Purpose

To develop drug-combination nanoparticles (DcNPs) composed of hydrophilic gemcitabine (G) and hydrophobic paclitaxel (T) and deliver both drugs to metastatic cancer cells.

Methods

GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed. A GT distribution study into cancer nodules (derived from 4 T1 cells) was performed.

Results

An optimized GT DcNP composition (d = 59.2 nm ±9.2 nm) was found to be suitable for IV formulation. Plasma exposure of G and T were enhanced 61-fold and 3.8-fold when given in DcNP form compared to the conventional formulation, respectively. Mechanism based pharmacokinetic modeling and simulation show that both G and T remain highly associated to DcNPs in vivo (G: 98%, T:75%). GT DcNPs have minimal distribution to healthy organs with selective distribution and retention in tumor burdened tissue. Tumor bearing lungs had a 5-fold higher tissue-to-plasma ratio of gemcitabine in GT DcNPs compared to healthy lungs.

Conclusions

DcNPs can deliver hydrophilic G and hydrophobic T together to cancer nodules and produce long acting exposure, likely due to stable GT association to DcNPs in vivo.

中文翻译：

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由吉西他滨和紫杉醇组成的新型长效药物组合纳米颗粒增强两种药物在转移性乳腺癌结节中的定位。

目的

开发由亲水性吉西他滨 (G) 和疏水性紫杉醇 (T) 组成的药物组合纳米粒子 (DcNPs)，并将这两种药物递送至转移性癌细胞。

方法

基于粒径和药物结合效率 (AE%) 评估 GT DcNP。DcNP 对 GT 血浆时间进程和组织分布的影响在小鼠中进行了表征，并开发了药代动力学模型。对癌症结节（源自 4 个 T1 细胞）进行了 GT 分布研究。

结果

发现优化的 GT DcNP 组合物 (d = 59.2 nm ±9.2 nm) 适用于 IV 制剂。与常规制剂相比，当以 DcNP 形式给药时，G 和 T 的血浆暴露分别增强了 61 倍和 3.8 倍。基于机制的药代动力学建模和模拟表明，G 和 T在体内仍与 DcNP 高度相关（G：98%，T：75%）。GT DcNPs 对健康器官的分布最小，在肿瘤负荷组织中选择性分布和保留。与健康肺相比，在 GT DcNP 中，带有肿瘤的肺的吉西他滨的组织与血浆比率高 5 倍。

结论

DcNPs 可以将亲水性 G 和疏水性 T 一起传递到癌症结节并产生长效暴露，这可能是由于 GT 与体内DcNPs 的稳定关联。