Issue 1, 2015

High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo

Abstract

Here we present the polymer conjugates where the core formed by poly(amido amine) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DTX) attached by a pH-sensitive hydrazone bond. DTX was derivatized with three different keto acids prior to attachment to the polymer carrier to introduce reactive keto groups into the drug. The therapeutic efficacy of such high-molecular-weight star conjugates is based on: (a) the enhanced permeability and retention (EPR) effect facilitating selective accumulation within solid tumors; (b) pH-controlled release of the drug, thus ensuring faster DTX release in the mildly acidic tumor microenvironment. The star DTX conjugate had a remarkably higher maximum tolerated dose in comparison with free DTX when administered as a single i.v. injection (∼160 mg kg−1vs. 40 mg kg−1 of DTX) in C57BL/6 mice. The star DTX conjugate showed significantly higher antitumor activity than free drug in the EL4 T cell lymphoma growing in syngeneic C57BL/6 mice even when given at the same dose (20 mg kg−1 of DTX eq.). Thus, the star DTX conjugates exert a much higher therapeutic activity and yet a lower systemic toxicity than free DTX.

Graphical abstract: High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo

Article information

Article type
Paper
Submitted
14 Aug 2014
Accepted
09 Sep 2014
First published
10 Sep 2014
This article is Open Access
Creative Commons BY-NC license

Polym. Chem., 2015,6, 160-170

High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo

T. Etrych, J. Strohalm, M. Šírová, B. Tomalová, P. Rossmann, B. Říhová, K. Ulbrich and M. Kovář, Polym. Chem., 2015, 6, 160 DOI: 10.1039/C4PY01120A

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements