Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumour-burdened lymph nodes after intravenous and subcutaneous administration in rats

Kaminskas, Lisa M., McLeod, Victoria M., Ascher, David B., Ryan, Gemma M., Jones, Seth, Haynes, John M., Trevaskis, Natalie L., Chan, Linda J., Sloan, Erica K., Finnin, Benjamin A., Williamson, Mark, Velkov, Tony, Williams, Elizabeth D., Kelly, Brian D., Owen, David J., & Porter, Christopher J.H. (2015) Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumour-burdened lymph nodes after intravenous and subcutaneous administration in rats. Molecular Pharmaceutics, 12(2), pp. 432-443.

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Abstract

The current study sought to explore whether the subcutaneous administration of lymph-targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumour activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumour-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumour growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumour-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumour activity, possibly suggesting constrained drug release at the site of action.

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ID Code: 80215
Item Type: Journal Article
Refereed: Yes
DOI: 10.1021/mp500531e
ISSN: 1543-8392
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > QUT Faculties and Divisions > Science & Engineering Faculty
Copyright Owner: Copyright 2014 American Chemical Society
Deposited On: 19 Jan 2015 02:11
Last Modified: 04 Jan 2016 10:52

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