Simultaneous Targeting of Primary Tumor, Draining Lymph Node, and Distant Metastases Through High Endothelial Venule-targeted Delivery

Overview

Journal Nano Today

Specialty Biotechnology

Date 2021 Jan 4

PMID 33391389

Citations 19

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Fankhauser M, Broggi M, Potin L, Bordry N, Jeanbart L, Lund A . Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Sci Transl Med. 2017; 9(407). DOI: 10.1126/scitranslmed.aal4712. View

Zhang L, Su H, Liu Y, Pang N, Li J, Qi X . Enhancing solid tumor therapy with sequential delivery of dexamethasone and docetaxel engineered in a single carrier to overcome stromal resistance to drug delivery. J Control Release. 2018; 294:1-16. DOI: 10.1016/j.jconrel.2018.12.004. View

Gerlini G, Urso C, Mariotti G, Di Gennaro P, Palli D, Brandani P . Plasmacytoid dendritic cells represent a major dendritic cell subset in sentinel lymph nodes of melanoma patients and accumulate in metastatic nodes. Clin Immunol. 2007; 125(2):184-93. DOI: 10.1016/j.clim.2007.07.018. View

Sammet B, Steinkuhler C, Sewald N . Antibody-drug conjugates in tumor therapy. Pharm Pat Anal. 2013; 1(1):65-73. DOI: 10.4155/ppa.12.4. View

Kovtun Y, Audette C, Ye Y, Xie H, Ruberti M, Phinney S . Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006; 66(6):3214-21. DOI: 10.1158/0008-5472.CAN-05-3973. View

Alitalo K . The lymphatic vasculature in disease. Nat Med. 2011; 17(11):1371-80. DOI: 10.1038/nm.2545. View

Mayor S, Pagano R . Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol. 2007; 8(8):603-12. PMC: 7617177. DOI: 10.1038/nrm2216. View

Li X, Bean A, Uehara M, Banouni N, Ben Nasr M, Kasinath V . Immune heterogeneity of head and tail pancreatic lymph nodes in non-obese diabetic mice. Sci Rep. 2019; 9(1):9778. PMC: 6611787. DOI: 10.1038/s41598-019-45899-1. View

Collins D, Bossenmaier B, Kollmorgen G, Niederfellner G . Acquired Resistance to Antibody-Drug Conjugates. Cancers (Basel). 2019; 11(3). PMC: 6468698. DOI: 10.3390/cancers11030394. View

10.

Kung Sutherland M, Sanderson R, Gordon K, Andreyka J, Cerveny C, Yu C . Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem. 2006; 281(15):10540-7. DOI: 10.1074/jbc.M510026200. View

11.

Wang L, Ganly I . Nodal metastases in thyroid cancer: prognostic implications and management. Future Oncol. 2016; 12(7):981-94. PMC: 4992997. DOI: 10.2217/fon.16.10. View

12.

Xia Y, Zhang B, Zhang H, Li W, Wang K, Shen H . Evaluation of lymph node metastasis in lung cancer: who is the chief justice?. J Thorac Dis. 2016; 7(Suppl 4):S231-7. PMC: 4700368. DOI: 10.3978/j.issn.2072-1439.2015.11.63. View

13.

Rawla P, Sunkara T, Gaduputi V . Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019; 10(1):10-27. PMC: 6396775. DOI: 10.14740/wjon1166. View

14.

Lambert A, Pattabiraman D, Weinberg R . Emerging Biological Principles of Metastasis. Cell. 2017; 168(4):670-691. PMC: 5308465. DOI: 10.1016/j.cell.2016.11.037. View

15.

Seyfried T, Huysentruyt L . On the origin of cancer metastasis. Crit Rev Oncog. 2012; 18(1-2):43-73. PMC: 3597235. DOI: 10.1615/critrevoncog.v18.i1-2.40. View

16.

Rybinski B, Franco-Barraza J, Cukierman E . The wound healing, chronic fibrosis, and cancer progression triad. Physiol Genomics. 2014; 46(7):223-44. PMC: 4035661. DOI: 10.1152/physiolgenomics.00158.2013. View

17.

Maarouf O, Uehara M, Kasinath V, Solhjou Z, Banouni N, Bahmani B . Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing. JCI Insight. 2018; 3(13). PMC: 6124521. DOI: 10.1172/jci.insight.120546. View

18.

Majzner R, Mackall C . Tumor Antigen Escape from CAR T-cell Therapy. Cancer Discov. 2018; 8(10):1219-1226. DOI: 10.1158/2159-8290.CD-18-0442. View

19.

Ernsting M, Hoang B, Lohse I, Undzys E, Cao P, Do T . Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle. J Control Release. 2015; 206:122-30. PMC: 4409566. DOI: 10.1016/j.jconrel.2015.03.023. View

20.

Fontebasso Y, Dubinett S . Drug Development for Metastasis Prevention. Crit Rev Oncog. 2016; 20(5-6):449-73. PMC: 6497172. DOI: 10.1615/CritRevOncog.v20.i5-6.150. View