Alzhrani Riyad F, Binobaid Lama, Aloraini Abdulaziz A, Alsahli Meshal S, Bakheit Ahmed H, Asiri Hanadi H, Attia Sabry M, Alhoshani Ali, Harisa Gamaleldin I
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Oncol Res. 2025 Mar 19;33(4):919-935. doi: 10.32604/or.2024.054537. eCollection 2025.
Prostate cancer (PCA) is the second most widespread cancer among men globally, with a rising mortality rate. Enzyme-responsive lipid nanoparticles (ERLNs) are promising vectors for the selective delivery of anticancer agents to tumor cells. The goal of this study is to fabricate ERLNs for dual delivery of gefitinib (GF) and simvastatin (SV) to PCA cells.
ERLNs loaded with GF and SV (ERLNGFSV) were assembled using bottom-up and top-down techniques. Subsequently, these ERLN cargoes were coated with triacylglycerol, and phospholipids and capped with chitosan (CS). The ERLNGFSV, and CS engineered ERLNGFSV (CERLNGFSV) formulations were characterized for particle size (PS), zeta potential (ZP), and polydispersity index (PDI). The biocompatibility, and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line. Additionally, molecular docking simulations (MDS) were conducted to examine the influence of GF and SV on succinate dehydrogenase (SDH), glutathione peroxidase-4 (GPX-4), and 5α-reductase (5α-RD).
These results showed that plain, ERLNGFSV, and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance. Moreover, ERLNGFSV and CERLNGFSV were biocompatible, with no detrimental effects on erythrocytes. Treatment with GF, SV, GF plus SV, ERLNGFSV, and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells. Particularly, the blend of GF and SV, as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death. Also, treating PC-3 cells with free drugs, their combination, ERLNGFSV, and CERLNGFSV formulations elevated the percentage of apoptotic cells. MDS studies demonstrated that GF and SV interact with the active sites of SDH, GPX-4, and 5α-reductase.
This study concludes that SVGF combination and ERLNs loading induce particular delivery, and synergism on PC-3 death through action on multiple pathways involved in cell proliferation, and apoptosis, besides the interaction with SDH, GPX-4, and 5α-RD. Therefore, GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment. studies are necessary to confirm these findings for clinical applications.
前列腺癌（PCA）是全球男性中第二大常见癌症，死亡率呈上升趋势。酶响应性脂质纳米颗粒（ERLNs）是将抗癌药物选择性递送至肿瘤细胞的有前景的载体。本研究的目的是制备用于将吉非替尼（GF）和辛伐他汀（SV）双重递送至PCA细胞的ERLNs。
采用自下而上和自上而下的技术组装负载GF和SV的ERLNs（ERLNGFSV）。随后，用三酰甘油、磷脂对这些ERLN载药进行包衣，并用壳聚糖（CS）封端。对ERLNGFSV和经CS修饰的ERLNGFSV（CERLNGFSV）制剂的粒径（PS）、zeta电位（ZP）和多分散指数（PDI）进行表征。使用红细胞和PC-3细胞系评估空白以及负载GF加SV的ERLN载药的生物相容性和细胞毒性。此外，进行分子对接模拟（MDS）以研究GF和SV对琥珀酸脱氢酶（SDH）、谷胱甘肽过氧化物酶-4（GPX-4）和5α-还原酶（5α-RD）的影响。
这些结果表明，空白、ERLNGFSV和CERLNGFSV载药具有纳米级尺寸且外观均匀。此外，ERLNGFSV和CERLNGFSV具有生物相容性，对红细胞无有害影响。与对照细胞相比，用GF、SV、GF加SV、ERLNGFSV和CERLNGFSV处理显著降低了PC-3细胞的活力。特别是，GF和SV以及ERLNGFSV和CERLNGFSV的组合增加了PC-3细胞死亡。此外，用游离药物、它们的组合、ERLNGFSV和CERLNGFSV制剂处理PC-3细胞提高了凋亡细胞的百分比。MDS研究表明，GF和SV与SDH、GPX-4和5α-还原酶的活性位点相互作用。
本研究得出结论，SVGF组合和负载ERLNs通过作用于细胞增殖和凋亡所涉及的多种途径以及与SDH、GPX-4和5α-RD的相互作用，诱导对PC-3细胞的特异性递送和协同作用，从而导致细胞死亡。因此，负载GFSV的ERLN载药是PCA治疗的一种有前景的策略。需要进一步研究以确认这些发现用于临床应用。
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