Development, Optimization and Evaluation of 2-Methoxy-Estradiol Loaded Nanocarrier for Prostate Cancer

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.

Optimized 2-methoxyestradiol invasomes fortified with apamin: a promising approach for suppression of A549 lung cancer cells

“…This could be attributed to the increased apoptosis in the 2ME-INVA-APA treated cells. Previous studies has reported similar effect of 2ME on Bax and Bcl-2 expression (Badr-Eldin et al., 2020 ; Alhakamy et al., 2021 ). These findings substantiate 2ME-INVA-APA’s anti-neoplastic ability.…”

“…A report deemed 2ME effective in fighting prostate cancer, although the plasma concentration of 2ME does not sustain for long (Sweeney et al., 2005 ). It was noted that a significantly high dose was required in human beings when administered orally; however, nano-2ME formulation shows enhanced pharmacokinetic properties in animal test subjects (Wang et al., 2011 ; Alhakamy et al., 2021 ).…”

“…Invasomes (INVA) are innovative elastic vesicles made of several chemicals, including terpene(s), ethanol, and phosphatidylcholine (Ahmed & Badr-Eldin, 2019 ), which enhance the absorption of water soluble and lipid soluble drugs (Alhakamy et al., 2021 ). This enhancement can likely be attributed to terpenes, which break down the tightly packed lipids in epidermal (Ahmed & Badr-Eldin, 2019 ) and engage with intracellular proteins (Attalla et al., 1996 ).…”

“…Apamin (APA, Figure 1(B) ), a peptide present in bee venom (apitoxin), has been employed in the delivery of specific drugs. APA has a wide range of pharmacological activities that might be modified for therapeutic purposes (Gu et al., 2020 ; Alhakamy et al., 2021 ). Furthermore, the cytotoxic action of bee venom components has been documented.…”

2-Methoxyestradiol TPGS Micelles Attenuate Cyclosporine A-Induced Nephrotoxicity in Rats through Inhibition of TGF-β1 and p-ERK1/2 Axis

“…These anti-inflammatory effect of 2ME-TPGS were more pronounced when compared with 2ME-Raw. This is consistent with Alhakamy et al [ 92 ]. The decreased expression of these inflammatory cytokines, namely TNF-α and IL-1β, has been reported to reduce apoptosis and pro-apoptotic signaling after kidney injury [ 27 , 93 ].…”