Methotrexate-Conjugated PEGylated Dendrimers Show Differential Patterns of Deposition and Activity in Tumor-Burdened Lymph Nodes after Intravenous and Subcutaneous Administration in Rats

详细信息    查看全文

• 作者：Lisa M. Kaminskas ; Victoria M. McLeod ; David B. Ascher ; Gemma M. Ryan ; Seth Jones ; John M. Haynes ; Natalie L. Trevaskis ; Linda J. Chan ; Erica K. Sloan ; Benjamin A. Finnin ; Mark Williamson ; Tony Velkov ; Elizabeth D. Williams ; Brian D. Kelly ; David J. Owen ; Christopher J. H. Porter
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：February 2, 2015
• 年：2015
• 卷：12
• 期：2
• 页码：432-443
• 全文大小：464K
• ISSN：1543-8392

文摘

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鈥揗TX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was 伪-carboxyl O-tert-butylated [D鈥揗TX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D鈥揗TX(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鈥揗TX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D鈥揗TX(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鈥揗TX(OH) and D鈥揗TX(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 tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.