Radiation-Induced Targeted Nanoparticle-Based Gene Delivery for Brain Tumor Therapy.
Gulsah Erel-AkbabaLitia A CarvalhoTian TianMax ZinterHasan AkbabaPierre J ObeidE Antonio ChioccaRalph WeisslederAyse Gulten KantarciBakhos A TannousPublished in: ACS nano (2019)
Targeted therapy against the programmed cell death ligand-1 (PD-L1) blockade holds considerable promise for the treatment of different tumor types; however, little effect has been observed against gliomas thus far. Effective glioma therapy requires a delivery vehicle that can reach tumor cells in the central nervous system, with limited systemic side effect. In this study, we developed a cyclic peptide iRGD (CCRGDKGPDC)-conjugated solid lipid nanoparticle (SLN) to deliver small interfering RNAs (siRNAs) against both epidermal growth factor receptor (EGFR) and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in tumor-associated macrophage-dependent fashion, we showed that low-dose radiation primes targeted SLN uptake into the brain tumor region, leading to enhanced downregulation of PD-L1 and EGFR. Bioluminescence imaging revealed that radiation therapy followed by systemic administration of targeted SLN leads to a significant decrease in glioblastoma growth and prolonged mouse survival. This study combines radiation therapy to prime the tumor for nanoparticle uptake along with the targeting effect of iRGD-conjugated nanoparticles to yield a straightforward but effective approach for combined EGFR inhibition and immunotherapy against glioblastomas, which can be extended to other aggressive tumor types.
Keyphrases
- epidermal growth factor receptor
- radiation therapy
- radiation induced
- tyrosine kinase
- cancer therapy
- small cell lung cancer
- low dose
- advanced non small cell lung cancer
- drug delivery
- photodynamic therapy
- cell proliferation
- locally advanced
- early stage
- sentinel lymph node
- adipose tissue
- high dose
- squamous cell carcinoma
- mesenchymal stem cells
- high grade
- mass spectrometry
- signaling pathway
- single cell
- replacement therapy
- energy transfer
- cerebrospinal fluid