Conjugation of chemotherapeutic drugs to a polymer allows specific delivery to the tumor by the enhanced permeability and retention (EPR) effect and provides an ideal platform for a combination treatment, since both drugs are given simultaneously in one injection and share the same pharmacokinetic profile(1,2).
We have found that the combination ofpaclitaxel (PTX) anddoxorubicin (DOX) displays a synergistic cytotoxic effect on cancer cell lines, such as MDA-MB-231human mammary adenocarcinoma and ES-2 human ovarian carcinoma.
PTX and DOX were bound to polyglutamic acid (PGA), a water-soluble, biocompatible polymer, which is biodegradable by enzymes overexpressed in tumor tissue, particularly cathepsin B. PTX was bound directly to the PGA backbone and DOX was coupled via an acid-labile hydrazone linker.
We show here that PGA-PTX-DOX exhibited a significant anti-proliferative and anti-migratory effect on MDA-MB-231 and ES-2 cells. More importantly, our novel conjugate was highly effective in inhibiting the growth of mammary tumors inoculated orthotropically into the mammary fat pad of nu/nu female mice, compared to combination of free drugs and drugs conjugated to polymer separately. Furthermore, PGA-PTX-DOX had no toxic effectsin vivoand did not induce immune response in human peripheral blood mononuclear cells in contrast to the free drugs.
Our results with PGA-PTX-DOX nano-conjugate present its potential use as a novel combination therapy for breast and ovarian cancer.
References
1. E. Markovskyet al.,J Control Release161, 446 (Jul 20, 2012).
2. A. Eldar-Boock, D. Polyak, A. Scomparin, R. Satchi-Fainaro,Curr Opin Biotechin press, (2013).
*Equal contribution
