In vivo comparative study of distinct polymeric architectures bearing a combination of paclitaxel and doxorubicin at a synergistic ratio

Hemda Baabur-Cohen, Laura Isabel Vossen, Harald Rune Krüger, Anat Eldar-boock, Eilam Yeini, Natalie Landa-Rouben, Galia Tiram, Stefanie Wedepohl, Ela Markovsky, Jonathan Leor, Marcelo Calderón*, Ronit Satchi-Fainaro

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Nowadays, combination therapy became a standard in oncology. In this study, we compare the activity of two polymeric carriers bearing a combination of the anticancer drugs paclitaxel (PTX) and doxorubicin (DOX), which differ mainly in their architecture and supramolecular assembly. Drugs were covalently bound to a linear polymer, polyglutamic acid (PGA) or to a dendritic scaffold, polyglycerol (PG) decorated with poly(ethylene glycol) (PEG), forming PGA-PTX-DOX and PG-PTX-bz-DOX-PEG, respectively. We explored the relationship between the polymeric architectures and their performance with the aim to augment the pharmacological benefits of releasing both drugs simultaneously at the tumor site at a synergistic ratio. We recently designed and characterized a PGA-PTX-DOX conjugate. Here, we describe the synthesis and characterization of PG dendritic scaffold bearing the combination of PTX and DOX. The performance of both conjugates was evaluated in a murine model of mammary adenocarcinoma in immunocompetent mice, to investigate whether the activity of the treatments is affected by the immune system. Drug conjugation to a nano-sized polymer enabled preferred tumor accumulation by extravasation-dependent targeting, making use of the enhanced permeability and retention (EPR) effect. Both PGA-PTX-DOX and PG-PTX-bz-DOX-PEG nano-sized conjugates exhibited superior anti-tumor efficacy and safety compared to the combination of the free drugs, at equivalent concentrations. However, while PGA-PTX-DOX was more efficient than a mixture of each drug conjugated to a separate PGA chain, as was previously shown, PG-PTX-bz-DOX-PEG had similar activity to the mixture of the PG-PTX-bz-PEG and PG-DOX-PEG conjugates. Our results show that both conjugates are potential candidates as precision combination nanomedicines for the treatment of breast cancer.

Original languageEnglish
Pages (from-to)118-131
Number of pages14
JournalJournal of Controlled Release
Volume257
DOIs
StatePublished - 10 Jul 2017

Funding

FundersFunder number
Israeli National Nanotechnology Initiative
Focus Area Nanoscale
Focal Technology Area
European Commission
Leona M. and Harry B. Helmsley Nanotechnology Research Fund
European Research Council617445
Bundesministerium für Bildung und Forschung13N12561
Israel Science Foundation918/14

    Keywords

    • Combination therapy
    • Dendritic polymer
    • Doxorubicin
    • Paclitaxel
    • Polyglutamic acid
    • Polyglycerol
    • Polymeric nanomedicines

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