PDF(Pubmed)
Abstract：
Tumor protein 53 (TP53) mutation in bladder carcinoma (BC), upregulates the transcription of carbamoyl phosphate synthetase 1 (CPS1), to reduce intracellular ammonia toxicity. To leverage ammonia combating BC, here, an intravesically perfusable nanoporter-encased hydrogel system is reported. A biomimetic fusogenic liposomalized nanoporter (FLNP) that is decorated with urea transporter-B (UT-B) is first synthesized with protonated chitosan oligosaccharide for bladder tumor-targeted co-delivery of urease and small interfering RNA targeting CPS1 (siCPS1). Mussel-inspired hydrogel featured with dual functions of bio-adhesion and injectability is then fabricated as the reservoir for intravesical immobilization of FLNP. It is found that FLNP-mediated UT-B immobilization dramatically induces urea transportation into tumor cells, and co-delivery of urease and siCPS1 significantly boosts ammonia accumulation in tumor inducing cell apoptosis. Treatment with hybrid system exhibits superior anti-tumor effect in orthotopic bladder tumor mouse model and patient-derived xenograft model, respectively. Combined with high-protein diet, the production of urinary urea increases, leading to an augmented intracellular deposition of ammonia in BC cells, and ultimately an enhanced tumor inhibition. Together, the work establishes that cascade modulation of ammonia in tumor cells could induce tumor apoptosis and may be a practical strategy for eradication of TP53-mutated bladder cancer.
摘要：
膀胱癌（BC）中的肿瘤蛋白53（TP53）突变，上调氨基甲酰磷酸合成酶1（CPS1）的转录，减少细胞内氨的毒性。为了利用氨对抗BC，在这里，据报道，一种可膀胱灌注的纳米载体包裹的水凝胶系统。首先用质子化的壳聚糖寡糖合成了用尿素转运蛋白B（UT-B）修饰的仿生融合脂质体纳米载体（FLNP），用于膀胱肿瘤靶向的尿素酶和靶向CPS1的小干扰RNA（siCPS1）的共递送。然后制造具有生物粘附和可注射性双重功能的贻贝启发的水凝胶作为FLNP膀胱内固定的储库。发现FLNP介导的UT-B固定显著诱导尿素转运进入肿瘤细胞,脲酶和siCPS1的共同递送显着增加了肿瘤诱导细胞凋亡的氨积累。在原位膀胱肿瘤小鼠模型和患者来源的异种移植模型中，混合系统治疗表现出优异的抗肿瘤效果。分别。结合高蛋白饮食，尿尿素的产生增加，导致BC细胞中氨的细胞内沉积增加，最终增强了肿瘤抑制作用。一起,这项工作确定了肿瘤细胞中氨的级联调节可以诱导肿瘤细胞凋亡，并且可能是根除TP53突变的膀胱癌的实用策略。
