Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression

Cancers Pub Date : 2024-08-08 DOI:10.3390/cancers16162792
Jesse Yu, Xiaolin Xu, J. I. Griffin, Qingxin Mu, Rodney J Y Ho
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Abstract

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth—by 100 to 140 times—in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.
含有吉西他滨和紫杉醇的药物组合纳米粒子可使离体 4T1 乳腺肿瘤消退
早期诊断、干预和治疗方法的进步延长了乳腺癌患者的生命;然而,即使采用分子靶向疗法,许多患者最终还是会发展为转移性癌症。最近的数据表明,残留的乳腺癌细胞在通过血液迅速扩散之前,通常会滞留在淋巴系统中。为了应对这一挑战,由吉西他滨(G)和紫杉醇(T)组成的有效药物组合在转移阶段依次静脉注射,但静脉注射GT可能会限制淋巴GT药物的可及性和淋巴内癌细胞的非同步药物暴露。为了确定细胞内吉西他滨和紫杉醇(简称GT)的共定位是否能克服这些限制并提高GT的疗效,我们在正位乳腺肿瘤模型中评估了之前报道的一种纳米颗粒GT药物组合(简称GT-in-DcNP)。此前,我们曾报道过使用吲哚菁绿标记的纳米粒子,皮下注射后 GT-in-DcNP 颗粒会被迅速吸收,并优先进入淋巴而不是血管。药代动力学研究表明,GT 在肿瘤内的共定位性增强,可能通过淋巴途径,然后药物在血浆中透明化,导致明显的长效血浆时间过程。与使用游离和可溶性 GT 制剂的同等剂量相比,这种机制可能与在髂下和腋窝区域抑制肿瘤生长的效果显著提高 100 到 140 倍有关。此外,GT-in-DcNP 还表现出剂量依赖效应,肿瘤明显消退。相比之下,即使使用最高剂量的游离 GT 复方制剂,肿瘤生长也仅有轻微下降。对 MDA-231-HM 人类乳腺癌进行的正位异种移植模型的初步研究表明,GT-in-DcNP 可有效抑制人类乳腺癌的生长。总之,GT-in-DcNP 通过淋巴系统同步输送到乳腺肿瘤可提高细胞存留率和疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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