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Development, Optimization and Evaluation of 2-Methoxy-Estradiol Loaded Nanocarrier for Prostate Cancer
Nabil A Alhakamy1,2,3, Osama A Ahmed1,2, Usama A Fahmy1,2
1Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
The therapeutic efficacy of antineoplastic agents possessing a selective target to the nucleus of the cancer cells could be enhanced through novel formulation approaches. Thus, toward the improvement of the anticancer potential of 2-methoxy estradiol (2 ME) on prostate cancer, the drug was entrapped into the hydrophobic micelles core formulated with Phospholipon 90G and d-α-tocopheryl polyethylene glycol succinate (TPGS). Optimization of the formulation was done by Box-Behnken statistical design using Statgraphics software to standardize percentages of TPGS and phospholipid to obtain the smallest particle size. The optimized formulation was found to be spherical with nanometer size of 152 ± 5.2 nm, and low PDI (0.234). The entrapment efficiency of the micelles was 88.67 ± 3.21% with >93% release of 2 ME within 24 h. There was a 16-fold increase in apoptosis and an 8-fold increase in necrosis of the PC-3 cells when incubated with 2 ME micellar delivery compared to control cells (2.8 ± 0.2%). This increased apoptosis was further correlated with increased BAX expression (11.6 ± 0.7) and decreased BCL-2 expression (0.29 ± 0.05) in 2 ME micelles treated cells when compared to the control group. Further, loss of mitochondrial membrane potential (∼50-fold) by the drug-loaded micelles and free drug compared to control cells was found to be due to the generation of ROS. Findings on cell cycle analysis revealed the significant arrest of the G2-M phase of the PC-3 cells when incubated with the optimized formulation. Simultaneously, a significantly increased number of cells in pre-G1 revealed the maximum apoptotic potential of the drug when delivered via micellar formulation. Finally, upregulation of caspase-9, p53, and NO, with downregulation of TNF-α, NF-κβ, and inflammatory mediators of the PC-3 cells established the superiority of the micellar approach against prostate cancer. In summary, the acquired results highlighted the potentiality of the 2 ME-micellar delivery tool for controlling the growth of prostate cancer cells for improved efficacy.
Insights
Novel micellar formulations of 2-methoxy estradiol (2 ME) enhance prostate cancer treatment by increasing cell death and reducing tumor growth. This targeted delivery system shows superior anticancer potential compared to free drugs.
Area of Science:
- * Pharmaceutical Nanotechnology
- * Cancer Biology
- * Drug Delivery Systems
Background:
- * Conventional antineoplastic agents can be improved with novel formulation strategies targeting cancer cell nuclei.
- * 2-methoxy estradiol (2 ME) is a potential anticancer agent for prostate cancer, but its efficacy can be enhanced.
- * Micellar drug delivery systems offer a promising approach to improve the therapeutic index of anticancer drugs.
Purpose of the Study:
- * To develop and optimize a micellar formulation of 2-methoxy estradiol (2 ME) for enhanced prostate cancer therapy.
- * To evaluate the physicochemical properties, drug release, and cellular effects of the optimized 2 ME-loaded micelles.
- * To investigate the mechanism of action, including apoptosis induction, cell cycle arrest, and modulation of key molecular markers in prostate cancer cells.
Main Methods:
- * Formulation of 2 ME-loaded micelles using Phospholipon 90G and d-α-tocopheryl polyethylene glycol succinate (TPGS).
- * Optimization of formulation parameters using Box-Behnken statistical design to achieve minimal particle size.
- * Characterization of micelles (size, PDI, entrapment efficiency) and in vitro drug release studies.
- * In vitro evaluation of cytotoxicity, apoptosis, necrosis, cell cycle, mitochondrial membrane potential, ROS generation, and molecular marker expression (BAX, BCL-2, caspase-9, p53, NO, TNF-α, NF-κβ) in PC-3 cells.
Main Results:
- * Optimized spherical micelles with a size of 152 ± 5.2 nm and low PDI (0.234) were successfully prepared.
- * High entrapment efficiency (88.67 ± 3.21%) and sustained drug release (>93% in 24 h) were achieved.
- * 2 ME micelles significantly increased apoptosis (16-fold) and necrosis (8-fold) in PC-3 cells, correlated with altered BAX/BCL-2 expression.
- * Significant G2-M phase arrest and pre-G1 accumulation were observed, indicating potent apoptotic induction via micellar delivery.
- * Micellar delivery led to mitochondrial dysfunction, ROS generation, and modulation of key signaling pathways (caspase-9, p53, NO, TNF-α, NF-κβ).
Conclusions:
- * The developed 2 ME-loaded micellar formulation demonstrates superior efficacy in inhibiting prostate cancer cell growth compared to the free drug.
- * Micellar delivery enhances 2 ME's anticancer potential by promoting apoptosis, inducing cell cycle arrest, and modulating critical cellular pathways.
- * This nanocarrier system holds significant promise as an effective tool for advanced prostate cancer therapeutics.
