Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids,European Journal of Nuclear Medicine and Molecular Imaging

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Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2022-07-08 , DOI: 10.1007/s00259-022-05878-7
Sumudu Katugampola ₁ , Jianchao Wang ₁ , Aprameya Prasad ₂ , Stavroula Sofou ₂ , Roger W Howell ₁

Affiliation

Purpose

The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (²²⁵Ac-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses.

Methods

Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R⁻A⁻, R⁻A⁺, R⁺A⁻, and R⁺A⁺. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or ²²⁵Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean ²²⁵Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with ²²⁵Ac-liposomes.

Results

The biological responses of the multicellular clusters treated with ²²⁵Ac-liposomes with physicochemical properties R⁺A⁺, R⁻A⁺, and R⁻A⁻ were predicted by MIRDcell with statistically significant accuracy. The prediction for R⁺A⁻ was not predicted accurately.

Conclusion

In most instances, MIRDcell predicts responses of spheroids treated with ²²⁵Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.

中文翻译：

使用 MIRDcell V3 预测微转移反应：225Ac-DOTA 封装脂质体的原理证明，可在肿瘤球体中产生不同的活性分布

目的

已知多细胞簇内放射性药物的空间分布对其生物反应具有显着影响。大多数治疗性放射性药物在组织中分布不均匀，这使得预测微转移的反应具有挑战性。这里介绍的工作分析了用 Actinium-225-DOTA 封装脂质体（²²⁵ Ac-脂质体）处理的肿瘤球体内已发表的时间依赖性非均匀活性分布，并在 MIRDcell V3.11 中使用这些数据来计算吸收剂量分布并预测生物反应。将预测响应与实验响应进行比较。

方法

制备了四种类型的脂质体，其膜具有不同的释放（R）和粘附（A）特性组合。组合为 R ⁻ A ⁻、R ⁻ A ⁺、R ⁺ A ⁻和 R ⁺ A ⁺。这些提供了不同的组织渗透特性。脂质体负载有羧基荧光素二乙酸琥珀酰亚胺酯 (CFDA-SE) 或²²⁵ Ac。用 CFDA-SE-脂质体处理 MDA-MB-231 球体，在不同时间收获，并测定球体内每个径向位置的时间积分 CFDA-SE 浓度。这被转化为平均²²⁵ Ac 衰变/细胞与径向位置的关系，上传到 MIRDcell，并模拟球形多细胞簇中细胞的存活分数。^{将 MIRD 细胞预测的存活分数与用225} Ac-脂质体处理后球体的实验分数进行比较。