The immunotoxin targeting PRLR increases tamoxifen sensitivity and enhances the efficacy of chemotherapy in breast cancer.

BACKGROUND: Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated. METHODS: High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts. RESULTS: PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer. CONCLUSIONS: PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer.

Dynamic DNA Nanostructures for Cell Manipulation.

Dynamic DNA nanostructures are DNA nanostructures with reconfigurable elements that can undergo structural transformations in response to specific stimuli. Thus, anchoring dynamic DNA nanostructures on cell membranes is an attractive and promising strategy for well-controlled cell manipulation. Here, we review the latest progress in dynamic DNA nanostructures for cell manipulation. Commonly used mechanisms for dynamic DNA nanostructures are first introduced. Subsequently, we summarize the anchoring strategies for dynamic DNA nanostructures on cell membranes and list possible applications (including programming cell membrane receptors, controlling ligand activity and drug delivery, capturing and releasing cells, and assembling cells into clusters). Finally, insights into the remaining challenges are presented.

Deoxyribonucleic acid anchored on cell membranes for biomedical application.

Engineering cellular membranes with functional molecules provides an attractive strategy to manipulate cellular behaviors and functionalities. Currently, synthetic deoxyribonucleic acid (DNA) has emerged as a promising molecular tool to engineer cellular membranes for biomedical applications due to its molecular recognition and programmable properties. In this review, we summarized the recent advances in anchoring DNA on the cellular membranes and their applications. The strategies for anchoring DNA on cell membranes were summarized. Then their applications, such as immune response activation, receptor oligomerization regulation, membrane structure mimicking, cell-surface biosensing, and construction of cell clusters, were listed. The DNA-enabled intelligent systems which were able to sense stimuli such as DNA strands, light, and metal ions were highlighted. Finally, insights regarding the remaining challenges and possible future directions were provided.

Metal-organic frameworks for virus detection.

Virus severely endangers human life and health, and the detection of viruses is essential for the prevention and treatment of associated diseases. Metal-organic framework (MOF), a novel hybrid porous material which is bridged by the metal clusters and organic linkers, has become a promising biosensor platform for virus detection due to its outstanding properties including high surface area, adjustable pore size, easy modification, etc. However, the MOF-based sensing platforms for virus detection are rarely summarized. This review systematically divided the detection platforms into nucleic acid and immunological (antigen and antibody) detection, and the underlying sensing mechanisms were interpreted. The nucleic acid sensing was discussed based on the properties of MOF (such as metal ion, functional group, geometry structure, size, porosity, stability, etc.), revealing the relationship between the sensing performance and properties of MOF. Moreover, antibodies sensing based on the fluorescence detection and antigens sensing based on molecular imprinting or electrochemical immunoassay were highlighted. Furthermore, the remaining challenges and future development of MOF for virus detection were further discussed and proposed. This review will provide valuable references for the construction of sophisticated sensing platform for the detection of viruses, especially the 2019 coronavirus.

Tumor microenvironment responsive drug delivery systems.

Conventional tumor-targeted drug delivery systems (DDSs) face challenges, such as unsatisfied systemic circulation, low targeting efficiency, poor tumoral penetration, and uncontrolled drug release. Recently, tumor cellular molecules-triggered DDSs have aroused great interests in addressing such dilemmas. With the introduction of several additional functionalities, the properties of these smart DDSs including size, surface charge and ligand exposure can response to different tumor microenvironments for a more efficient tumor targeting, and eventually achieve desired drug release for an optimized therapeutic efficiency. This review highlights the recent research progresses on smart tumor environment responsive drug delivery systems for targeted drug delivery. Dynamic targeting strategies and functional moieties sensitive to a variety of tumor cellular stimuli, including pH, glutathione, adenosine-triphosphate, reactive oxygen species, enzyme and inflammatory factors are summarized. Special emphasis of this review is placed on their responsive mechanisms, drug loading models, drawbacks and merits. Several typical multi-stimuli responsive DDSs are listed. And the main challenges and potential future development are discussed.

Dynamic DNA Assemblies in Biomedical Applications.

Deoxyribonucleic acid (DNA) has been widely used to construct homogeneous structures with increasing complexity for biological and biomedical applications due to their powerful functionalities. Especially, dynamic DNA assemblies (DDAs) have demonstrated the ability to simulate molecular motions and fluctuations in bionic systems. DDAs, including DNA robots, DNA probes, DNA nanochannels, DNA templates, etc., can perform structural transformations or predictable behaviors in response to corresponding stimuli and show potential in the fields of single molecule sensing, drug delivery, molecular assembly, etc. A wave of exploration of the principles in designing and usage of DDAs has occurred, however, knowledge on these concepts is still limited. Although some previous reviews have been reported, systematic and detailed reviews are rare. To achieve a better understanding of the mechanisms in DDAs, herein, the recent progress on the fundamental principles regarding DDAs and their applications are summarized. The relative assembly principles and computer-aided software for their designing are introduced. The advantages and disadvantages of each software are discussed. The motional mechanisms of the DDAs are classified into exogenous and endogenous stimuli-triggered responses. The special dynamic behaviors of DDAs in biomedical applications are also summarized. Moreover, the current challenges and future directions of DDAs are proposed.

Aptamer-Pyropheophorbide a Conjugates with Tumor Spheroid Targeting and Penetration Abilities for Photodynamic Therapy.

Pyropheophorbide a (Pyro) is a widely used photosensitizer for photodynamic therapy (PDT). However, poor water solubility, aggregation-induced fluorescence quenching, and lack of selectivity to targeted cells seriously limit its application. In this work, we prepared aptamer-Pyro conjugates (APCs) by linking Pyro to hydrophilic nucleic acid aptamer to enhance its water solubility and endow it with protein tyrosine kinase 7 (PTK7) overexpressed tumor spheroid specific targeting and penetration abilities for photodynamic therapy. The molecular conjugate was successfully synthesized and dissolved well in an aqueous solution. The APCs showed strong near-infrared fluorescence in the aqueous solution and produced singlet oxygen both in the solution and cells under laser irradiation, indicating its generation of singlet oxygen during PDT was guaranteed. Owing to the cancer cell targeting ability of the aptamer, the APCs specifically bound with PTK7 overexpressed cancerous cells and showed fluorescence signal for tumor cell imaging and diagnosis. The APCs exhibited favorable enhanced phototoxicity to target tumor cells compared with control cells. More importantly, due to the small size of the molecular conjugate, the APCs efficiently penetrated into the interior of multicellular tumor spheroids (MCTS) and caused cell damage. All these results indicated that the robust aptamer-Pyro conjugate is a promising selective tumor-targeting and penetrable molecule for cancer photodynamic therapy.

Interfacing DNA with nanoparticles: Surface science and its applications in biosensing.

The knowledge on the mechanisms of DNA interfacing with nanoparticles holds great potential for the design, assembly and usage of DNA in biological applications. A wave of understanding and exploitation of the mechanisms in DNA-nanoparticles interfacial phenomenon has raised. Although some previous reviews have been reported, systematic and detailed reviews are rare. To achieve a better understanding of the mechanisms in the interaction between DNA and nanoparticles, here, we summarized the recent progresses on the fundamental principles regarding the DNA-nanoparticle interactions and their applications in biosensing. Special focus was put on inorganic nanoparticles such as metal nanoparticles, carbon-based materials, metal oxides and quantum dots. For each material, the surface properties, the interfacing mechanisms, and the kinetics and spatial control of DNA adsorption were summarized and discussed. We also highlighted some of the recent technologies based on DNA-NPs interactions for biomolecules detection. Finally, the challenges and future directions were discussed and proposed. This review provides a systematic understanding of the mechanisms in the interaction of DNA-nanoparticles, which, in turn, can inspire new insights for designing biosensors with improved properties.

Metal-organic frameworks for stimuli-responsive drug delivery.

Metal-organic framework (MOF), a novel hybrid porous material which is composited by metal ions and organic linkers, has drawn increasing attention and became a promising material in the biomedical field owing to their unique properties including large pore volume, high surface area, tunable pore size, versatile functionality and high drug loading efficiency. However, the MOF families and members, and the drug release mechanisms in MOF-based stimuli-responsive drug delivery systems (DDSs) are rarely summarized. Here, we systematically classified the families of MOF and introduced some representative members in MOF families. Moreover, the underlying drug release mechanisms were interpreted according to endogenous stimuli (include pH, glutathione (GSH), adenosine-triphosphate (ATP), ion, glucose, enzyme, H2S, and etc.) and the exogenous stimuli (include light, temperature, pressure, and etc.). Furthermore, the remaining challenges and future directions of DDSs based on MOF are discussed and proposed. This review revealed the relationship between the structure and properties of MOF. A better understanding of these release mechanisms under different stimuli would benefit the designing of sophisticated DDSs based on the promising material of MOF.

Advances in aptamer screening technologies.

Systematic evolution of ligands by exponential enrichment (SELEX) is a well-established technology for the screening of aptamers binding to various targets with relatively high specificity and affinity. The screened aptamers have shown great achievements in bio-sensing and targeted therapeutics, which in turn stimulate continuous development of SELEX technology. To date, many SELEX technologies have been established, such as cell-SELEX, mag-SELEX, capillary electrophoresis SELEX and some novel modifications of SELEX. This review highlights current screening technologies and comprehensively pinpoints their principles, pros and cons. Some main aptamers screened by SELEX or involved in clinical trials are summarized. While, there are still challenges in obtaining of aptamer with high affinity and in an efficient way. The limitations and possible future directions on the screening of aptamers are also outlined.

Cancer protein biomarker discovery based on nucleic acid aptamers.

Identification of biomarkers is essential for diagnosis, targeted therapy and prognosis evaluation of diseases, especially cancers. Currently, the number of ideal clinical biomarkers is still limited partially because of lacking efficient methods in biomarker discovery. Nucleic acid aptamers are artificial single-stranded DNA or RNA sequences that can selectively bind to various targets with high specificity and affinity. Moreover, aptamers possess desirable advantages, including easy synthesis, convenient modification, relative chemical stability and low immunogenicity. Recently, different aptamer-based strategies have been developed to facilitate the discovery of biomarkers. Based on cell-SELEX technology, the selected aptamers can be used to identify cell-surface protein biomarkers of different cancer cells. SOMAscan can analyze thousands of proteins of different biological samples, which becomes a multiplexed protein biomarker discovery platform. Additionally, secreted protein biomarkers can be discovered by aptamers screened through secretome SELEX. In order to facilitate the identification of target proteins, several covalent cross-linking strategies have been developed, such as aptamer-based affinity labeling (ABAL), DNA-templated aptamer and protein-aptamer template (PAT). In this review, we mainly highlight the emerging nucleic acid aptamer-based biomarker discovery strategies and demonstrate their unique technological advantages in discovering cancer biomarkers. The challenges and perspectives of aptamer-based methods are also discussed.