Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in
Paul M Kuhn1,2, Gabriella C Russo1,2, Ashleigh J Crawford1,2
1Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Abstract:
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.
Insights
This study introduces a novel hydrogel-liposome system for targeted drug delivery in breast cancer. It effectively reduces tumor progression and improves survival by locally releasing MEK inhibitors and doxorubicin, minimizing toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Clinical use of MEK inhibitors is limited by toxicity and lack of predictive biomarkers.
- E-cadherin is identified as a potential biomarker for MEK inhibitor efficacy in breast cancer.
- Systemic nanoparticle delivery of therapeutics requires frequent, high-dose injections, leading to toxicity.
Purpose of the Study:
- To develop a localized, sustained-release drug delivery system for MEK inhibitors and doxorubicin.
- To overcome the challenges of MEK inhibitor toxicity and improve treatment outcomes in E-cadherin-positive triple-negative breast cancer (TNBC).
- To investigate the therapeutic potential of a hydrogel-liposome system functionalized with a peptide targeting α5β1 integrin.
Main Methods:
- Fabrication of a thermosensitive, biodegradable triblock co-polymer hydrogel for sustained drug release.
- Functionalization of liposomes with PR_b peptide to target α5β1 integrin overexpressed in E-cadherin-positive TNBC.
- Local injection of the hydrogel-liposome system containing MEK inhibitor PD0325901 and doxorubicin into TNBC models.
Main Results:
- The hydrogel-liposome system demonstrated local and sustained release of both PD0325901 and doxorubicin.
- Targeted delivery to E-cadherin-positive TNBC models significantly reduced tumor progression.
- Improved animal survival rates were observed without significant toxic side effects.
Conclusions:
- This study presents the first localized, sustained delivery of MEK inhibitors to E-cadherin-positive tumors.
- The developed hydrogel-liposome system offers a safe and promising therapeutic strategy for TNBC treatment.
- This approach addresses MEK inhibitor toxicity and enhances therapeutic efficacy through targeted delivery.
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