Abstract
Pulsed-mode ultrasound (pUS) in combination with intravenously (IV) administered microbubbles (MBs) can enhance local drug delivery by temporarily enhancing capillary permeability. This study evaluates the use of epidermal growth factor receptor (EGFR)-targeting MBs after pUS treatment to enhance the effects of therapeutic-EGFR antibody delivery to glioma tumor cells in mice. Three animal groups were compared: (1) IV-injected non-targeting MBs, (2) IV-injected targeting MBs, and (3) IV-injected targeting MBs combined with pUS treatment. All animals were analyzed using high-frequency small-animal US imaging. The mean halftime of circulating targeting MBs was significantly increased from 3.13 min of targeting bubble alone to 5.86 min by targeting MBs combined with pUS treatment, compared to 2.34 min for non-targeting MBs. Compared to targeting bubble administration alone, pUS exposure prior to injection of targeting MBs was also significantly better at suppressing tumor growth when monitored for up to 35 days (p < 0.05). The final relative tumor volumes were 2664, 700, and 188 mm3 for non-targeting MBs, targeting MBs, and targeting MBs combined with pUS treatment, respectively. pUS treatment prolonged the mean circulatory halftime of targeting MBs and enhanced the anti-tumor effect of EGFR antibodies in a human glioma model in mice. Targeting MBs combined with pUS treatment thus has potential for enhanced therapeutic antibody delivery for facilitating anti-glioma treatment.
Highlights
Epidermal growth factor receptor (EGFR) is a single transmembrane receptor tyrosine kinase
This study evaluates the use of epidermal growth factor receptor (EGFR)-targeting MBs after Pulsed-mode ultrasound (pUS) treatment to enhance the effects of therapeuticEGFR antibody delivery to glioma tumor cells in mice
The mean halftime of circulating targeting MBs was significantly increased from 3.13 min of targeting bubble alone to 5.86 min by targeting MBs combined with pUS treatment, compared to 2.34 min for non-targeting MBs
Summary
Epidermal growth factor receptor (EGFR) is a single transmembrane receptor tyrosine kinase. The binding of a ligand, such as epidermal growth factor (EGF) or transforming growth factor-a (TGF-a), to the extracellular domain of EGFR induces its conformational change, dimerization, and trans-phosphorylation of specific receptor tyrosine residues. These phosphorylated-tyrosine residues generate docking sites for downstream signaling molecules, leading to the activation of phosphoinositide 3 kinase/AKT, mitogen-activated protein (MAP) kinase, and JNK-STATs pathways. These signaling activities promote cell proliferation, mobility, and anti-apoptosis [1, 2].
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