Polymer Therapeutics Rationally-Designed for a Combination Therapy of Paclitaxel and Doxorubicin

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 of paclitaxel (PTX) and doxorubicin (DOX) displays a synergistic cytotoxic effect on cancer cell lines, such as MDA-MB-231 human 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 effects in vivo and 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.

Keywords: Polymer therapeutics, nanomedicines, combination therapy, EPR effect

References

1. E. Markovsky et al., J Control Release 161, 446 (Jul 20, 2012).
2. A. Eldar-Boock, D. Polyak, A. Scomparin, R. Satchi-Fainaro, Curr Opin Biotech in press, (2013).