Martinez Jonathan O, Evangelopoulos Michael, Bhavane Rohan, Acciardo Stefania, Salvatore Francesco, Liu Xuewu, Ferrari Mauro, Tasciotti Ennio
Houston Methodist Research Institute, 6670 Bertner Avenue MS R7-414, Houston, TX 77030-2602, USA.
Curr Drug Targets. 2015;16(14):1582-90. doi: 10.2174/1389450115666141015113914.
Nanoparticles have considerable potential for cancer imaging and therapy due to their small size and prolonged circulation. However, biological barriers can impede the delivery of a sufficient dose of a drug to the target site, thereby also resulting in the accumulation of toxic compounds within healthy tissues, and systemic toxicity. Multistage nanovectors (MSV) preferentially accumulate on inflamed endothelium, and can thus serve as carriers for drugs and nanoparticles. Herein, we describe the loading of free (i.e., melittin) and nano-encapsulated (i.e., doxorubicin-loaded micelles) drugs into MSV, and report the impact of surface charge and pore size on drug loading. For both drug formulations, negatively charged MSV (i.e., oxidized) with larger pores were shown to retain higher concentrations of payloads compared to positively charged (i.e., APTES-modified) MSV with small pores. Treatment of human umbilical vein endothelial cells (HUVEC) with melittin-loaded MSV (MEL@MSV) resulted in an 80% reduction in cell viability after 3 days. Furthermore, MEL@MSV conjugated with antivascular endothelial growth factor receptor 2 (VEGFR2) antibodies displayed preferential targeting and delivery of MEL to activated HUVEC expressing VEGFR2. Treatment of HUVEC and MCF7 cells with doxorubicin-loaded micelles (DOXNP@MSV) resulted in a 23% and 47% reduction in cell viability, respectively. Taken together, these results demonstrate increased loading of a payload in oxidized, large pore MSV, and effective delivery of free and nano-encapsulated drugs to endothelial and cancer cells.
由于纳米颗粒尺寸小且循环时间长，它们在癌症成像和治疗方面具有巨大潜力。然而，生物屏障会阻碍足够剂量的药物输送到靶位点，从而导致有毒化合物在健康组织内积累以及全身毒性。多级纳米载体（MSV）优先积聚在炎症内皮上，因此可作为药物和纳米颗粒的载体。在此，我们描述了将游离药物（即蜂毒肽）和纳米封装药物（即载有阿霉素的胶束）加载到MSV中，并报告了表面电荷和孔径对药物加载的影响。对于这两种药物制剂，与带正电荷（即APTES修饰）的小孔径MSV相比，带负电荷（即氧化）且孔径较大的MSV显示出能保留更高浓度的负载物。用载有蜂毒肽的MSV（MEL@MSV）处理人脐静脉内皮细胞（HUVEC）3天后，细胞活力降低了80%。此外，与抗血管内皮生长因子受体2（VEGFR2）抗体偶联的MEL@MSV表现出对表达VEGFR2的活化HUVEC优先靶向并递送MEL。用载有阿霉素的胶束（DOXNP@MSV）处理HUVEC和MCF7细胞后，细胞活力分别降低了23%和47%。综上所述，这些结果表明氧化的大孔径MSV中负载物的加载量增加，并且游离和纳米封装的药物能有效递送至内皮细胞和癌细胞。
