Jose Ashok David, Chong Celine Hui-Ning, Cheah Ernest, Jaiswal Jagdish, Wu Zimei, Thakur Sachin Sunil
School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Int J Pharm. 2025 Apr 15;674:125443. doi: 10.1016/j.ijpharm.2025.125443. Epub 2025 Mar 8.
Tumour hypoxia poses a significant challenge in cancer treatment. There is mounting evidence that reoxygenating tumours increases their sensitivity to conventional cancer therapies. Oxygenated microbubbles (OMB) show promise for this application but suffer from poor stability and rapid clearance. Embedding OMB in a thermosensitive hydrogel (OMBHG) may prolong tumour oxygenation and improve therapeutic outcomes.
To formulate and evaluate OMB loaded in a temperature sensitive hydrogel on an in vitro model of tumour hypoxia.
OMB generated from a liposomal precursor were dispersed at various concentrations in a poloxamer hydrogel. OMB size, hydrogel rheology, injectability, oxygen loading/release, and impact on efficacy of radiotherapy against HCT116 colon cancer cells under hypoxia/normoxia were evaluated.
DSPC:DSPE-PEG2000 (94:6 molar ratio) liposomes dispersed in a poloxamer 407: poloxamer 188 (21:6.5 % w/w) hydrogel generated OMB predominantly sized < 1 µm. OMBHG formulations were deemed injectable (force to inject < 38 N) at 20 °C and gelled before 37 °C and demonstrated both greater oxygen loading and prolonged oxygen release than OMB alone. Cancer cells were significantly less sensitive to radiotherapy under hypoxic conditions. Pre-treatment of the cells with OMB or OMBHG enhanced radiotherapy significantly, reducing clonogenic survival rates in HCT116 cells by 78 % in hypoxic conditions and by 68 % in normoxic conditions (p < 0.0001 in both cases). Notably, this treatment restored the radiotherapy sensitivity of hypoxic cells to the levels seen with normoxic cells.
Reoxygenation with a newly developed OMB hydrogel formulation effectively sensitised HCT116 to radiotherapy in vitro. Ongoing studies are exploring the importance of reoxygenation rate and extent for optimal tumour sensitisation.
肿瘤缺氧在癌症治疗中构成重大挑战。越来越多的证据表明，使肿瘤再充氧可提高其对传统癌症治疗的敏感性。氧化微泡（OMB）在该应用中显示出前景，但稳定性差且清除迅速。将OMB包埋在热敏水凝胶（OMBHG）中可能会延长肿瘤氧合并改善治疗效果。
在肿瘤缺氧的体外模型上制备并评估负载于温度敏感水凝胶中的OMB。
由脂质体前体产生的OMB以不同浓度分散在泊洛沙姆水凝胶中。评估了OMB大小、水凝胶流变学、可注射性、氧负载/释放以及在缺氧/正常氧条件下对HCT116结肠癌细胞放疗疗效的影响。
分散在泊洛沙姆407：泊洛沙姆188（21：6.5% w/w）水凝胶中的DSPC：DSPE-PEG2000（摩尔比94：6）脂质体产生的OMB主要尺寸<1 µm。OMBHG制剂在20°C时被认为可注射（注射力<38 N），并在37°C之前凝胶化，且与单独的OMB相比，显示出更高的氧负载和更长的氧释放时间。癌细胞在缺氧条件下对放疗的敏感性显著降低。用OMB或OMBHG对细胞进行预处理可显著增强放疗效果，在缺氧条件下将HCT116细胞的克隆形成存活率降低78%，在正常氧条件下降低68%（两种情况下p<0.0001）。值得注意的是，这种治疗将缺氧细胞的放疗敏感性恢复到了正常氧细胞的水平。
新开发的OMB水凝胶制剂再充氧有效地使HCT116在体外对放疗敏感。正在进行的研究正在探索再充氧速率和程度对最佳肿瘤致敏的重要性。
