PO.CH01.04 · 化学
用于宫颈癌治疗的新一代sabizabulin纳米制剂
Next-generation sabizabulin nanoformulation for cervical cancer treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：宫颈癌（CC）仍是女性面临的重大全球健康负担，其内在性和获得性化疗耐药限制了治疗疗效。Sabizabulin（VERU-111）是一种口服生物利用度良好的秋水仙碱结合位点抑制剂，通过靶向微管动力学并改变HPV驱动的CC表型，为癌症治疗提供了一种新途径。然而，优化其药物制剂对于在最大化疗效的同时最小化全身毒性并改善肿瘤特异性药物蓄积至关重要。在本研究中，我们设计并评估了一种新一代sabizabulin纳米颗粒制剂，以增强其生物利用度、改善肿瘤靶向递送，并克服CC模型中的化疗耐药。
方法：我们设计了一种多层结构的、由Pluronic F127和聚乙烯醇稳定并经聚-L-赖氨酸包被的载sabizabulin的聚（乳酸-羟基乙酸共聚物）纳米颗粒制剂（PSab-NPs）。通过TEM、FT-IR、DSC、TGA和HPLC对PSab-NPs的理化性质、稳定性和载药效率进行表征。在CC细胞中与PSab-NPs孵育6小时后评估细胞内化。为确定PSab-NPs的治疗疗效，我们采用CC细胞进行了多种体外实验（MTS、划痕愈合、Boyden小室、实时xCELLigence和凋亡检测）以及体内异种移植小鼠模型实验。我们采用Western blot、免疫组织化学（IHC）、共聚焦显微镜和qRT-PCR评估了PSab-NPs对多种关键致癌信号通路的影响。
结果：我们的新型PSab-NPs制剂在动态光散射（DLS）中平均粒径为120-150 nm，zeta电位为-10.46至-12.73 mV，并具有出色的载药效率。细胞摄取和内化研究表明，PSab-NPs能够有效逃避溶酶体降解，促进强烈的内体释放进入胞质。PSab-NPs在多种CC细胞（HeLa、SiHa、CaSki和C33A）中表现出显著的抗癌潜力。在机制上，PSab-NPs能更有效地调节PI3K/AKT/MDM2信号通路，并在体外及CaSki细胞来源的裸鼠异种移植瘤中抑制HPV E6和E7。
结论：综上所述，我们的研究结果表明，PSab-NPs是一种新型、有前景的纳米颗粒平台，其抗癌潜力优于游离sabizabulin。PSab-NPs可能降低游离sabizabulin的毒性并改善其生物利用度，可用于CC的有效管理。
查看英文原文 English abstract
Background: Cervical cancer (CC) remains a significant global health burden in women, with intrinsic and acquired chemotherapy resistance limiting therapeutic efficacy. Sabizabulin (VERU-111) is an orally bioavailable colchicine-binding site inhibitor that offers a new way to treat cancer by targeting microtubule dynamics and changing the HPV-driven CC phenotype. However, optimization of its pharmaceutical formulation is critical to maximize efficacy while minimizing systemic toxicity and improving tumor-specific drug accumulation. In this study, we engineered and evaluated a next-generation nanoparticle formulation of sabizabulin to enhance its bioavailability, improve tumor-targeted delivery, and overcome chemotherapy resistance in CC models.
Methods: We engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated Sabizabulin-loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PSab-NPs). PSab-NPs were characterized for physicochemical properties, stability, and drug loading efficiency by TEM, FT-IR, DSC, TGA, and HPLC. Cellular internalization was assessed after 6 hours of incubation with PSab-NPs in CC cells. To determine the therapeutic efficacy of PSab-NPs, we performed various in vitro (MTS, wound healing, Boyden chamber, real-time xCELLigence, and apoptosis assays) and in vivo xenograft mouse models using CC cells. We evaluated the effect of PSab-NPs on various key oncogenic signaling pathways using Western blot, immunohistochemistry (IHC), confocal microscopy, and qRT-PCR.
Results: Our novel PSab-NPs formulation provided an average size of 120-150 nm in dynamic light scattering (DLS) and exhibited -10.46 to -12.73 mV zeta potential with an outstanding loading efficiency. Cellular uptake and internalization studies demonstrate that PSab-NPs efficiently evade lysosomal degradation, facilitating strong endosomal release into the cytosol. PSab-NPs showed remarkable anti-cancer potential in various CC cells (HeLa, SiHa, CaSki, and C33A). Mechanistically, PSab-NPs more effectively modulate the PI3K/AKT/MDM2 signaling pathway and suppress HPV E6 and E7 in vitro and CaSki cell-derived xenografts in athymic nude mice.
Conclusions: Taken together, our findings suggest that PSab-NPs represent a novel, promising nanoparticle platform that has more anti-cancer potential than free sabizabulin. PSab-NPs may reduce the toxicity and improve the bioavailability of free sabizabulin and could be used for the effective management of CC.
利益披露 Disclosure
V. K. Kashyap, None..
P. K. Nagesh, None..
Q. Wang, None..
U. Nayek, None..
T. Sharma, None..
B. B. Hafeez, None..
D. D. Miller, None..
W. Li, None..
M. M. Yallapu, None..
S. Chauhan, None.