The poor prognosis of triple-negative breast cancer (TNBC) is attributed largely to the lack of tumor-selective therapeutic modalities that effectively deliver lethal doses at the sites of metastatic disease. Tumor-selective drug delivery strategies that aim to improve uniformity in intratumoral drug microdistributions and to prolong exposure of these cancer cells to delivered therapeutics may improve therapeutic efficacy against established TNBC metastases. In this study, we present lipid carriers for selective (due to their nanometer size) tumor delivery, which are loaded with cisplatin and designed to exhibit the following properties when in the tumor interstitium: (1) interstitial drug release (for deeper tumor penetration of cisplatin) and/or (2) intratumoral/interstitial adhesion of the carriers to tumors' extracellular matrix (ECM)-not accompanied by cell internalization-for delayed tumor clearance of carriers prolonging cancer cell exposure to the cisplatin being released. We show that on large multicellular spheroids, used as surrogates of avascular solid tumor regions, greater growth inhibition was strongly correlated with spatially more uniform drug concentrations (due to interstitial drug release) and with longer exposure to the released drug (i.e., higher time-integrated drug concentrations enabled by slow clearing of adhesive nanoparticles). Lipid nanoparticles with both the release and adhesion properties were the most effective, followed by nanoparticles with only the releasing property and then by nanoparticles with only the adhering property. In vivo, cisplatin-loaded nanoparticles with releasing and/or adhering properties significantly inhibited the growth of spontaneous TNBC metastases compared to conventional liposomal cisplatin, and the efficacy of different property combinations followed the same trends as in spheroids. This study demonstrates the therapeutic potential of a general strategy to bypass treatment limitations of established TNBC metastases due to the lack of cell-targeting markers: aiming to optimize the temporal intratumoral drug microdistributions for more uniform and prolonged drug exposure.

中文翻译：

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深部肿瘤穿透和缓慢清除肿瘤的化疗抑制转移性三阴性乳腺癌的生长：具有间质药物释放的肿瘤粘附脂质体的案例。

三阴性乳腺癌 (TNBC) 的不良预后主要归因于缺乏在转移性疾病部位有效提供致死剂量的肿瘤选择性治疗方式。旨在提高肿瘤内药物微分布均匀性并延长这些癌细胞暴露于递送治疗剂的肿瘤选择性药物递送策略可能会提高对已确定的 TNBC 转移的治疗效果。在这项研究中，我们提出了用于选择性（由于它们的纳米尺寸）肿瘤递送的脂质载体，其负载顺铂并设计为在肿瘤间质中表现出以下特性：（1）间质药物释放（用于更深的肿瘤穿透顺铂）和/或（2）载体与肿瘤的瘤内/间质粘附' 细胞外基质 (ECM) - 不伴有细胞内化 - 用于延迟肿瘤清除载体，延长癌细胞暴露于释放的顺铂。我们表明，在用作无血管实体瘤区域替代物的大型多细胞球体上，更大的生长抑制与空间上更均匀的药物浓度（由于间质药物释放）和释放药物的更长暴露时间（即更长的时间-通过缓慢清除粘合剂纳米颗粒实现的综合药物浓度）。具有释放和粘附特性的脂质纳米粒子最有效，其次是仅具有释放特性的纳米粒子，然后是仅具有粘附特性的纳米粒子。体内，与传统脂质体顺铂相比，具有释放和/或粘附特性的载有顺铂的纳米颗粒显着抑制了自发性 TNBC 转移瘤的生长，并且不同特性组合的功效遵循与球体相同的趋势。这项研究证明了由于缺乏细胞靶向标志物而绕过已建立的 TNBC 转移的治疗限制的一般策略的治疗潜力：旨在优化暂时的肿瘤内药物微分布，以实现更均匀和更长时间的药物暴露。