PET imaging of a 68Ga labeled modified HER2 affibody in breast cancers: from xenografts to patients.

OBJECTIVE: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancers provides promising opportunities for imaging and targeted therapy. Developing HER2 targeted positron emission tomography (PET) probes might be benefit for management of the disease. Small high-affinity scaffold proteins, affibodies, are ideal vectors for imaging HER2 overexpressed tumors. Despite of the initial success on development of 18F labeled ZHER2:342 affibody, the tedious synthesis producers, low yields and unfavorable pharmacokinetics may hinder the clinical use. 68Ga is an attractive positron emitter for PET imaging. A simple preparation of 68Ga labeled ZHER2:342 analog, 68Ga-NOTA-MAL-Cys-MZHER2:342, was reported in the study. The in vivo performances of the tracer for assessing HER2 status in breast cancers were also evaluated. METHODS: NOTA-MAL conjugated Cys-MZHER2:342 was radiolabeled with 68Ga. The probe was evaluated by in vitro tests including stability and cell binding studies in breast cancer cells with different HER2 levels. In vivo evaluation was performed in mice bearing tumors using microPET imaging and biodistribution experiments. A PET/CT imaging study was initially performed in patients with breast cancers. RESULTS: The tracer was synthesized in a straightforward chelation method with satisfactory non-decay corrected yield (81±5%) and radiochemical purity (>95%). In vivo micro-PET imaging showed that HER2 high levels expressed BT474 xenografts were more clear visualized than HER2 low levels expressed MCF-7 tumors (16.12 ± 2.69 ID%/g vs 1.32 ± 0.19 ID%/g at 1 h post-injection). The outcome was consistent with the immunohistochemical analysis. No significant radioactivity was accumulated in healthy tissues (less than 2% ID/g) except kidneys. In a preliminary clinical study, 68Ga-NOTA-MAL-Cys-MZHER2:342 PET imaging allowed more high-contrast detection of HER2 positive primary tumors (maximum standardized uptake value = 2.16±0.27) than those in HER2 negative primary focus (maximum standardized uptake value = 0.32±0.05). No detectable side-effects were found. CONCLUSION: In summary, this study indicates the significant efficiency of the 68Ga labeled HER2 affibody. Preclinical and clinical studies support the possibility of monitoring HER2 levels in breast cancers using 68Ga-NOTA-MAL-Cys-MZHER2:342. ADVANCES IN KNOWLEDGE: The research investigated the feasibility of a 68Ga labeled HER2 affibody modified with a hydrophilic linker for breast cancer PET imaging. Favorable outcomes showed that the probe might be valuable for determining HER2 status of the disease.

Combinatory effects of vaccinia virus VG9 and the STAT3 inhibitor Stattic on cancer therapy.

The recombinant vaccinia virus VG9 and the STAT3 inhibitor Stattic were combined to kill cancer cells via both oncolytic activity and inhibition of STAT3 phosphorylation in cells. The combinatory anti-tumour activity of these compounds was superior to the activity of VG9 or Stattic alone in vivo. The inhibition of tumour growth occurred via increased apoptosis and autophagy pathways. Furthermore, the combinatory anti-tumour activity was more efficient than that of VG9 or Stattic alone on xenografts, especially in nude mice.

Polyphenol-Poloxamer Self-Assembled Supramolecular Nanoparticles for Tumor NIRF/PET Imaging.

Self-assembled supramolecular nanoparticles have remarkable benefits in bioimaging and drug delivery. Here it is first reported that polyphenol and poloxamer self-assemble supramolecular nanoparticles (PPNPs). PPNPs are fabricated by multivalent hydrogen bonding between tannic acid and Pluronic F-127 together with hydrophobic interactions of poly(propylene oxide) chains, to be applied in tumor near-infrared fluorescence (NIRF) imaging and positron emission tomography (PET) imaging. With near-infrared fluorescent dyes such as IR780 encapsulated via hydrophobic interactions, PPNPs are used in NIRF imaging. PPNPs with excess phenolic hydroxyl groups chelating positron emitting radionuclide 89 Zr function as a PET contrast agent. The in vivo results show surprisingly higher fluorescence intensity in tumors than in other tissues. In addition, PPNPs exhibit good biocompatibility in various cell lines and do not induce hemolysis in vitro. In this study, it is demonstrated that biodegradable and biocompatible PPNPs are an excellent bimodal contrast agent for in vivo tumor imaging.

PET of HER2 Expression with a Novel 18FAl Labeled Affibody.

Background: Human epidermal growth factor receptor type 2 (HER2) is abundant in a wide variety of tumors and associated with the poor prognosis. Radiolabeled affibodies are potential candidates for detecting HER2-positive lesions. However, laborious multiple-step synthetic procedure and high abdomen background may hinder the widespread use. Herein, cysteinylated ZHER2:342 modified with a new hydrophilic linker (denoted as MZHER2:342) was designed and labeled using 18FAl-NOTA strategies. The biologic efficacy of the novel tracer and its feasibilities for in vivo monitoring HER2 levels were also investigated in xenograft models with different HER2 expressions. Method: MZHER2:342 was conjugated with MAL-NOTA under standard reaction conditions. The affibody molecule was then radiolabeled with 18FAl complex. The binding specificity of the tracer, 18FAl-NOTA-MAL-MZHER2:342, with HER2 was primarily characterized via in vitro studies. MicroPET imaging were performed in nude mice bearing tumors (SKOV-3, JIMT-1 and MCF-7) after injection. The HER2 levels of xenografts were determined using Western blotting analysis. Results:18FAl-NOTA-MAL-MZHER2:342 can be efficiently produced within 30 min with a non-decaycorrected yield of about 10% and a radiochemical purity of more than 95%. In vitro experiments revealed that the modified affibody retained the specific affinity to HER2. PET imaging showed that SKOV-3 and JIMT-1 xenografts were clearly visualized with excellent contrast and low abdomen backgrounds. On the contrary, the signals of MCF-7 tumor were difficult to visualize. The ROI values ranged from16.54±2.69% ID/g for SKOV-3 to 8.42±1.20 %ID/g for JIMT-1 tumors at 1h postinjection respectively. Poor uptake was observed from MCF-7 tumors with 1.71±0.34% ID/g at the same time point. Besides, a significant linear correlation between % ID/g values and relative HER2 expression levels was also found. Conclusions:18FAl-NOTA-MAL-MZHER2:342 is a promising tracer for in vivo detecting HER2 status with the advantages of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers.