Yuyan Li

Lipid nanoparticles (LNPs) have emerged as a powerful platform for mRNA vaccine delivery, with ionizable lipids playing a pivotal role in enhancing cellular uptake and endosomal escape, thereby improving therapeutic efficacy. In this study, we designed and synthesized 12 novel ionizable lipids via molecular hybridization, incorporating a hydroxyalkylamine headgroup, an ester linkage, and a cis-double bond tail. These lipids were then formulated into LNPs with helper lipids and eGFP or LUC mRNA. Through cell transfection and in vivo imaging experiments, the O2-N5-OLE LNP was identified with superior mRNA delivery capabilities, particularly in immune cells. Subsequently, it was employed to encapsulate the tumor model antigen ovalbumin (OVA) mRNA vaccine, and its preventive effects against mouse melanoma were evaluated. The results demonstrated that O2-N5-OLE LNP@OVA mRNA exhibits superior tumor suppression. Additionally, the OVA mRNA delivered by O2-N5-OLE LNP significantly elevated serum OVA-IgG and IFN-γ levels and activated dendritic cells and CD8⁺ T lymphocytes, indicating that the vaccine effectively activated both humoral and cellular immunity. Coupled with the excellent biocompatibility of the O2-N5-OLE LNP, these findings highlight its remarkable delivery efficacy and provide a strong experimental foundation for its potential clinical application.

Amyloid-β oligomers (AβOs), crucial toxic proteins in early Alzheimer's disease (AD), precede the formation of Aβ plaques and cognitive impairment. In this context, we present our iterative process for developing novel near-infrared fluorescent (NIRF) probes specifically targeting AβOs, aimed at early AD diagnosis. An initial screening identified compound 18 as being highly selective for AβOs. Subsequent analysis revealed that compound 20 improved serum stability while retaining affinity for AβOs. The most promising iteration, compound 37, demonstrated exceptional qualities: a high affinity for AβOs, emission in the near-infrared region, and good biocompatibility. Significantly, ex vivo double staining indicated that compound 37 detected AβOs in AD mouse brain and in vivo imaging experiments showed that compound 37 could differentiate between 4-month-old AD mice and age-matched wild-type mice. Therefore, compound 37 has emerged as a valuable NIRF probe for early detection of AD and a useful tool in exploring AD's pathological mechanisms.

Multimodality imaging recognized as a promising monitoring strategy can serve the needs of accurate diagnosis and treatment of cancer by providing molecular and anatomic information about tumor sites. However, the probes based on multiple imaging modalities for surgery navigation remain limited due to poor biocompatibility and tumor targeting specificity. Herein, we present a small-molecule near-infrared fluorescence/magnetic resonance (NIRF/MR) imaging probe, Gd-NMC-3, covalently coupled with DCDSTCY and Gd-DOTA via butane diamine, for precise detection and intraoperative visualization. The in vitro and in vivo studies demonstrated that Gd-NMC-3 could be effectively accumulated in tumor sites as a bimodal imaging molecule exhibiting significant fluorescence accumulation and reasonable relaxation property in tumors with low cytotoxicity and good biocompatibility. Furthermore, Gd-NMC-3 was successfully applied to provide real-time visual navigation in LM3 orthotopic and subcutaneous tumor models to guide the resection of tumors. Importantly, no more fluorescence was observed in mice after operation, implying the total removal of tumor tissues. In conclusion, Gd-NMC-3 has great potential to be applied in the clinic based on its high resolution and sensitivity in tumor imaging.

Background: Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, and it is still incurable. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. Mounting evidence indicates that the neurotoxic effects might be attributed to Soluble β-Amyloid Oligomers (SAβO). The SAβO are believed to be neurotoxic peptides more predominant than Aβ plaques in the early stage, and their key role in AD is self-evident. Unfortunately, identification of SAβO proves to be difficult due to their heterogeneous and transient nature. In spite of many obstacles, multiple techniques have recently been developed to target SAβO effectively. This review focuses on the recent progress in the approaches towards SAβO detection in order to shed some light on the future development of SAβO assays. Methods : Literatures were obtained from the following libraries: Web of Science, PubMed, EPO, SIPO, USPTO. Articles were critically reviewed based on their titles, abstracts, and contents. Results: A total of 85 papers are referenced in the review. Results are divided into three categories based on the types of detection methods: small molecule fluorescence probes, oligomer-specific antibodies and electrochemical biosensors. Finally, the improvements and challenges of these approaches applied in the early diagnosis of AD were discussed. Conclusion: This review article covers three kinds of strategies that could be translated into clinic practice and lead to earlier diagnosis and therapeutic interventions of AD.

With currently available molecular imaging techniques, hepatocellular carcinoma (HCC), a liver cancer with high mortality rates and poor treatment responses, is mostly diagnosed at its late stage. This is largely due to the lack of highly sensitive contrast agents with high liver specificity. Herein, we report a novel bimodal contrast agent molecule CNCI-1 for the ef-fective detection of HCC at its early stage both in vitro and in vivo. The agent has high liver specificity with effective X-ray computed tomography (CT) /near-infrared (NIR) imaging functions. It has been successfully applied to in vivo NIR imag-ing with high sensitivity and high selectivity to the HCC region of the HepG2 tumor-xenografted mice model and LM3 or-thotopic hepatoma mice model. Moreover, the agent was found to be noninvasive and hepatocarcinoma cells preferential. Furthermore, it also enhanced the tumor imaging by revealing the blood vessels nearby for the CT image acquisition in the VX2 orthotopic hepatoma rabbit model. Our design strategy provides a new avenue to develop the medical relevant bimodal contrast agents for diagnosis of HCC at its early stage.

In this report, we demonstrate a “V-shaped” NIRF probe PTO-29, which can monitor Aβ oligomers with high selectivity. PTO-29 was designed and showed significant response to Aβ oligomers in the fluorescence spectral tests and good properties. In vivo imaging results indicate that 4 month APP/PS1 AD mice have higher signals in the brain than age-matched wild type mice.

FGFs and their receptors (FGFRs) are critical for many biologic processes, including angiogenesis, wound healing and tissue regeneration. Aberrations in FGFR signaling are common in cancer, making FGFRs a promising target in antitumor studies. To date, many FGFR inhibitors are being detected in clinical studies, and resistance to some inhibitors has emerged. Understanding the mechanisms of resistance is a fundamental step for further implementation of targeted therapies. In this review, we will describe the basic knowledge regarding FGF/FGFR signaling and categorize the clinical FGFR inhibitors. The mechanisms of resistance to FGFR inhibitors and corresponding strategies of overcoming drug resistance will also be discussed.