of subcutaneous injection, intravenous injection and intralymphatic injection. Middle panel illustrates the lymph node specific nanomedicine design strategies including vesicle detach, surface modification, responsive drug release, and NPs dissociate. Below panel illustrates the lymph node specific nanomedicine optimization strategies

Fig. 2

Structure and physiology of lymph nodes. A cross section of a lymph node is shown. The architecture of the lymph node can be divided into distinct areas: fluid-filled lumen structures (lymphatics, high endothelial venules (HEVs), capillaries and sinuses), cellular locations (B cells in follicles, dendritic cells and T cells in the paracortex and macrophages in the subcapsular sinus and medulla) and structural units (cortex, paracortex and medulla). Lymphocyte extravasation occurs in the HEVs. The distribution of antigens within the reticular structure is regulated by haemodynamic size and molecular weight by the capsule and conduit. Circulating lymphocytes enter through the vasculature and exit through the efferent lymphatics [22]. Copyright © 2019 Springer Nature

Fig. 3

Design of cationic liposome nanomaterials for lymphatic targeting based on polyethylene glycol surface modification and functionalization. A An example of a lipid nanoparticle composed of phospholipids, targeting ligands, PEGylated lipids, drugs, and nucleic acids. B An example of an extracellular vesicle (EV) containing phospholipids, receptors, proteins, nucleic acids, MHC (major histocompatibility complex) molecules, and ligands [53]. Copyright © 2018 Elsevier B.V

Fig. 4

Screening and optimization of lipid nanoparticles (LNPs) with targeting ability to lymph nodes (LNs). A The chemical structure of lipids used in this study. B The bioluminescence within inguinal LNs after treatment with LNP/mLuc. C The bioluminescence within inguinal LNs after treatment by LNP/mLuc. D Representative images of bioluminescence distribution in mice treated with 113-O12B/mLuc and ALC-0315/mLuc. E Ratio of radiance in liver and inguinal LNs after subcutaneous injection of mLuc [58]. Copyright © 2022 National Academy of Sciences

Fig. 5

Photothermal therapy and anti-tumor evaluation of T-MP in metastatic sentinel lymph nodes in a mouse model of HER2 HT-29 colon cancer cells. A Illustration of the treatment of the surgical resection of orthotopic tumor and follow-up laser irradiation of the meta-static LNs. B Temperature increase of the metastatic LNs was recorded using Testo 890 thermal imager. C Representative TEM images of LN sections after photothermal therapy. D Representative bioluminescence imaging of the mice before tumor resection and after tumor resection and photothermal therapy. E Quantified bioluminescence intensity in panel D. F Survival of the mice with indicated treatments. G Mice body weight [69]. Copyright © 2021 OAHOST

Fig. 6

Design and partial characterization of gene-engineered cell membrane nanovesicles for integrated antigen self-presentation and immune checkpoint blockade. A Generation of DCNVs derived from adenovirus-infected mature dendritic cells. B Schematic illustration of the generation of DCNV-rAd-Ag. C Cryo-electron microscopy. D Dynamic light scattering analyses. E The western blot on membrane proteins from DCNV-rAd-GFP. F Comparison of upregulated immune-response-related proteins in NVs and DCs. G The relative abundance of antigen presentation and migration-related proteins on DCNV-rAd-GFP [100]. Copyright © 2022 The Authors

Fig. 7

Preparation and anticipated tumor inhibition mechanism of macrophage-tumor chimeric exosomes. Biologically reprogrammed macrophage-tumor chimeric exosomes were constructed by introducing tumor nuclei into activated macrophages (aMT-exos). This strategy generated exosomes with tumor components as well as classical activated macrophage (M1) properties, including tumor-antigen-MHC molecules, co-stimulatory molecules, immune-activated cytokines and other tumor components [101]. Copyright © 2021 American Association for the Advancement of Science

Fig. 8

Synthesis scheme of the 12 types of dendrimer for biodistribution assay and SPECT imaging (A), and the fused SPECT/CT images of radiolabeled dendrimer-injected rats after 24 h. Left and right panels are anterior and lateral views, respectively. Arrows and arrow heads indicate the SLN and the injection site, respectively (B) [112]. Copyright © 2015 Elsevier Inc

Fig. 9

Simplified preparation of nanogel, modified spectral analysis of fluorescent agent, and imaging of mouse axillary lymph nodes before and after front limb injection. Fluorescent (A) and optical (B) images of FDNG (5-AF) selectively entering LVs and SLN. Fluorescent (C) and optical (D) images of FDNG(5-AF) and methylene blue co-injected mice after skin removal. Fluorescent (E) and optical (F) images of dissected SLN and adjacent fat tissues. G Immunohistofluorescence staining of dissected SLN from FDNG(5-AF) treated mouse after 12 h of injection. (H) The partially enlarged image of (G) [117]. Copyright © 2014 Elsevier Ltd

Fig. 10

Schematic illustration of intramesorectal injection of nanocarbon (A) and intraoperative imaging and clearance images of mesorectal lymph nodes during surgery (B) and anterior resection of rectum (C) [126]. Copyright © 2020 Foundation of Clinical Oncology

Fig. 11

Schematic of SLN mapping in the head and neck using ¹²⁴I-cRGDY-PEG-Cdots. A Injection of ¹²⁴I-cRGDY-PEG-C dots about an oral cavity lesion with drainage to preauricular and submandibular nodes. B ¹²⁴I-cRGDY-PEG-ylated core–shell silica nanoparticle with surfacebearing radiolabels and peptides and core-containing reactive dye molecules (insets) [129]. Copyright © 2013 The Royal Society of Chemistry