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Dox-HCl and miR-145 co-delivery through CD44-targeted PEGylated liposomes inhibit Breast Cancer in vitro via
Chu Xin Ng1, Sau Har Lee1,2, Pei Pei Chong1,2
1School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia.
Aims:
The aim of this study deals with integrating a CD44-targeting short peptide, A6 (KPSSPPEE) onto the PEGylated liposomes to enhance the in vitro anticancer activities of doxorubicin hydrochloride and tumor suppressor miR-145 mimics on triple-negative breast cancer.
Methods:
A CD44-targeting short peptide, A6 (KPSSPPEE) was integrated onto the optimized PEGylated liposomes, and its effects on cellular uptake, anti-proliferation, and anti-metastasis activities were assessed in triple-negative breast cancer, MDA-MB-231 cells.
Results:
The resulting formulation (A6-PEG-lipo-Dox-miR145) demonstrated enhanced cellular uptake by CD44-expressing MDA-MB-231 cells within 2 h of incubation. In vitro study showed that A6-PEG-lipo-Dox-miR145 exerted a greater anti-proliferative activity with higher selectivity (Dox-HCl IC50 = 1.60 ± 0.07 μM; selectivity index (SI) = 1.30) against MDA-MB-231 cells when compared to MCF10A cells, which an enhanced suppression of PI3K/AKT pathway was observed, highlighting its potential as a targeted therapy for TNBC. Additionally, A6-PEG-lipo-Dox-miR145 showed anti-migration and improved anti-invasion activities on MDA-MB-231 cells, which correlated with its ability in reversing endothelial-to-mesenchymal transition (EMT) through modulating both N-cadherin and E-cadherin expression.
Conclusion:
Our findings indicate that the incorporation of A6 peptide represents a simple and straightforward strategy to improve the targetability and therapeutic effects of PEGylated liposome, warranting further investigation.
Insights
This study enhanced doxorubicin and miR-145 delivery for triple-negative breast cancer using CD44-targeting liposomes. The A6 peptide improved cancer cell uptake and reduced tumor growth, migration, and invasion.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and lack of targeted treatment options.
- Liposomal drug delivery systems offer potential for improved cancer therapy, but targeted delivery remains crucial for efficacy.
- CD44 receptor is overexpressed in many cancer types, including TNBC, making it a promising target for drug delivery.
Purpose of the Study:
- To develop and evaluate CD44-targeting PEGylated liposomes loaded with doxorubicin hydrochloride and miR-145 mimics for enhanced TNBC treatment.
- To assess the impact of integrating the A6 peptide on liposome characteristics, cellular uptake, and in vitro anticancer efficacy.
Main Methods:
- A CD44-targeting peptide (A6) was conjugated to optimized PEGylated liposomes encapsulating doxorubicin hydrochloride and miR-145 mimics.
- Cellular uptake, anti-proliferation, anti-migration, and anti-invasion assays were performed on MDA-MB-231 (TNBC) and MCF10A cells.
- The modulation of key signaling pathways (PI3K/AKT) and epithelial-mesenchymal transition (EMT) markers (N-cadherin, E-cadherin) was investigated.
Main Results:
- The A6-conjugated liposomes (A6-PEG-lipo-Dox-miR145) showed enhanced cellular uptake in CD44-expressing MDA-MB-231 cells within 2 hours.
- A6-PEG-lipo-Dox-miR145 exhibited significantly greater anti-proliferative activity and selectivity against TNBC cells compared to non-cancerous cells.
- The formulation demonstrated potent anti-migration and anti-invasion effects, reversing EMT by modulating N-cadherin and E-cadherin expression, alongside PI3K/AKT pathway suppression.
Conclusions:
- The incorporation of the A6 peptide onto PEGylated liposomes is an effective strategy to enhance targetability and therapeutic outcomes for TNBC.
- This targeted liposomal formulation holds promise as a novel therapeutic approach for triple-negative breast cancer.
- Further preclinical investigations are warranted to explore the full potential of this targeted delivery system.
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