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.
早期诊断、干预及治疗进展已延长了乳腺癌患者的生存期；然而，即使采用分子靶向治疗，许多患者最终仍会进展为转移性癌症。近期研究表明，残留的乳腺癌细胞常在通过血液快速扩散前，长期滞留于淋巴系统。为应对这一挑战，临床上在转移阶段会序贯静脉注射由吉西他滨（G）与紫杉醇（T）组成的有效联合化疗方案，但静脉输注GT可能限制药物在淋巴系统的可及性，并导致淋巴内癌细胞的药物暴露不同步。为探究细胞内吉西他滨与紫杉醇（简称GT）的共定位能否突破这些限制并增强GT疗效，我们通过原位乳腺肿瘤模型评估了一种先前报道的纳米颗粒载药组合（简称GT-in-DcNP）。此前我们利用吲哚菁绿标记纳米颗粒的研究表明，皮下给药后GT-in-DcNP颗粒能快速且优先被淋巴系统摄取而非血管。药代动力学研究显示，在血浆药物显效前，GT在肿瘤内的共定位显著增强，这很可能通过淋巴途径实现，并形成长效血浆时间曲线。其作用机制可能在于：相较于等剂量的游离可溶性GT制剂，GT-in-DcNP对髂下区与腋窝区肿瘤生长的抑制效果提升了100至140倍。此外，GT-in-DcNP表现出剂量依赖性效应，能显著促使肿瘤消退。相比之下，即使使用最高剂量的游离GT联合方案，仅能观察到有限的肿瘤生长抑制。在MDA-231-HM人乳腺癌原位移植模型中的初步研究表明，GT-in-DcNP可能有效抑制人类乳腺肿瘤的生长。综上所述，通过淋巴系统将GT-in-DcNP同步递送至乳腺肿瘤，可增强细胞滞留效应并提升治疗效果。
肿瘤(癌症)患者之家