Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in E-Cadherin-Positive Breast Cancer

Paul M. Kuhn; Gabriella C. Russo; Ashleigh J. Crawford; Aditya Venkatraman; Nanlan Yang; Bartholomew A. Starich; Zachary Schneiderman; Pei-Hsun Wu; Thi Vo; Denis Wirtz; Efrosini Kokkoli

doi:10.3390/pharmaceutics16080981

Pharmaceutics (Jul 2024)

Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in E-Cadherin-Positive Breast Cancer

Paul M. Kuhn,
Gabriella C. Russo,
Ashleigh J. Crawford,
Aditya Venkatraman,
Nanlan Yang,
Bartholomew A. Starich,
Zachary Schneiderman,
Pei-Hsun Wu,
Thi Vo,
Denis Wirtz,
Efrosini Kokkoli

Affiliations

Paul M. Kuhn: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Gabriella C. Russo: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Ashleigh J. Crawford: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Aditya Venkatraman: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Nanlan Yang: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Bartholomew A. Starich: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Zachary Schneiderman: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Pei-Hsun Wu: Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Thi Vo: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Denis Wirtz: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Efrosini Kokkoli: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA

DOI: https://doi.org/10.3390/pharmaceutics16080981
Journal volume & issue: Vol. 16, no. 8
p. 981

Abstract

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Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α5β1 integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy.

Published in Pharmaceutics

ISSN: 1999-4923 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceutics/

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