PMID- 38212302 OWN - NLM STAT- MEDLINE DCOM- 20240124 LR - 20240131 IS - 1936-086X (Electronic) IS - 1936-0851 (Linking) VI - 18 IP - 3 DP - 2024 Jan 23 TI - MRI Detection of Lymph Node Metastasis through Molecular Targeting of C-C Chemokine Receptor Type 2 and Monocyte Hitchhiking. PG - 2091-2104 LID - 10.1021/acsnano.3c09201 [doi] AB - Biopsy is the clinical standard for diagnosing lymph node (LN) metastasis, but it is invasive and poses significant risk to patient health. Magnetic resonance imaging (MRI) has been utilized as a noninvasive alternative but is limited by low sensitivity, with only approximately 35% of LN metastases detected, as clinical contrast agents cannot discriminate between healthy and metastatic LNs due to nonspecific accumulation. Nanoparticles targeted to the C-C chemokine receptor 2 (CCR2), a biomarker highly expressed in metastatic LNs, have the potential to guide the delivery of contrast agents, improving the sensitivity of MRI. Additionally, cancer cells in metastatic LNs produce monocyte chemotactic protein 1 (MCP1), which binds to CCR2(+) inflammatory monocytes and stimulates their migration. Thus, the molecular targeting of CCR2 may enable nanoparticle hitchhiking onto monocytes, providing an additional mechanism for metastatic LN targeting and early detection. Hence, we developed micelles incorporating gadolinium (Gd) and peptides derived from the CCR2-binding motif of MCP1 (MCP1-Gd) and evaluated the potential of MCP1-Gd to detect LN metastasis. When incubated with migrating monocytes in vitro, MCP1-Gd transport across lymphatic endothelium increased 2-fold relative to nontargeting controls. After administration into mouse models with initial LN metastasis and recurrent LN metastasis, MCP1-Gd detected metastatic LNs by increasing MRI signal by 30-50% relative to healthy LNs. Furthermore, LN targeting was dependent on monocyte hitchhiking, as monocyte depletion decreased accumulation by >70%. Herein, we present a nanoparticle contrast agent for MRI detection of LN metastasis mediated by CCR2-targeting and demonstrate the potential of monocyte hitchhiking for enhanced nanoparticle delivery. FAU - Trac, Noah AU - Trac N AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. FAU - Chen, Zixi AU - Chen Z AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. FAU - Oh, Hyun-Seok AU - Oh HS AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. FAU - Jones, Leila AU - Jones L AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. FAU - Huang, Yi AU - Huang Y AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. FAU - Giblin, Joshua AU - Giblin J AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. FAU - Gross, Mitchell AU - Gross M AD - Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, California 90064, United States. AD - Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States. FAU - Sta Maria, Naomi S AU - Sta Maria NS AD - Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute and Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States. FAU - Jacobs, Russell E AU - Jacobs RE AD - Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute and Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States. FAU - Chung, Eun Ji AU - Chung EJ AUID- ORCID: 0000-0002-7726-5555 AD - Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States. AD - Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States. AD - Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States. AD - Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States. AD - Department of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States. AD - Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States. AD - Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States. LA - eng PT - Journal Article DEP - 20240111 PL - United States TA - ACS Nano JT - ACS nano JID - 101313589 RN - 0 (Contrast Media) RN - 0 (Receptors, Chemokine) SB - IM MH - Animals MH - Mice MH - Humans MH - *Lymph Nodes/diagnostic imaging/pathology MH - *Contrast Media/chemistry MH - Monocytes MH - Lymphatic Metastasis/diagnostic imaging/pathology MH - Molecular Targeted Therapy MH - Magnetic Resonance Imaging/methods MH - Receptors, Chemokine OTO - NOTNLM OT - CCR2 OT - MRI OT - hitchhiking OT - lymph node OT - metastasis OT - micelle OT - monocyte EDAT- 2024/01/12 00:42 MHDA- 2024/01/24 06:43 CRDT- 2024/01/11 23:13 PHST- 2024/01/24 06:43 [medline] PHST- 2024/01/12 00:42 [pubmed] PHST- 2024/01/11 23:13 [entrez] AID - 10.1021/acsnano.3c09201 [doi] PST - ppublish SO - ACS Nano. 2024 Jan 23;18(3):2091-2104. doi: 10.1021/acsnano.3c09201. Epub 2024 Jan 11.