5.2.1. EGFR-Targeting Probes

EGFR is a receptor binding the extracellular epidermal growth factor family (EGF family) [156]. In many tumor types, including TC, increased EGFR expression or activity initiates the tumor cell progression [112]. Recently, EGFR has been the target of the newly created nanoparticle (called C-HPNs) based on a core-shell system loaded with EGFRtargeted cetuximab and 10-hydroxycamptothecin (10-HCPT, chemotherapy agent). The EGFR antibody ligands enable nanoparticles to attach to cells which overexpress EGFR. With low-intensity focused ultrasound (LIFU) assistance, the liquid perfluoropentane (PFP) core in the nanoparticles would become vaporized and transformed into microbubbles, enhancing ultrasound contrast for tumor diagnosing. The core explosion induced by PFP boiling causes the release of 10-HCPT, providing more targeted delivery of the chemotherapeutic drug [154] (Figure 15).

**Figure 15.** Theranostic applications of nanoparticles targeting EGFR. (**A**) Schematic illustration of the nanoparticles for chemotherapy drug delivery and enhanced diagnosis via LIFU. (**B**) Ultrasound imaging of tumors in B-mode before and after LIFU treatments. Reproduced with permission from [154], copyright 2019 Royal Society of Chemistry.

5.2.2. Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11, SHP2)-Targeting Probes

Another example is the SHP2, which is a tumor biomarker, acting as a signal of cell proliferation and immortality [157]. Hu et al. created an SHP2-targeted core-shell nanoparticle chelated with the contrast agent Gd3+ on the surface (NPs-SHP2). Similar to the EGFR-targeted nanoparticles mentioned previously, PFP-based LIFU can facilitate the probe carrying contrast agent been accumulated in the thyroid tumor area for enhanced MRI [155] (Figure 16).

**Figure 16.** MRI in subcutaneous thyroid squamous cell cancer (TSCC) xenograft (blue dashed line) with NPs-SHP2 nanoparticles after LIFU treatment. (**A**) injection of SHP2-targeted nanoparticles. (**B**) injection of non-targeted nanoparticles (control). Reproduced with permission from [155], copyright Dove Medical Press Inc.
