Effect of Dose and Selection of Two Different Ligands on the Deposition and Antitumor Efficacy of Targeted Nanoparticles in Brain Tumors.
Effect of Dose and Selection of Two Different Ligands on the Deposition and Antitumor Efficacy of Targeted Nanoparticles in Brain Tumors.
复制标题
两种不同配体的剂量和选择对脑肿瘤中靶向纳米颗粒的沉积和抗肿瘤功效的影响。
DOI：
10.1021/acs.molpharmaceut.9b00693
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发表时间：
2019
影响因子：
4.9
通讯作者：
Karathanasis,Efstathios
中科院分区：
文献类型：
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作者：
Turan,Oguz;Bielecki,Peter;Tong,Kathleen;Covarrubias,Gil;Moon,Taylor;Rahmy,Abdelrahman;Cooley,Shane;Park,Youngjun;Peiris,PubuduM;Ghaghada,KetanB;Karathanasis,Efstathios
纳米颗粒在肿瘤中的沉积通常可以通过靶向肿瘤中过表达的受体来增强。然而，肿瘤可能表现出有限数量的生物标志物，这些生物标志物可被纳米颗粒接近和靶向，从而限制了可用的着陆点。为了探索这一点，我们选择了两种不同的生物标志物，它们可以有效地将纳米颗粒定位在脑肿瘤中。具体地说，我们使用αvβ 3整合素靶向肽或纤连蛋白靶向肽作为分别称为RGD-NP和CREKA-NP的纳米颗粒上的配体。在多形性胶质母细胞瘤的小鼠模型中，我们全身注射了不同剂量范围为2至8 mg/kg药物的载有细胞毒性药物的纳米颗粒。RGD-NP的剂量阈值上限为102 mg/kg。CREKA-NP在5 mg/kg时达到其剂量上限阈值。对于两种靶向纳米颗粒变体，更高的剂量并不能确保更高的肿瘤内药物水平，但它有助于提高脱靶沉积和潜在的更大毒性。然后以对应于每种制剂的剂量阈值上限的剂量施用组合RGD-NP和CREKA-NP的混合物，导致比单独制剂高3倍的肿瘤内沉积。对于每种纳米颗粒变体，在适当剂量下的两种不同靶向方案的组合促进了肿瘤内药物水平的显著增加，这是单独的靶向纳米颗粒无法实现的。
Deposition of nanoparticles to tumors often can be enhanced by targeting receptors overexpressed in a tumor. However, a tumor may exhibit a finite number of a biomarker that is accessible and targetable by nanoparticles, limiting the available landing spots. To explore this, we selected two different biomarkers that effectively home nanoparticles in brain tumors. Specifically, we used either an αvβ3integrin-targeting peptide or a fibronectin-targeting peptide as a ligand on nanoparticles termed RGD-NP and CREKA-NP, respectively. In mouse models of glioblastoma multiforme, we systemically injected the nanoparticles loaded with a cytotoxic drug at different doses ranging from 2 to 8 mg/kg drug. The upper dose threshold of RGD-NP is ∼2 mg/kg. CREKA-NP reached its upper dose threshold at 5 mg/kg. For both targeted nanoparticle variants, higher dose did not ensure higher intratumoral drug levels, but it contributed to elevated off-target deposition and potentially greater toxicity. A cocktail combining RGD-NP and CREKA-NP was then administered at a dose corresponding to the upper dose threshold for each formulation resulting in a 3-fold higher intratumoral deposition than the individual formulations. The combination of the two different targeting schemes at the appropriate dose for each nanoparticle variant facilitated remarkable increase in intratumoral drug levels that was not achievable by a sole targeting nanoparticle alone.