Abstract
Trastuzumab is a monoclonal antibody targeting human epidermal growth factor 2 (HER2), which has been successfully used in the treatment of patients with breast cancer and gastric cancer; however, problems concerning its cardiotoxicity, drug resistance, and unpredictable efficacy still remain. Herein, we constructed novel organic dopamine–melanin nanoparticles (dMNs) as a carrier and then surface-loaded them with trastuzumab to construct a multifunctional nanoprobe named Her-PEG-dMNPs. We used micro-PET/CT and PET/MRI multimodality imaging to evaluate the retention effect of the nanoprobe in HER2 expression in gastric cancer patient-derived xenograft (PDX) mice models after labeling of the radionuclides 64Cu or 124I and MRI contrast agent Mn2+. The nanoprobes can specifically target the HER2-expressing SKOV-3 cells in vitro (3.61 ± 0.74 vs. 1.24 ± 0.43 for 2 h, P = 0.002). In vivo, micro-PET/CT and PET/MRI showed that the 124I-labeled nanoprobe had greater contrast and retention effect in PDX models than unloaded dMNPs as carrier (1.63 ± 0.07 vs. 0.90 ± 0.04 at 24 h, P = 0.002), a similarity found in 64Cu-labeled Her-PEG-dMNPs. Because 124I has a longer half-life and matches the pharmacokinetics of the nanoparticles, we focused on the further evaluation of 124I-Her-PEG-dMNPs. Furthermore, immunohistochemistry staining confirmed the overexpression of HER2 in the animal model. This study developed and validated novel HER2-specific multimodality imaging nanoprobes for quantifying HER2 expression in mice. Through the strong retention effect of the tumor site, it can be used for the promotion of monoclonal antibody treatment effect and process monitoring.
Highlights
Human epidermal growth factor was discovered in 1962, while structurally related receptors were discovered in 1978 [1]
Scheme 1 shows the reaction flowchart of the Her-PEG-Dopamine–melanin nanoparticles (dMNPs) imaging probe
Typical scanning electron microscopy (SEM) and transmission electron microscopy (TEM) imaging showed that the synthesized dMNPs and Her-PEG-DMNPs had clear structures and uniform and regular shapes and sizes (Figures 1A, B)
Summary
Human epidermal growth factor was discovered in 1962, while structurally related receptors were discovered in 1978 [1]. As for the HER family, it is mainly composed of four receptors, HER1, HER2, HER3, and HER4, which can interact with each other in regulating different biological behaviors such as cell proliferation, differentiation, and survival. Human epidermal growth factor 2 (HER2) is a transmembrane glycoprotein, known as CERBB-2 and ERbb, which promotes malignant biological behaviors such as cell proliferation and migration through the formation of homologous or heterologous dimers with family members [2]. Positive HER2 expression was found in 15%–20% of breast cancers, which had a high degree of malignancy and poor prognosis [4]. HER2 is an ideal molecular target for cancer, highly expressed in a variety of cancer cells, such as colorectal cancer, ovarian cancer, prostate cancer, bladder cancer, and lung cancer, especially gastric and esophageal cancer [3,4,5,6]
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