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PCL-based nanoparticles for doxorubicin-ezetimibe co-delivery: A combination therapy for prostate cancer using a drug
Mina Yousefnezhad1, Soodabeh Davaran2,3, Mirzaagha Babazadeh1
1Department of Chemistry, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
Introduction:
Drug repurposing is an effective strategy for identifying the use of approved drugs for new therapeutic purposes. This strategy has received particular attention in the development of cancer chemotherapy. Considering that a growing body of evidence suggesting the cholesterol-lowering drug ezetimibe (EZ) may prevent the progression of prostate cancer, we investigated the effect of EZ alone and in combination with doxorubicin (DOX) on prostate cancer treatment.
Methods:
In this study, DOX and EZ were encapsulated within a PCL-based biodegradable nanoparticle. The physicochemical properties of drug containing nanoparticle based on PCL-PEG-PCL triblock copolymer (PCEC) have been exactly determined. The encapsulation efficiency and release behavior of DOX and EZ were also studied at two different pHs and temperatures.
Results:
The average size of nanoparticles (NPs) observed by field emission scanning electron microscopy (FE-SEM) was around 82±23.80 nm, 59.7±18.7 nm, and 67.6±23.8 nm for EZ@PCEC, DOX@PCEC, and DOX+EZ@PCEC NPs, respectively, which had a spherical morphology. In addition, DLS measurement showed a monomodal size distribution of around 319.9, 166.8, and 203 nm hydrodynamic diameters and negative zeta potential (-30.3, -6.14, and -43.8) mV for EZ@PCEC, DOX@PCEC, and DOX+EZ@PCEC NPs, respectively. The drugs were released from the NPs sustainably in a pH and temperature-dependent manner. Based on the MTT assay results, PCEC copolymer exhibited negligible cytotoxicity on the PC3 cell line. Therefore, PCEC was a biocompatible and suitable nano-vehicle for this study. The cytotoxicity of the DOX-EZ-loaded NPs on the PC3 cell line was higher than that of NPs loaded with single drugs. All the data confirmed the synergistic effect of EZ in combination with DOX as an anticancer drug. Furthermore, fluorescent microscopy and DAPI staining were performed to show the cellular uptake, and morphological changes-induced apoptosis of treated cells.
Conclusion:
Overall, the data from the experiments represented the successful preparation of the nanocarriers with high encapsulation efficacy. The designed nanocarriers could serve as an ideal candidate for combination therapy of cancer. The results corroborated each other and presented successful EZ and DOX formulations containing PCEC NPs and their efficiency in treating prostate cancer.
Insights
Drug repurposing using ezetimibe (EZ) and doxorubicin (DOX) in nanoparticles shows promise for prostate cancer treatment. This combination therapy demonstrated enhanced cytotoxicity against cancer cells, suggesting a synergistic effect for improved therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Drug repurposing is a cost-effective strategy for discovering new cancer therapies.
- Ezetimibe (EZ), a cholesterol-lowering drug, has shown potential in preventing prostate cancer progression.
- Doxorubicin (DOX) is a widely used chemotherapy agent.
Purpose of the Study:
- To investigate the efficacy of ezetimibe (EZ) alone and in combination with doxorubicin (DOX) for prostate cancer treatment.
- To develop and characterize biodegradable nanoparticles (PCEC) for co-delivery of EZ and DOX.
- To evaluate the synergistic effect of the combined drug therapy on prostate cancer cells.
Main Methods:
- Encapsulation of DOX and EZ into PCL-PEG-PCL (PCEC) nanoparticles.
- Characterization of nanoparticle physicochemical properties (size, morphology, zeta potential).
- In vitro cytotoxicity assays (MTT) and cellular uptake studies on PC3 prostate cancer cells.
Main Results:
- PCEC nanoparticles were successfully prepared with spherical morphology and appropriate hydrodynamic diameters.
- Drug release from nanoparticles was pH and temperature-dependent.
- DOX-EZ co-loaded nanoparticles exhibited significantly higher cytotoxicity against PC3 cells compared to single-drug loaded nanoparticles, indicating a synergistic effect.
- Evidence of enhanced cellular uptake and apoptosis induction was observed.
Conclusions:
- Biodegradable PCEC nanoparticles are suitable nano-vehicles for co-delivering EZ and DOX.
- The combination of EZ and DOX within nanoparticles demonstrates a synergistic effect, enhancing anti-prostate cancer activity.
- This nanoparticle-based combination therapy holds potential for effective prostate cancer treatment.
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