Journal article
Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumor-burdened lymph nodes after intravenous and subcutaneous administration in rats
LM Kaminskas, VM McLeod, DB Ascher, GM Ryan, S Jones, JM Haynes, NL Trevaskis, LJ Chan, EK Sloan, BA Finnin, M Williamson, T Velkov, ED Williams, BD Kelly, DJ Owen, CJH Porter
Molecular Pharmaceutics | AMER CHEMICAL SOC | Published : 2015
DOI: 10.1021/mp500531e
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 antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-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 ..
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Funding Acknowledgements
This work was funded by an ARC linkage grant. L.M.K. and T.V. were supported by an NHMRC Career Development fellowship. D.B.A. was supported by a Victoria Fellowship from the Victorian Government and the Leslie (Les) J. Fleming Churchill Fellowship from The Winston Churchill Memorial Trust. G.M.R. was supported by a Cancer Council Victoria Postgraduate Scholarship. Funding was received from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute of Medical Research.