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

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 metho...

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Published in:Pharmaceutics 2024-07, Vol.16 (8), p.981
Main Authors: Kuhn, Paul M, Russo, Gabriella C, Crawford, Ashleigh J, Venkatraman, Aditya, Yang, Nanlan, Starich, Bartholomew A, Schneiderman, Zachary, Wu, Pei-Hsun, Vo, Thi, Wirtz, Denis, Kokkoli, Efrosini
Format: Article
Language:English
Subjects:
Biomarkers
Breast cancer
doxorubicin
Drug dosages
E-cadherin positive breast cancer
Genotype & phenotype
hydrogel
Hydrogels
MEK inhibitor
Melanoma
Metastasis
Nanoparticles
Peptides
Phase transitions
Polyethylene glycol
Polymers
PR_b-targeted liposomes
Temperature
Toxicity
Tumors
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Summary: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- -lactide)- -poly(ethylene-glycol)- -poly(δ-valerolactone- -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 α β 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.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics16080981