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Mol Pharm. 2019 Oct 7;16(10):4352-4360. doi: 10.1021/acs.molpharmaceut.9b00693. Epub 2019 Sep 3.

Effect of Dose and Selection of Two Different Ligands on the Deposition and Antitumor Efficacy of Targeted Nanoparticles in Brain Tumors.

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Department of Biomedical Engineering, School of Medicine , Case Western Reserve University , Cleveland , Ohio 44106 , United States.
Case Comprehensive Cancer Center , Case Western Reserve University , Cleveland , Ohio 44106 , United States.
Edward B. Singleton Department of Pediatric Radiology , Texas Children's Hospital , Houston , Texas 77030 , United States.


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 αvβ3 integrin-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.


brain tumors; fibronectin and integrin targeting; mesoporous silica nanoparticles; radiofrequency-triggered drug release; targeted nanoparticles

[Available on 2020-10-07]

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