Enhanced anti proliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention
Enhanced anti proliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention
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DOI：
10.1021/mp050032z
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发表时间：
2005-09-01
影响因子：
4.9
通讯作者：
Labhasetwar, Vinod
中科院分区：
文献类型：
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作者：
Sahoo, Sanjeeb K.;Labhasetwar, Vinod
我们研究了紫杉醇纳米粒(TX-NPs)在转铁蛋白(Tf)配体偶联后对乳腺癌细胞株更有效的分子机制。用生物可降解聚合物聚(乳酸-乙交酯)(PLGA)包裹TX，并通过环氧键连接到TF配体，制备了NPS。在MCF-7和MCF-7/ADR细胞中，Tf标记的NPs在剂量和时间依赖的研究中显示出比溶液药物或未结合的NPs更强和持续的抗增殖活性。与非结合纳米粒相比，与非结合纳米粒相比，结合纳米粒具有更强的抗增殖活性的机制被确定为其更大的细胞摄取和减少的胞吐作用，从而导致更高和更持久的细胞内药物水平。该药物在与转移因子结合的纳米粒在MCF-7/ADR细胞中的抗增殖活性随孵育时间的延长而增加，这表明可以通过维持细胞内药物滞留来克服耐药性。转铁蛋白结合的纳米粒通过转铁蛋白受体在细胞内摄取后在细胞内的分布特征可能与未结合的纳米粒通过非特异性内吞途径的不同，从而影响对纳米粒的摄取和细胞内滞留，从而影响微囊化药物的治疗效果。
We studied the molecular mechanism of greater efficacy of paclitaxel-loaded nanoparticles (Tx-NPs) following conjugation to transferrin (Tf) ligand in breast cancer cell line. NPs were formulated using biodegradable polymer, poly(lactic-co-glycolide) (PLGA), with encapsulated Tx and conjugated to Tf ligand via an epoxy linker. Tf-conjugated NPs demonstrated greater and sustained anti proliferative activity of the drug in dose- and time-dependent studies compared to that with drug in solution or unconjugated NPs in MCF-7 and MCF-7/Adr cells. The mechanism of greater antiproliferative activity of the drug with conjugated NPs was determined to be due to their greater cellular uptake and reduced exocytosis compared to that of unconjugated NPs, thus leading to higher and sustained intracellular drug levels. The increase in antiproliferative activity of the drug with incubation time in MCF-7/Adr cells with Tf-conjugated NPs suggests that the drug resistance can be overcome by sustaining intracellular drug retention. The intracellular disposition characteristics of Tf-conjugated NPs following their cellular uptake via Tf receptors could have been different from that of unconjugated NPs via nonspecific endocytic pathway, thus influencing the NP uptake, their intracellular retention, and hence the therapeutic efficacy of the encapsulated drug.