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Published on: August 28, 2015
DOPE/CHEMS-Based EGFR-Targeted Immunoliposomes for Docetaxel Delivery: Formulation Development, Physicochemical
Thais da Silva Moreira1, Alan Denis Olivindo Silva1, Bianca Rodrigues Farias Vasconcelos1
1Department of Pharmacy, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza 60430-355, CE, Brazil.
Abstract:
Docetaxel (DTX) is a non-selective antineoplastic agent with low solubility and a series of side effects. The technology of pH-sensitive and anti-epidermal growth factor receptor (anti-EGFR) immunoliposomes aims to increase the selective delivery of the drug in the acidic tumor environment to cells with EFGR overexpression. Thus, the study aimed to develop pH-sensitive liposomes based on DOPE (dioleoylphosphatidylethanolamine) and CHEMS (cholesteryl hemisuccinate), using a Box-Behnken factorial design. Furthermore, we aimed to conjugate the monoclonal antibody cetuximab onto liposomal surface, as well as to thoroughly characterize the nanosystems and evaluate them on prostate cancer cells. The liposomes prepared by hydration of the lipid film and optimized by the Box-Behnken factorial design showed a particle size of 107.2 ± 2.9 nm, a PDI of 0.213 ± 0.005, zeta potential of -21.9 ± 1.8 mV and an encapsulation efficiency of 88.65 ± 20.3%. Together, FTIR, DSC and DRX characterization demonstrated that the drug was properly encapsulated, with reduced drug crystallinity. Drug release was higher in acidic pH. The liposome conjugation with the anti-EGFR antibody cetuximab preserved the physicochemical characteristics and was successful. The liposome containing DTX reached an IC50 at a concentration of 65.74 nM in the PC3 cell line and 28.28 nM in the DU145 cell line. Immunoliposome, in turn, for PC3 cells reached an IC50 of 152.1 nM, and for the DU145 cell line, 12.60 nM, a considerable enhancement of cytotoxicity for the EGFR-positive cell line. Finally, the immunoliposome internalization was faster and greater than that of liposome in the DU145 cell line, with a higher EGFR overexpression. Thus, based on these results, it was possible to obtain a formulation with adequate characteristics of nanometric size, a high encapsulation of DTX and liposomes and particularly immunoliposomes containing DTX, which caused, as expected, a reduction in the viability of prostate cells, with high cellular internalization in EGFR overexpressing cells.
Insights
This study developed pH-sensitive immunoliposomes for docetaxel (DTX) delivery, enhancing prostate cancer cell targeting. The novel formulation demonstrated improved cytotoxicity and cellular uptake in EGFR-overexpressing cancer cells.
Area of Science:
- Nanomedicine
- Drug Delivery Systems
- Oncology
Background:
- Docetaxel (DTX) is an effective antineoplastic agent but suffers from low solubility and systemic side effects.
- Targeted drug delivery aims to improve therapeutic efficacy and reduce toxicity by concentrating drugs at the tumor site.
- Epidermal Growth Factor Receptor (EGFR) is overexpressed in several cancers, including prostate cancer, making it a viable therapeutic target.
Purpose of the Study:
- To develop pH-sensitive liposomes encapsulating docetaxel (DTX).
- To conjugate cetuximab, an anti-EGFR monoclonal antibody, onto the liposome surface to create immunoliposomes.
- To evaluate the physicochemical properties, drug release, cytotoxicity, and cellular internalization of the developed nanocarriers in prostate cancer cells.
Main Methods:
- Liposomes were formulated using dioleoylphosphatidylethanolamine (DOPE) and cholesteryl hemisuccinate (CHEMS) and optimized via a Box-Behnken factorial design.
- Cetuximab antibody was conjugated to the liposome surface.
- Physicochemical characterization included particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, FTIR, DSC, and DRX.
- In vitro drug release studies were conducted at different pH values.
- Cytotoxicity was assessed using IC50 values on PC3 and DU145 prostate cancer cell lines.
- Cellular internalization was evaluated using flow cytometry.
Main Results:
- Optimized liposomes exhibited a particle size of 107.2 nm, PDI of 0.213, zeta potential of -21.9 mV, and 88.65% encapsulation efficiency.
- Characterization confirmed successful DTX encapsulation with reduced crystallinity and higher drug release at acidic pH.
- Liposome conjugation with cetuximab was successful, preserving physicochemical properties.
- Immunoliposomes showed enhanced cytotoxicity against EGFR-overexpressing prostate cancer cells (DU145) compared to non-targeted liposomes.
- Internalization of immunoliposomes was significantly greater in DU145 cells than in PC3 cells, correlating with EGFR expression levels.
Conclusions:
- pH-sensitive immunoliposomes effectively encapsulate docetaxel (DTX) and target EGFR-overexpressing prostate cancer cells.
- The developed nanocarrier system demonstrates improved cytotoxicity and enhanced cellular uptake in relevant cancer cell lines.
- This targeted delivery approach holds promise for improving the efficacy of docetaxel chemotherapy in prostate cancer treatment.
