P-P11 A tumour responsive, oxygen-generating nanoparticle to combat hypoxia in pancreatic tumours
P-P11 A tumour responsive, oxygen-generating nanoparticle to combat hypoxia in pancreatic tumours
复制标题
P-P11 一种肿瘤响应型产氧纳米颗粒，可对抗胰腺肿瘤的缺氧
DOI：
10.1093/bjs/znab430.235
复制
发表时间：
2021
影响因子：
9.6
通讯作者：
Farrell S
中科院分区：
文献类型：
--
作者：
Farrell S
背景胰腺癌仍然是一个重大的治疗挑战，其不良预后在过去的40年中保持相对不变。 胰腺肿瘤是高度促结缔组织增生和不可穿透的病变，其中气体和质量转移严重受损。 这导致肿瘤内缺氧的发展，并且这损害了依赖于细胞毒性活性氧物质的治疗方法，例如光动力疗法、声动力疗法和放射疗法。 缺氧还导致肿瘤微环境内的pH值相对较低。 在这里，我们描述了一种pH敏感的纳米颗粒，可以产生氧气在肿瘤中，并提高ROS产生治疗approaches.MethodsCaO2纳米颗粒产生暴露于低频超声，随后使用聚甲基丙烯酸酯聚合物，在pH 6.4成为可溶性的涂层。 在一些研究中，将声敏剂虎红附着在颗粒上。 通过在IV施用颗粒后将溶解氧探针插入肿瘤中来证明肿瘤中的氧产生（BxPC3）。 还使用人异种移植物和同基因胰腺肿瘤模型将颗粒与光动力疗法（PDT）和声动力疗法（SDT）一起使用。 在某些情况下，回收肿瘤组织并使用流式细胞术分析肿瘤浸润免疫细胞。结果显示聚合物包被的颗粒响应于pH值的降低而产生氧气。纳米颗粒的直径约为240 nm，并且显示在IV给药后被肿瘤吸收。显示颗粒增强PDT。在双侧肿瘤模型中，SDT为基础的治疗一个肿瘤导致了显着的abscopal效果在未经治疗的tumor.This SDT诱导abscopal效果被证明是免疫介导的，数据表明，这是由于减少免疫抑制调节T cells.ConclusionsCoating CaO2纳米粒子与pH敏感的聚合物提供了在肿瘤中原位氧生成。氧的瞬时供应增强了依赖于细胞毒性活性氧物质的产生的治疗。当与SDT一起使用时，并且使用双侧同基因胰腺肿瘤模型，观察到强大的远位效应，并且这被证明是免疫介导的。上述数据表明，颗粒可用于增强依赖于ROS产生的其他疗法，例如放射疗法，并进一步表明该方法可用于治疗局部或播散形式的胰腺癌。
BackgroundPancreatic cancer remains a significant therapeutic challenge and its poor prognosis has remained relatively unchanged for the past 40 years. Pancreatic tumours are highly desmoplastic and impenetrable lesions in which both gas and mass transfer is severely compromised. This leads to the development of hypoxia within the tumour and this compromises therapeutic approaches that rely on cytotoxic reactive oxygen species, e.g. photodynamic therapy, sonodynamic therapy and radiotherapy. Hypoxia also results in a relatively low pH within the tumour microenvironment. Here we describe a pH sensitive nanoparticle that can generate oxygen in the tumour and enhance ROS generating therapeutic approaches.MethodsCaO2NPs were generated by exposing to low frequency ultrasound and subsequently coated using a polymethacrylate polymer that becomes soluble at pH 6.4. For some studies, the sonosensitiser, Rose Bengal was attached to the particles. Oxygen generation in tumours (BxPC3) was demonstrated by inserting a dissolved oxygen probe into tumours following IV administration of particles. Particles were also employed together with photodynamic therapy (PDT) and sonodynamic therapy (SDT) using human xenograft and syngeneic pancreatic tumour models. In some cases, tumour tissues were recovered and analysed for tumour infiltrating immune cells using flow cytometry.ResultsPolymer coated particles were shown to generate oxygen in response to a decrease in pH.Nanoparticles had an approximate diameter of 240 nm and were shown to be taken up by tumours following IV administration.Particles were shown to enhance PDT.In a bilateral tumour model, SDT-based treatment of one tumour led to a dramatic abscopal effect at the untreated tumour.This SDT induced abscopal effect was shown to be immune-mediated and data suggested that this resulted from a decrease in immunosuppressive regulatory T cells.ConclusionsCoating CaO2nanoparticles with a pH sensitive polymer provides in situ oxygen generation in tumours. Transient provision of oxygen enhances therapies that depend on the generation of cytotoxic reactive oxygen species. When used with SDT, and using a bilateral syngeneic pancreatic tumour model, a powerful abscopal effect was observed and this was shown to be immune-mediated. The above data suggest that the particles may be exploited to enhance other therapies that depend on the generation of ROS, e.g. radiotherapy, and further suggest that the approach can be used to treat either local or disseminated forms of pancreatic cancer.