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HER-2 Receptor and αvβ3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy
Dilip Kumar Arya1, Hemali Deshpande2, Ashish Kumar3
1Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India.
Abstract:
Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.
Insights
This study developed dual-ligand functionalized liposomes co-loaded with Gefitinib and Lycorine hydrochloride for HER2-positive breast cancer. These liposomes showed enhanced cellular uptake and anti-cancer effects, suggesting a promising therapeutic strategy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Metastatic HER2-positive breast cancer remains a leading cause of cancer mortality worldwide.
- Targeted therapies like Trastuzumab have improved treatment but challenges persist.
- Novel drug delivery systems are needed to enhance therapeutic efficacy and overcome resistance.
Purpose of the Study:
- To develop and characterize dual surface-decorated liposomes (DSDLs) co-loaded with Gefitinib (GFB) and Lycorine hydrochloride (LCH).
- To functionalize liposomes with Trastuzumab (Trast) and iRGD peptide for targeted delivery to HER2-positive breast cancer.
- To evaluate the in-vitro efficacy, cellular uptake, and biosafety of the developed DSDLs.
Main Methods:
- Solvent injection method was used to prepare TPGS-COOH-coated liposomes co-encapsulating GFB and LCH.
- Liposomes were surface-functionalized with Trastuzumab (Trast) and the tumor-homing peptide iRGD.
- Characterization included particle size, PDI, zeta potential, surface morphology, in-vitro drug release, encapsulation efficiency, and cytotoxicity assays on SK-BR-3 and MDA-MB-231 cells.
Main Results:
- DSDLs exhibited enhanced cellular uptake and significantly reduced IC-50 values compared to single-ligand liposomes in both HER2-positive (SK-BR-3) and HER2-negative (MDA-MB-231) breast cancer cell lines.
- Functionalization with iRGD and Trast significantly improved cellular uptake, as confirmed by CLSM.
- Wound-healing assays showed reduced MDA-MB-231 cell migration, and blood compatibility studies indicated minimal hemolysis, suggesting good biosafety.
Conclusions:
- TPGS-COOH-coated liposomes co-loaded with GFB and LCH, and dual-ligand functionalized with iRGD and Trast, represent a promising multifunctional nanoplatform.
- This strategy demonstrates potential for enhanced therapeutic efficacy against HER2-positive metastatic breast cancer.
- The developed DSDLs show good biocompatibility and biosafety, warranting further investigation for clinical translation.
