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Functionalized PAMAM-based Nanoformulation for Targeted Delivery of 5-Fluorouracil in Hepatocellular Carcinoma
Siwei Chen1,2, Hu Ouyang1, Dongxiu He1,2
1Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China.
Background:
The efficacy of a traditional anticancer drug is challenged by adverse effects of the drug, including its nonspecific bio-distribution, short half-life, and side effects. Dendrimer-based targeted drug delivery system has been considered a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs.
Objective:
This study analyzed the feasibility of whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing the toxicity of the PAMAM and improving the targeting property of 5-FU during delivery.
Methods:
The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve the therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability, and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation, and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice.
Results:
The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with a size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25%, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC50 of 30.80 ± 4.04 μg/mL than free 5-FU (114.93 ± 1.43 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency.
Conclusion:
The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy.
Insights
This study developed a targeted nanoformulation for 5-fluorouracil (5-FU) to treat liver cancer. The new delivery system enhances 5-FU efficacy while reducing side effects, offering a promising solution for hepatocellular carcinoma chemotherapy.
Area of Science:
- Nanotechnology in drug delivery
- Cancer therapy and targeted drug delivery
- Biomedical engineering and materials science
Background:
- Traditional anticancer drugs face challenges like poor biodistribution and severe side effects.
- Dendrimer-based targeted drug delivery systems offer a strategy to improve drug targeting and reduce toxicity.
- Hepatocellular carcinoma (HCC) requires innovative therapeutic approaches to overcome limitations of conventional chemotherapy.
Purpose of the Study:
- To evaluate the feasibility of delivering 5-fluorouracil (5-FU) using a functionalized dendrimer.
- To enhance the targeting of 5-FU to liver cancer cells while minimizing toxicity.
- To improve the therapeutic efficacy of 5-FU in hepatocellular carcinoma (HCC) treatment.
Main Methods:
- Fabrication of a functionalized poly(amidoamine) (PAMAM) dendrimer nanoformulation (WP05-G5.0NHAC-FUA) loaded with 5-FU.
- Characterization of physicochemical properties, including particle size, zeta potential, stability, and in vitro drug release.
- In vitro assessment of targeting, biocompatibility, anti-proliferation, and anti-migration effects, and in vivo evaluation in a human hepatoma xenograft mouse model.
Main Results:
- The WP05-G5.0NHAC-FUA nanoformulation exhibited spherical nanoparticles (174.20 ± 3.59 nm) with a zeta potential of 5.62 ± 0.41 mV and drug loading of 28.67 ± 1.25%.
- The 5-FU-loaded formulation demonstrated significantly higher cytotoxicity against Bel-7402 liver cancer cells (IC50 = 30.80 ± 4.04 μg/mL) compared to free 5-FU (IC50 = 114.93 ± 1.43 μg/mL).
- Reduced toxicity in normal liver cells (L02) and enhanced tumor accumulation and therapeutic efficiency were observed in vivo.
Conclusions:
- The developed WP05-G5.0NHAC-FUA nanoformulation is a promising platform for targeted 5-FU delivery.
- This approach offers a potential solution for improving the efficacy of chemotherapy in hepatocellular carcinoma.
- The study highlights the potential of functionalized dendrimers in enhancing anticancer drug delivery and reducing systemic toxicity.
