Targeted Immunoliposomal Delivery of a 5-Fluorouracil Analog in EGFR-Expressing Pancreatic Cancer Models
Esther Frimpong1, Raviteja Bulusu1, Joy Okoro1
1College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA.
Abstract:
IntroductionDysregulated epidermal growth factor receptor (EGFR) signaling is a key mechanism driving cancer progression and metastasis. Owing to its frequent overexpression in pancreatic cancer (PCa), EGFR has become a desirable molecular target for targeted therapies. XYZ-I-73 (N-(5-fluoro-2-oxo-1-(tetrahydrofuran-2-yl)-1,2-dihydropyrimidin-4-yl) dodecanamide), a structural analog of 5-fluorouracil (5-FU), has been previously synthesized and shown to exhibit cytotoxicity against PCa cells.MethodsXYZ-I-73 was entrapped in liposomes via thin-film hydration and subsequently conjugated to EGFR antibodies to produce an immunoliposome formulation- Ab-XYZ-I-73LnP (where 'Ab' denotes antibody-conjugated and 'LnP' denotes liposomal nanoparticle). In vitro efficacy was assessed by measuring cell viability and apoptosis in MiaPaCa-2 and PANC-1 cells, while pharmacokinetics and antitumor efficacy were determined in a cell line-derived xenograft (CDX) mouse model.ResultsAb-XYZ-I-73LnP exhibited a mean particle size of 143nm ± 2.3, PDI (0.37), and zeta potential -46.2 ± 1.3mV. In MiaPaCa-2 cells, Ab-XYZ-I-73LnP showed remarkably higher cytotoxicity than 5-FU in both 2D (IC50 = 2.5 ± 0.9μM vs 13.2 ± 1.1μM) and 3D cultures (IC50 = 8.1 ± 1.1μM vs 26.7 ± 1.1 μM). Similarly, in PANC-1 cells, Ab-XYZ-I-73LnP showed lower IC50 values compared to 5-FU;2D (IC50 = 2.9 ±1.1 μM vs 20.4±1.2 μM), 3D (IC50 = 12.9 ± 0.6μΜ vs 37.1±0.9 μM). Pharmacokinetic analysis revealed a prolonged half-life for Ab-XYZ-I-73LnP compared with free 5-FU (t1/2 = 1.62 ± 0.03 h vs 0.49 ± 0.01 h, p < 0.001). There was about a 2-fold increase in the area under the curve (AUC) for Ab-XYZ-I-73LnP compared to 5-FU (AUC= 0.32 ± 0.04µg/(L*hr) vs 0.15 ± 0.02µg/(L*hr), p<0.01).ConclusionOverall, the study supports the formulation of an immunoliposome of modified 5-FU, which may significantly enhance drug bioavailability and therapeutic potential for the treatment of PCa.
Insights
This study developed an antibody-conjugated liposomal nanoparticle (Ab-XYZ-I-73LnP) formulation of a 5-fluorouracil analog, showing enhanced cytotoxicity and bioavailability. This novel approach holds promise for improving pancreatic cancer (PCa) targeted therapy.
Area of Science:
- Nanotechnology in drug delivery
- Cancer biology and targeted therapy
- Pharmaceutical sciences
Background:
- Dysregulated epidermal growth factor receptor (EGFR) signaling drives cancer progression, particularly in pancreatic cancer (PCa).
- EGFR is a key therapeutic target in PCa due to its frequent overexpression.
- XYZ-I-73, a 5-fluorouracil (5-FU) analog, demonstrated prior cytotoxicity against PCa cells.
Purpose of the Study:
- To formulate and evaluate an EGFR-targeted immunoliposome encapsulating XYZ-I-73 (Ab-XYZ-I-73LnP) for enhanced PCa treatment.
- To assess the in vitro efficacy, pharmacokinetics, and antitumor potential of the Ab-XYZ-I-73LnP formulation.
Main Methods:
- Liposomal encapsulation of XYZ-I-73 using thin-film hydration.
- Conjugation of liposomes to EGFR antibodies to create Ab-XYZ-I-73LnP.
- In vitro cytotoxicity assays (2D and 3D cultures) and in vivo pharmacokinetic and antitumor studies in a mouse xenograft model.
Main Results:
- Ab-XYZ-I-73LnP nanoparticles exhibited favorable physicochemical properties (size: 143nm, PDI: 0.37, zeta potential: -46.2mV).
- Significantly enhanced cytotoxicity of Ab-XYZ-I-73LnP compared to free 5-FU in MiaPaCa-2 and PANC-1 cells across 2D and 3D cultures.
- Ab-XYZ-I-73LnP demonstrated a prolonged half-life (1.62 h vs 0.49 h) and increased AUC (0.32 vs 0.15 µg/(L*hr)) compared to 5-FU, indicating improved bioavailability.
Conclusions:
- The developed Ab-XYZ-I-73LnP immunoliposome formulation effectively enhances the delivery and efficacy of XYZ-I-73.
- This targeted nanoparticle approach shows significant potential for improving drug bioavailability and therapeutic outcomes in pancreatic cancer treatment.
- Further investigation into Ab-XYZ-I-73LnP is warranted for its clinical application in PCa therapy.
