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Evaluation of Anticancer Activity of Zhubech, a New 5-FU Analog Liposomal Formulation, against Pancreatic Cancer
Nkafu Bechem Ndemazie1, Raviteja Bulusu1, Xue You Zhu1
1College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Abstract:
Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancers have been masked by high drug toxicities, adverse reactions, and resistance. The use of nanocarriers such as liposomes to overcome these unwanted effects has become very popular. This study aims to formulate 1,3-bistertrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and to evaluate itsstability, release kinetics, in vitro and in vivo anticancer activities, and biodistribution in different tissues. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticles (Rho-LnPs) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP), as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnPs in vivo using inductively coupled plasma mass spectrometry (ICP-MS). The mean hydrodynamic diameters of blank LnPs and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4 °C and 25 °C for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R2 value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroid (IC50Zhubech = 3.4 ± 1.0 μM vs. IC50MFU = 6.8 ± 1.1 μM) and organoid (IC50Zhubech = 9.8 ± 1.4 μM vs. IC50MFU = 42.3 ± 1.0 μM) culture models. Confocal imaging confirmed a high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor-efficacy studies in a PDX bearing mouse model revealed a more than 9-fold decrease in mean tumor volumes in Zhubech-treated (108 ± 13.5 mm3) compared to 5-FU-treated (1107 ± 116.2 mm3) animals, respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.
Insights
This study developed Zhubech, a novel liposomal nanoparticle formulation for pancreatic cancer treatment. Zhubech demonstrated enhanced stability, effective drug delivery, and significantly reduced tumor growth in vivo compared to traditional chemotherapy.
Area of Science:
- Nanotechnology
- Oncology
- Drug Delivery
Background:
- Pancreatic cancer is a leading cause of cancer death with limited effective treatments.
- Conventional chemotherapy faces challenges including toxicity, resistance, and adverse reactions.
- Liposomal nanocarriers offer a promising approach to improve drug efficacy and reduce side effects.
Purpose of the Study:
- To formulate and characterize 1,3-bistertrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles, named Zhubech.
- To evaluate the stability, drug release kinetics, in vitro and in vivo anticancer activity, and biodistribution of Zhubech.
- To assess the potential of Zhubech as a drug delivery system for pancreatic cancer.
Main Methods:
- Formulation of MFU-loaded liposomal nanoparticles (Zhubech).
- Characterization of particle size, zeta potential, and stability.
- In vitro drug release studies using the Higuchi model.
- In vitro cytotoxicity assays on pancreatic cancer cell lines (Miapaca-2, Panc-1) in 3D spheroid and organoid models.
- Cellular uptake studies using rhodamine-entrapped liposomal nanoparticles (Rho-LnPs) and confocal microscopy.
- In vivo efficacy studies in a pancreatic ductal adenocarcinoma (PDX) bearing mouse model, evaluating tumor volume reduction.
- Biodistribution studies using gadolinium hexanoate (Gd-Hex) entrapped liposomal nanoparticles (Gd-Hex-LnP) and ICP-MS.
Main Results:
- Zhubech nanoparticles exhibited favorable size (124.9 ± 3.2 nm) and excellent stability at 4 °C and 25 °C for 30 days.
- In vitro drug release followed the Higuchi model (R² = 0.95).
- Zhubech significantly reduced cancer cell viability in 3D spheroid and organoid models, showing 2-4 fold lower IC50 values compared to MFU alone.
- Confocal microscopy confirmed time-dependent cellular uptake of Rho-LnPs.
- In vivo studies showed a >9-fold decrease in mean tumor volume in Zhubech-treated mice compared to 5-FU-treated mice.
Conclusions:
- Zhubech demonstrates superior stability and controlled drug release properties.
- Zhubech exhibits enhanced in vitro and in vivo anticancer efficacy against pancreatic cancer compared to free MFU.
- These findings suggest Zhubech holds significant potential as an effective nanocarrier for pancreatic cancer therapy.
