scholarly journals Overcoming physiological barriers by nanoparticles for intravenous drug delivery to the lymph nodes

2021 ◽  
pp. 153537022110107
Author(s):  
Noah Trac ◽  
Eun Ji Chung
Keyword(s):  
Drug Delivery ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Subcutaneous Administration ◽  
Mononuclear Phagocyte ◽  
Intravenous Drug ◽  
Rapid Clearance ◽  
Nanoparticle Design ◽  
Lymph Node Targeting

The lymph nodes are major sites of cancer metastasis and immune activity, and thus represent important clinical targets. Although not as well-studied compared to subcutaneous administration, intravenous drug delivery is advantageous for lymph node delivery as it is commonly practiced in the clinic and has the potential to deliver therapeutics systemically to all lymph nodes. However, rapid clearance by the mononuclear phagocyte system, tight junctions of the blood vascular endothelium, and the collagenous matrix of the interstitium can limit the efficiency of lymph node drug delivery, which has prompted research into the design of nanoparticle-based drug delivery systems. In this mini review, we describe the physiological and biological barriers to lymph node targeting, how they inform nanoparticle design, and discuss the future outlook of lymph node targeting.

scholarly journals VEGF-C–induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1010-1017 ◽  
Author(s):  
Satoshi Hirakawa ◽  
Lawrence F. Brown ◽  
Shohta Kodama ◽  
Karri Paavonen ◽  
Kari Alitalo ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Fluorescent Protein ◽  
Sentinel Lymph Nodes ◽  
Primary Tumors ◽  
Metastatic Cells ◽  
Good Target ◽  
Green Fluorescent ◽  
Factor C

Abstract The mechanisms by which tumors metastasize to sentinel and distant lymph nodes, and beyond, are poorly understood. We developed transgenic mice that overexpress vascular endothelial growth factor-C (VEGF-C) and green fluorescent protein specifically in the skin and studied the effects of chemically-induced skin carcinogenesis in this model. We found that in contrast to VEGF-A, VEGF-C does not increase the growth of primary tumors, but instead induces expansion of lymphatic networks within sentinel lymph nodes, even before the onset of metastasis. Once the metastatic cells arrived at the sentinel lymph nodes, the extent of lymphangiogenesis at these sites increased. Of importance, in mice with metastasis-containing sentinel lymph nodes, tumors that expressed VEGF-C were more likely to metastasize to additional organs, such as distal lymph nodes and lungs. No metastases were observed in distant organs in the absence of lymph node metastases. These findings indicate an important role of VEGF-C–induced lymph node lymphangiogenesis in the promotion of cancer metastasis beyond the sentinel lymph nodes. VEGF-C is therefore a good target to slow or even prevent the onset of metastasis.

Cell-derived Exosomes as Promising Carriers for Drug Delivery and Targeted Therapy

2018 ◽  
Vol 18 (4) ◽  
pp. 347-354 ◽  
Author(s):  
Xinyi Wang ◽  
Haiyang Zhang ◽  
Haiou Yang ◽  
Ming Bai ◽  
Tao Ning ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Therapy ◽  
Mononuclear Phagocyte ◽  
Targeted Therapeutics ◽  
Protein Protein Interaction ◽  
Chemotherapy Drugs ◽  
Donor Cells ◽  
Rapid Clearance ◽  
Low Efficiency ◽  
Electroporation Transfection

Exosomes are small vesicles that are secreted by various types of cells, known to mediate signal transduction between cells. During recent years, novel carriers for the delivery of targeted drugs, chemotherapy drugs and RNAs are under development, which is believed to be beneficial for patients. Considering issues of drug nano-formulations in bloodstream, such as nano-toxicity and rapid clearance by mononuclear phagocyte system, exosomes derived from either patient’s cells or bodyfluids, seem to be an optimal option. This review presents the current patterns of drug-loaded into exosomes and discusses how exosomes were reconstructed for targeted therapy. Loading either exosomes directly or their donor cells is an alternative, including incubation, electroporation, transfection of exosomes or transfection, incubation, activation of the parent cells. To solve the low efficiency of cargo loading into exosomes, protein loading via optically reversible protein-protein interaction can realize a novel exosomal protein carrier. In addition, targeted therapeutics with exosomes is achieved by three means, via adding targeting peptides into the surface of exosomes, by transferring specific genes within exosomes into tumors to establish a therapeutic target and, lastly, by targeting at exosomes containing tumor associated antigens. Nevertheless, purification and mass production of exosomes need further exploration, as well as more approaches were applied to targeted therapy. Therefore, exosomes could serve as an effective tool for drug delivery and targeted therapy.

scholarly journals The lymphatic system and sentinel lymph nodes: conduit for cancer metastasis

2021 ◽  
Author(s):  
Stanley P. Leong ◽  
Alexander Pissas ◽  
Muriel Scarato ◽  
Francoise Gallon ◽  
Marie Helene Pissas ◽  
...  
Keyword(s):  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Lymph Nodes ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Lymphatic System ◽  
Early Cancer ◽  
Lymphatic Vessels ◽  
Review Article ◽  
Cancer Spread

AbstractThe lymphatic system is a complicated system consisting of the lymphatic vessels and lymph nodes draining the extracellular fluid containing cellular debris, excess water and toxins to the circulatory system. The lymph nodes serve as a filter, thus, when the lymph fluid returns to the heart, it is completely sterile. In addition, the lymphatic system includes the mucosa-associated lymphoid tissue, such as tonsils, adenoids, Peyers patches in the small bowel and even the appendix. Taking advantage of the drainage system of the lymphatics, cancer cells enter the lymphatic vessels and then the lymph nodes. In general, the lymph nodes may serve as a gateway in the majority of cases in early cancer. Occasionally, the cancer cells may enter the blood vessels. This review article emphasizes the structural integrity of the lymphatic system through which cancer cells may spread. Using melanoma and breast cancer sentinel lymph node model systems, the spread of early cancer through the lymphatic system is progressive in a majority of cases. The lymphatic systems of the internal organs are much more complicated and difficult to study. Knowledge from melanoma and breast cancer spread to the sentinel lymph node may establish the basic principles of cancer metastasis. The goal of this review article is to emphasize the complexity of the lymphatic system. To date, the molecular mechanisms of cancer spread from the cancer microenvironment to the sentinel lymph node and distant sites are still poorly understood and their elucidation should take major priority in cancer metastasis research.

scholarly journals Pan and Sentinel Lymph Node Visualization Using a Near-Infrared Fluorescent Probe

2003 ◽  
Vol 2 (1) ◽  
pp. 153535002003021
Author(s):  
Lee Josephson ◽  
Umar Mahmood ◽  
Patrick Wunderbaldinger ◽  
Yi Tang ◽  
Ralph Weissleder
Keyword(s):  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Lymph Nodes ◽  
Subcutaneous Injection ◽  
Near Infrared ◽  
Subcutaneous Administration ◽  
Tissue Destruction ◽  
Live Animal ◽  
Nirf Imaging ◽  
Tissue Specimens

A number of different types of agents have been employed to aid in the visualization of lymph nodes, particularly the sentinel lymph node, and to decrease the tissue destruction associated with the diagnosis of nodal metastases. The current study was performed to see if a novel macromolecular near-infrared fluorescent (NIRF) probe could be used to visualize lymph nodes after intravenous administration (pan-node visualization) or subcutaneous administration (sentinel node visualization), and serve as method for guiding dissection with interventional radiologic and surgical procedures. Cy5.5-PGC, the near-infrared dye Cy5.5 coupled to a protected graft copolymer (PGC), was injected (iv or sc) into nude mice. Twenty-four hours later white light and NIRF images were obtained on (i) the live animal, (ii) a partially dissected animal, and (iii) tissue specimens. With Cy5.5-PGC administered intravenously, axillary nodes were visualized from outside a living mouse. With partial dissection, iliac and aortic nodes were visible as concentrated foci of high-intensity NIRF signals. With subcutaneous injection in the front extremity, axillary and brachial nodes draining the injection site were easily visualized. NIRF imaging provides a nonradioactive method of visualizing lymph nodes through layers of tissue that can be employed with intravenous or subcutaneous injection.

scholarly journals Axillary lymph nodes and breast cancer metastasis.

2021 ◽  
Vol 28 (7) ◽  
pp. 978-982
Author(s):  
Shahid Hussain Soomro ◽  
◽  
Abdul Sattar Abro ◽  
Vaqar-e-Sahar Shah ◽  
Saima Ather Shaikh ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Axillary Dissection ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Axillary Lymph Nodes ◽  
Lymph Node Status ◽  
Axillary Lymph ◽  
Carcinoma Breast ◽  
Female Patients

Objectives: The purpose of current study is to evaluate the correlation of axillary lymph node status with metastases in patients presented with carcinoma breast. Study Design: Prospective study. Setting: Surgical Unit 1, CMC Hospital Larkana. Period: March 2019 to January 2020. Material & Methods: Female patients presented with carcinoma breast were assessed clinically and by investigation then underwent a mastectomy and axillary dissection (sampling or clearance). Data was entered into pre-designed proforma. After proper staging, surgery was done in all patients accordingly. Lymph node involvement was confirmed histopathology. Then it was correlated with clinical findings. Results: Fifty-five female patients of proven carcinoma breast underwent a mastectomy and axillary dissection. The majority of the patients (76%) were between 30-60 years, the median age being 45 years. The left breast contained the tumor in 30 (55.5%) patients while the rest of the patients had the right breast involved. The size of the tumor varied from 2cm to 12cm. 33 (61%) patients were in the pre-menopausal state while 21 (38.88%) were in postmenopausal state. In 07 patients (13%) the axillary lymph nodes were not palpable while in the rest of the 47 patients (87%), the axillary lymph nodes were palpable to a variable extent. Most of the patients were in an advanced stages. Among seven patients (N0), histopathology revealed positive lymph nodes in 3/7 (42.85%) patients. Conclusion: Breast carcinoma is a serious type of carcinoma affecting the younger generation in our community, usually diagnosed at a late stage. Clinical examination is not an effective way for proper staging. Further investigations should be performed for accurate staging and management.

scholarly journals Cancer-Derived VEGF-C Increases Chemokine Production in Lymphatic Endothelial Cells to Promote CXCR2-Dependent Cancer Invasion and MDSC Recruitment

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1120
Author(s):  
Jing-Yi Chen ◽  
You-Syuan Lai ◽  
Pei-Yi Chu ◽  
Shih-Hsuan Chan ◽  
Lu-Hai Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Cancer Invasion ◽  
Lymphatic Endothelial Cells ◽  
Chemokine Production ◽  
Factor C

Breast cancer-derived vascular endothelial growth factor-C (VEGF-C) has been shown to enhance lymphangiogenesis in lymph nodes to accelerate cancer metastasis. However, the remodeling of lymph node microenvironments by VEGF-C remains elusive. By in vivo selection, we established a subline (named as “LC”) with strong lymphatic tropism and high VEGF-C expression from the human MDA-MB-231 breast cancer cell line. Co-culture with LC cells or treatment with LC-conditioned medium upregulated the expression of CXC chemokines in lymphatic endothelial cells (LECs), which could be inhibited by pre-incubation with VEGF-C-neutralizing antibodies and VEGFR3 inhibitors. The chemokines produced by LECs enhanced recruitment of myeloid-derived suppressor cells (MDSCs) to tumor-draining and distant lymph nodes in tumor-bearing mice. Treatment with a CXCR2 inhibitor after tumor cell inoculation dramatically decreased the number of MDSCs in lymph nodes, suggesting the importance of the chemokine/CXCR2 signaling axis in MDSC recruitment. In addition, LEC-released chemokines also stimulated the expression of serum amyloid A1 (SAA1) in cancer cells, enhancing their lymphatic invasion by increasing VE-cadherin phosphorylation, junction disruption, and vascular permeability of LECs. Clinical sample validation confirmed that SAA1 expression was associated with increased lymph node metastasis. Collectively, we reveal a novel mechanism by which cancer cell-derived VEGF-C remodels lymphovascular microenvironments by regulating chemokine production in LECs to promote cancer invasion and MDSC recruitment. Our results also suggest that inhibition of CXCR2 is effective in treating lymphatic metastasis.

scholarly journals Lymph Node-Targeting Nanovaccine through Antigen-CpG Self-Assembly Potentiates Cytotoxic T Cell Activation

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaobo Xi ◽  
Lijun Zhang ◽  
Guihong Lu ◽  
Xiaoyong Gao ◽  
Wei Wei ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Self Assembly ◽  
Cytotoxic T Cell ◽  
Therapeutic Vaccines ◽  
Loading Efficiency ◽  
Lymph Node Targeting

Therapeutic vaccines that arouse the cytotoxic T cell immune response to reject infected cells have been investigated extensively for treating disease. Due to the large amounts of resident antigen-presenting cells (APCs) and T cells in lymph nodes, great efforts have been made to explore the strategy of targeting lymph nodes directly with nanovaccines to activate T cells. However, these nanovaccines still have several problems, such as a low loading efficiency and compromised activity of antigens and adjuvants derived from traditional complicated preparation. There are also safety concerns about materials synthesized without FDA approval. Herein, we construct an assembled nanoparticle composed of an antigen (ovalbumin, OVA) and adjuvant (CpG) to ensure its safety and high loading efficiency. The activity of both components was well preserved due to the mild self-assembly process. The small size, narrow distribution, negative charge, and good stability of the nanoparticle endow these nanovaccines with superior capacity for lymph node targeting. Correspondingly, the accumulation at lymph nodes can be improved by 10-fold. Subsequently, due to the sufficient APC internalization and maturation in lymph nodes, ~60% of T cells are stimulated to proliferate and over 70% of target cells are specifically killed. Based on the effective and quick cellular immune response, the assembled nanoparticles exhibit great potential as therapeutic vaccines.

Tyrosine kinase receptor AXL in human breast cancer is expressed differentially in metastasis of the lymph node

2021 ◽  
Author(s):  
Mairead Paul ◽  
Brandon Weston ◽  
Oliwier Morin
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Disease Free Survival ◽  
Tyrosine Kinase Receptor ◽  
Axillary Lymph ◽  
Primary Tumors ◽  
Node Metastasis

The most diagnosed malignancy in women is breast cancer1. Metastases in people diagnosed with cancer are the main cause of mortality. 2. Patients with breast cancer are predicted to do worse as the number of metastasized axillary lymph nodes increases3. In order to uncover the genes related with metastases in lymph nodes, the early events of the breast cancer metastasis, we mined the published and multiplexed mRNA quantitation datasets4, 5. When lymph node metastasis was compared to original breast tumors by patients diagnosed with breast cancer, we identified substantial differential expression of AXL encoding. The lower expression of AXL in primary tumors is associated with reduced disease-free survival in patients with breast cancer. AXL may be important in mechanisms that underlie lymph node metastasis.

scholarly journals ASSOCIATION OF MICRORNA EXPRESSION WITH EARLY STAGE OF BREAST CANCER METASTASIS

2018 ◽  
Vol 23 (3-6) ◽  
pp. 129-133
Author(s):  
Kristina A. Grishina ◽  
N. I Pospekhova ◽  
V. A Khaylenko ◽  
A. V Karpukhin
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Mirna Expression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Metastatic Breast ◽  
Mesenchymal Transition

A serious complication of breast cancer is metastasis of tumor cells. The initiation of this process takes place in the nearby lymphatic vessels. To date, the molecular mechanisms of metastasis are not well understood and further research is required. In this regard, the level of miRNA expression can provide information both on the mechanisms of metastasis development and also be a source of markers for the prognosis of metastatic breast cancer. In the present work, according to the literature, we selected four microRNAs (miR-34a, miR-145, miR-125b and miR-222), potentially capable of being associated with metastasis, to study their association with metastasis to lymph nodes at an early stage. The measurement of the expression of four selected miRNAs on 40 paired samples (tumor-norm) was performed using real-time PCR. Frequencies of miR-34a, miR-145, miR-125b, and miR-222 relative to normal tissue were determined for reduced or increased miR-mRNA expression. For a more detailed study of the association of miRNA expression with lymph node metastasis, miR-125b and miR-222 were selected. An association of expression of these two miRNAs was found with the onset of metastasis to the lymph nodes: with the same level of confidence, differences (p = 0.01). Both miRNAs (miR-125b and miR-222) are involved in the metastasis of breast cancer, apparently by influencing the epithelial-mesenchymal transition. They can potentially act as prognostic biomarkers to assess the likelihood of early lymph node metastases in breast cancer.

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