Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial venule-targeted delivery

Liwei Jiang; Sungwook Jung; Jing Zhao; Vivek Kasinath; Takaharu Ichimura; John Joseph; Paolo Fiorina; Andrew S Liss; Khalid Shah; Nasim Annabi; Nitin Joshi; Tomoya O Akama; Jonathan S Bromberg; Motohiro Kobayashi; Kenji Uchimura; Reza Abdi

doi:10.1016/j.nantod.2020.101045

Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial venule-targeted delivery

Nano Today. 2021 Feb:36:101045. doi: 10.1016/j.nantod.2020.101045. Epub 2020 Dec 14.

Authors

Liwei Jiang¹, Sungwook Jung¹, Jing Zhao¹, Vivek Kasinath¹, Takaharu Ichimura², John Joseph³, Paolo Fiorina⁴, Andrew S Liss⁵, Khalid Shah⁶, Nasim Annabi^{7

8}, Nitin Joshi^{3

9}, Tomoya O Akama¹⁰, Jonathan S Bromberg¹¹, Motohiro Kobayashi¹², Kenji Uchimura^{13

14}, Reza Abdi¹

Affiliations

¹ Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Department of Surgery and the Andrew L. Warshaw, MD Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women's Hospital, Harvard medical School, Boston, MA, 02115, USA.
⁷ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA, 90095, USA.
⁸ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁰ Department of Pharmacology, Kansai Medical University, Osaka, 570-8506, Japan.
¹¹ Departments of Surgery and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹² Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
¹³ Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
¹⁴ CNRS, UMR 8576, Unit of Glycobiology Structures and Functions, University of Lille, F-59000 Lille, France.

Abstract

Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data, for the first time, indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.

Abstract

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