Citation

En Ren, Junqing Wang, Gang Liu. Cell-surface cascaded landing location for nanotheranostics[J]. Chin. Chem. Lett., 2017, 28(9): 1799-1800  

En Ren, Junqing Wang, Gang Liu    

Theranostics, combining diagnosis and therapy, is an appealing approach for disease treatment in precision medicine which exhibits improved biodistribution, selective targeting ability, and minimum side effects [1-3]. The role of diagnosis tools, noninvasive imaging methods (e.g., PET, MRI, ultrasound, etc.) in theranostics have been developed and refined to reveal information of the diseased state before and after specific treatment in real-time [4-8]. Considering the complex in vivo microenvironment, it is still a critical challenge to design smart strategies which can precisely accumulate the functional probes/drugs into targeted disease areas for early-stage diagnosis and effective treatment [9-13]. Traditional strategies solely rely on specific recognition of the endogenous protein receptors and the antibody-antigen technology has achieved great success [14-16]. However, varying expression levels of the receptors, and dynamic physiological cellular environments may cause nonspecific recognition for the proteinmediated tumor affinity. Thus, a potent surrogate for conventional targeting drug delivery is needed in the field of precision medicine [17, 18]. For example, some modified bioorthogonal reporters can selectively interact with exogenous probes through electrostatic interaction or covalent reaction, and trigger the cascaded anchoring effects to locate functional nanostructures in disease site [17, 19, 20]. Specifically, cell-surface molecules are ideal biomarkers for the design of disease-targeting technologies, as it has long been postulated to impart specific surface identities on disease phenotype [21-23]. The design of cell-surface cascaded landing location could be an effective strategy to develop a functional drugloading platform for disease theranostics [24, 25].

Recently, Yang et al. [18] had demonstrated a novel approach to detect bacterial infection efficiently. In this process, the vancomycin specifically binding to _D-Ala-_D-Ala moiety that is specific to Gram-positive bacteria membrane [26] was used and a dual fluorescent-and isotopic-labeled vancomycin (¹²⁵I-Rho-FF-Van) was synthesized for infection theranostics. This modified vancomycin could self-assemble to form nanoaggregates on the bacterial surface, resulting in significantly amplified fluorescence signal and strong radioactive signal in methicillin-resistant Staphylococcus aureus (MRSA) infected myositis and lungs in mice (Scheme 1, 2a). The combination of optical and nuclear imaging could allow for non-invasive imaging with high sensitivity and accuracy to monitor bacterial infections and the early response to treatment in real-time. This presented strategy validates that biosurfaceinduced in situ self-assembly promises a new way for Grampositive bacterial infection theranostics and offers more precise diagnostic tools to overcome the challenge of lacking the amount of natural receptors for disease.

Scheme1

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Scheme1. The strategies of cell-surface cascaded landing location for theranostic application

To precisely manipulate cell-surface molecules, a simple strategy based on the native metabolic glyco-biosynthesis was used to achieve site-specific covalent localization of NIR-lightresponsive upconversion nanocrystals (UCNs) on the cell surface through a copper-free click reaction under living conditions (Scheme 1, 2b) [27]. In order to achieve precise regulation of membrane channel activities, a light-gated ion-channel protein, channelrhodopsin-2 (ChR2), was genetically engineered on the cell surface to mediate the influx of essential signaling ions (e.g., Ca²⁺) in the cytoplasm. Upon 808 nm NIR light irradiation, the blue emission (at 480 nm) from UCNs could remotely activate the photosensitive ion channel (ChR2) and effectively manipulate the cation influx in living cells and zebrafish. This strategy provides a site-specific and effective approach for covalent labeling of nanoparticles on the cell membrane. Furthermore, the method of NIR-light-based manipulation of cation influx holds great potential to precisely regulate the cellular membrane-associated activities under in vivo conditions.

Based on these smart designs, cell-surface cascaded landing location has been an effective strategy to help address the problem of inadequate affinity and unexceptional efficiency upon binding to target receptors [28] in living cells or whole organisms by taking advantage of unique physical/chemical reactivity for theranostic applications in personalized nanomedicine. Moreover, it has attracted more attention that not only NIR-light but also some alternative stimulation pathways [29, 30] (e.g., magnetic field, ultrasound, etc.) could remotely and precisely manipulate the specific functions of various cells due to their excellent penetration depth in living system. Therefore, the strategy of cell-surface cascaded landing location of functional substrates makes a major conceptual advance, providing great potential to theranostics in future clinical translation.

This work was supported by the Major State Basic Research Development Program of China (Nos. 2017YFA0205201, 2014CB744503, and 2013CB733802), and the National Natural Science Foundation of China (NSFC) (Nos. 81422023, 81371596, 51273165, and U1505221).