Lymphatic transport and lymph node targeting of methotrexate-conjugated PEGylated dendrimers are enhanced by reducing the length of the drug linker or masking interactions with the injection site

Gemma M Ryan, Victoria M McLeod, Dharmini Mehta, Brian D Kelly, Pauline C Stanislawski, David J. Owen, Lisa M. Kaminskas, Christopher J H Porter

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Drug conjugation to dendrimer-based delivery systems has been shown to enhance delivery to the lymphatic system after subcutaneous administration. Dendrimer interaction with components of the interstitium at the injection site, however, may prevent drainage from the injection site. The current study sought to vary the length of a linker employed to conjugate methotrexate (MTX) to a PEGylated dendrimer, in an attempt to reduce MTX interaction with interstitial binding sites and enhance lymphatic drainage. Dendrimers with shorter linkers resulted in higher lymphatic drainage, presumably via shielding of interaction sites by the PEG mantle, but were not retained in lymph nodes. Improved drainage of dendrimers with longer linkers was achieved through coadministration with dextran to mask interactions at the injection site while maintaining retention within the node. Enhanced drug exposure to the lymph node has the potential to enhance the treatment of lymph-node resident cancer metastases.

Original languageEnglish
Pages (from-to)2485-2494
Number of pages10
JournalNanomedicine-Nanotechnology Biology and Medicine
Volume13
Issue number8
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • Dendrimer
  • Lymphatic
  • Methotrexate
  • Pharmacokinetics
  • Subcutaneous

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