Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, China.
Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Control Release. 2014 May 28;182:90-6. doi: 10.1016/j.jconrel.2014.03.016. Epub 2014 Mar 15.
Tumors grown in a stroma-rich mouse model resembling clinically advanced bladder carcinoma with UMUC3 and NIH 3T3 cells have high levels of fibroblasts and an accelerated tumor growth rate. We used this model to investigate the synergistic effect of combined gemcitabine monophosphate (GMP) nanoparticles and Cisplatin nanoparticles (Combo NP) on tumor-associated fibroblasts (TAFs). A single injection of Combo NP had synergistic anti-tumor effects while the same molar ratio of combined GMP and Cisplatin delivered as free drug (Combo Free) fell outside of the synergistic range. Combo NP nearly halted tumor growth with little evidence of general toxicity while Combo Free had only a modest inhibitory effect at 16mg/kg GMP and 1.6mg/kg Cisplatin. Combo NP increased levels of apoptosis within the tumor by approximately 1.3 folds (TUNEL analysis) and decreased α-SMA-positive fibroblast recruitment by more than 87% (immunofluorescence) after multiple injections compared with Combo Free, GMP NP or Cisplatin NP alone. The TAF-targeting capability of Combo NP was evaluated by double staining for TUNEL and α-SMA at various time points after a single injection. On day one after injection, 57% of the TUNEL-positive cells were identified as α-SMA-positive fibroblasts. By day four, tumor stroma was 85% depleted and 87% of the remaining TAFs were TUNEL-positive. Combo NP-treated tumors became 2.75 folds more permeable than those treated with Combo Free as measured by Evans Blue. We conclude that the antineoplastic effect of Combo NP works by first targeting TAFs and is more effective as an anti-tumor therapy than Combo Free, GMP NP or Cisplatin NP alone.
在一种富含基质的小鼠模型中生长的肿瘤类似于具有 UMUC3 和 NIH 3T3 细胞的临床晚期膀胱癌，具有高水平的成纤维细胞和加速的肿瘤生长速度。我们使用该模型研究了吉西他滨单磷酸盐 (GMP) 纳米颗粒和顺铂纳米颗粒 (Combo NP) 联合对肿瘤相关成纤维细胞 (TAFs) 的协同作用。单次注射 Combo NP 具有协同的抗肿瘤作用，而相同摩尔比的组合 GMP 和顺铂作为游离药物 (Combo Free) 给药则不在协同范围内。Combo NP 几乎停止了肿瘤生长，几乎没有一般毒性的证据，而 Combo Free 在 16mg/kg GMP 和 1.6mg/kg 顺铂时仅具有适度的抑制作用。与 Combo Free、GMP NP 或 Cisplatin NP 单独给药相比，多次注射后，Combo NP 使肿瘤内的细胞凋亡水平增加了约 1.3 倍（TUNEL 分析），并使α-SMA 阳性成纤维细胞募集减少了 87%以上（免疫荧光）。通过对单次注射后不同时间点的 TUNEL 和α-SMA 进行双重染色，评估了 Combo NP 的 TAF 靶向能力。注射后第一天，57%的 TUNEL 阳性细胞被鉴定为α-SMA 阳性成纤维细胞。到第四天，肿瘤基质减少了 85%，剩余的 TAFs 中有 87%为 TUNEL 阳性。与 Combo Free 相比，Combo NP 处理的肿瘤的通透性增加了 2.75 倍，如 Evans Blue 测量所示。我们得出结论，Combo NP 的抗肿瘤作用首先靶向 TAFs，并且作为抗肿瘤疗法比 Combo Free、GMP NP 或 Cisplatin NP 单独使用更有效。
