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

Abstract

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 α v β 3 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.

Stimuli‐Responsive Iron Oxide Nanotheranostics: A Versatile and Powerful Approach for Cancer Therapy

“…In addition to standard iron oxide nanoparticles, next generation designs include doped SPIONs, [ 46a ] iron oxide nanoworms, [ 47 ] iron oxide nanochains, [ 36c,d,48 ] iron oxide cores within mesoporous silica or gold shells, [ 36a,b,49 ] and liposomal encapsulation of iron oxide cores. [ 50 ] Specifically, to further increase the magnetic properties of SPIONs, iron oxide crystals can be doped with Mn, Co, or Ni.…”

“…Specifically, the multicomponent Fe@MSNs were utilized as vehicles for targeted delivery and controlled release of therapeutic molecules for the treatment of glioblastoma multiforme (GBM). [ 36a,b,49a ] Iron oxide nanoparticles (≈20 nm) were synthesized using the coprecipitation method under inert gas and were subsequently coated with citric acid. The IONPs were then coated with a mesoporous silica shell using standard sol–gel chemistry, and the MSN pores were further functionalized to encapsulate different small molecule drugs.…”

“…The IONPs were then coated with a mesoporous silica shell using standard sol–gel chemistry, and the MSN pores were further functionalized to encapsulate different small molecule drugs. [ 36a,b,49a ] The resulting Fe@MSNs were conjugated with targeting ligands corresponding to receptors specifically overexpressed on the diseased tumor endothelium. Application of an external, low‐power RF field (50 kHz, 5 mT) triggers rapid release of encapsulated drug, which can penetrate the tumor interstitium more efficiently than the nanoparticles themselves ( Figure ).…”

“…[ 36b ] Drug delivery was further optimized by tailoring the dose administered for nanoparticles incorporating ligands for either α ν β 3 integrin (cRGD) and fibronectin (CREKA). [ 49a ] The coadministration of Fe@MSNs(DOX) and Fe@MSNs loaded with the glioma stem cell inhibitor 1400 W significantly prolonged survival in orthotopic models of brain cancer. [ 36a ] Notably, the combination therapy produced complete disease regression in 60% of animals bearing orthotopic 9L glioma tumors.…”

Engineering Tumor-Targeting Nanoparticles as Vehicles for Precision Nanomedicine

“…The key advantages of NPs include their unique biological interactions based on their physical and chemical properties including charge, size, shape, and surface chemistry. Their high surface area to volume ratio also allows for loading therapeutics at a high concentration and dense display of targeting ligands, which can increase the localized effect by controlled release of the drug within targeted cells [9,10]. Additionally, integrating the diagnostic and therapeutic cargo in NPs holds promise for multimodal theranostic particles.…”