Purpose

This study aimed to develop a hydrogel system for treating aggressive triple negative breast cancer (TNBC) via kinetically-controlled delivery of the synergistic drug pair doxorubicin (DOX) and gemcitabine (GEM). A 2D assay was adopted to evaluate therapeutic efficacy by determining combination index (CI), and a 3D assay using cancer spheroids was implemented to assess the potential for translation in vivo.

Methods

The release of DOX and GEM from an acetylated-chitosan (ACS, degree of acetylation χ_Ac = 40 ± 5%) was characterized to identify a combined drug loading that affords release kinetics and dose that are therapeutically synergistic. The selected DOX/GEM-ACS formulation was evaluated in vitro with 2-D and 3-D models of TNBC to determine the combination index (CI) and the tumor volume reduction, respectively.

Results

Therapeutically desired release dosages and kinetics of GEM and DOX were achieved. When evaluated with a 2-D model of TNBC, the hydrogel afforded a CI of 0.14, indicating a stronger synergism than concurrent administration of DOX and GEM (CI = 0.23). Finally, the therapeutic hydrogel accomplished a notable volume reduction of the cancer spheroids (up to 30%), whereas the corresponding dosages of free drugs only reduced growth rate.

Conclusions

The ACS hydrogel delivery system accomplishes drug release kinetics and molar ratio that affords strong therapeutically synergism. These results, in combination with the choice of ACS as affordable and highly abundant source material, provide a strong pre-clinical demonstration of the potential of the proposed system for complementing surgical resection of aggressive solid tumors.

中文翻译：

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壳聚糖水凝胶用于向三阴性乳腺癌细胞和球体协同递送化疗药物。

目的

本研究旨在开发一种水凝胶系统，通过动力学控制递送协同药物对阿霉素 (DOX) 和吉西他滨 (GEM) 来治疗侵袭性三阴性乳腺癌 (TNBC)。采用 2D 测定通过确定组合指数 (CI) 来评估治疗效果，并使用癌症球体进行 3D 测定以评估体内翻译的潜力。

方法

对乙酰化壳聚糖（ACS，乙酰化度 χ _Ac  = 40 ± 5%）中 DOX 和 GEM 的释放进行表征，以确定提供治疗协同作用的释放动力学和剂量的组合载药量。使用 TNBC 的 2-D 和 3-D 模型对所选 DOX/GEM-ACS 制剂进行体外评估，分别确定组合指数 (CI) 和肿瘤体积减少情况。

结果

GEM 和 DOX 达到了治疗所需的释放剂量和动力学。当用 TNBC 的二维模型进行评估时，水凝胶的 CI 为 0.14，表明比同时施用 DOX 和 GEM (CI = 0.23) 具有更强的协同作用。最后，治疗性水凝胶显着减少了癌症球体的体积（高达 30%），而相应剂量的游离药物仅降低了生长速度。

结论

ACS 水凝胶递送系统实现了药物释放动力学和摩尔比，提供了强大的治疗协同作用。这些结果与选择 ACS 作为负担得起且高度丰富的来源材料相结合，为所提出的系统补充侵袭性实体瘤手术切除的潜力提供了强有力的临床前证明。