Xiangzhao Ai

In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics

The development of precision nanomedicines to direct nanostructure-based reagents into tumour-targeted areas remains a critical challenge in clinics. Chemical reaction-mediated localization in response to tumour environmental perturbations offers promising opportunities for rational design of effective nano-theranostics. Here, we present a unique microenvironment-sensitive strategy for localization of peptide-premodified upconversion nanocrystals (UCNs) within tumour areas. Upon tumour-specific cathepsin protease reactions, the cleavage of peptides induces covalent cross-linking between the exposed cysteine and 2-cyanobenzothiazole on neighbouring particles, thus triggering the accumulation of UCNs into tumour site. Such enzyme-triggered cross-linking of UCNs leads to enhanced upconversion emission upon 808 nm laser irradiation, and in turn amplifies the singlet oxygen generation from the photosensitizers attached on UCNs. Importantly, this design enables remarkable tumour inhibition through either intratumoral UCNs injection or intravenous injection of nanoparticles modified with the targeting ligand. Our strategy may provide a multimodality solution for effective molecular sensing and site-specific tumour treatment.

Recent Advances of Light-Mediated Theranostics

Currently, precision theranostics have been extensively demanded for the effective treatment of various human diseases. Currently, efficient therapy at the targeted disease areas still remains challenging since most available drug molecules lack of selectivity to the pathological sites. Among different approaches, light-mediated therapeutic strategy has recently emerged as a promising and powerful tool to precisely control the activation of therapeutic reagents and imaging probes in vitro and in vivo, mostly attributed to its unique properties including minimally invasive capability and highly spatiotemporal resolution. Although it has achieved initial success, the conventional strategies for light-mediated theranostics are mostly based on the light with short wavelength (e.g., UV or visible light), which may usually suffer from several undesired drawbacks, such as limited tissue penetration depth, unavoidable light absorption/scattering and potential phototoxicity to healthy tissues, etc. Therefore, a near-infrared (NIR) light-mediated approach on the basis of long-wavelength light (700-1000 nm) irradiation, which displays deep-tissue penetration, minimized photo-damage and low autofluoresence in living systems, has been proposed as an inspiring alternative for precisely phototherapeutic applications in the last decades. Despite numerous NIR light-responsive molecules have been currently proposed for clinical applications, several inherent drawbacks, such as troublesome synthetic procedures, low water solubility and limited accumulation abilities in targeted areas, heavily restrict their applications in deep-tissue therapeutic and imaging studies. Thanks to the amazing properties of several nanomaterials with large extinction coefficient in the NIR region, the construction of NIR light responsive nanoplatforms with multifunctions have become promising approaches for deep-seated diseases diagnosis and therapy. In this review, we summarized various light-triggered theranostic strategies and introduced their great advances in biomedical applications in recent years. Moreover, some other promising light-assisted techniques, such as photoacoustic and Cerenkov radiation, were also systemically discussed. Finally, the potential challenges and future perspectives for light-mediated deep-tissue diagnosis and therapeutics were proposed.

Remote Regulation of Membrane Channel Activity by Site‐Specific Localization of Lanthanide‐Doped Upconversion Nanocrystals

The spatiotemporal regulation of light-gated ion channels is a powerful tool to study physiological pathways and develop personalized theranostic modalities. So far, most existing light-gated channels are limited by their action spectra in the ultraviolet (UV) or visible region. Simple and innovative strategies for the specific attachment of photoswitches on the cell surface without modifying or genetically encoding channel structures, and more importantly, that enable the remote activation of ion-channel functions within near-infrared (NIR) spectral window in living systems, remain a challenging concern. Herein, metabolic glycan biosynthesis is used to achieve site-specific covalent attachment of near-infrared-light-mediated lanthanide-doped upconversion nanocrystals (UCNs) to the cell surface through copper-free click cyclization. Upon irradiation with 808 nm light, the converted emission at 480 nm could activate a light-gated ion channel, channelrhodopsins-2 (ChR2), and thus remotely control the cation influx. This unique strategy provides valuable insights on the specific regulation membrane-associated activities in vivo.

Near infrared light-mediated photoactivation of cytotoxic Re(I) complexes by using lanthanide-doped upconversion nanoparticles

Platinum-based chemotherapy, although it has been well proven to be effective in the battle against cancer, suffers from limited specificity, severe side effects and drug resistance. The development of new alternatives with potent anticancer effects and improved specificity is therefore urgently needed. Recently, there are some new chemotherapy reagents based on photoactive Re(i) complexes which have been reported as promising alternatives to improve specificity mainly attributed to the spatial and temporal activation process by light irradiation. However, most of them respond to short-wavelength light (e.g. UV, blue or green light), which may cause unwanted photo damage to cells. Herein, we demonstrate a system for near-infrared (NIR) light controlled activation of Re(i) complex cytotoxicity by integration of photoactivatable Re(i) complexes and lanthanide-doped upconversion nanoparticles (UCNPs). Upon NIR irradiation at 980 nm, the Re(i) complex can be locally activated by upconverted UV light emitted from UCNPs and subsequently leads to enhanced cell lethality. Cytotoxicity studies showed effective inactivation of both drug susceptible human ovarian carcinoma A2780 cells and cisplatin resistant subline A2780cis cells by our UCNP based system with NIR irradiation, and there was minimum light toxicity observed in the whole process, suggesting that such a system could provide a promising strategy to control localized activation of Re(i) complexes and therefore minimize potential side effects.

Semiconducting photothermal nanoagonist for remote-controlled specific cancer therapy

Nanomedicine have shown success in cancer therapy, but the pharmacological actions of most nanomedicine are often nonspecific to cancer cells because of utilization of the therapeutic agents that induce cell apoptosis from inner organelles. We herein report the development of semiconducting photothermal nanoagonists that can remotely and specifically initiate the apoptosis of cancer cells from cell membrane. The organic nanoagonists comprise semiconducting polymer nanoparticles (SPNs) and capsaicin (Cap) as the photothermally responsive nanocarrier and the agonist for activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), respectively. Under multiple NIR laser irradiation at the time scale of seconds, the nanoagonists can repeatedly and locally release Cap to multiply activate TRPV1 channels on the cellular membrane; the cumulative effect is the overinflux of ions in mitochondria followed by the induction of cell apoptosis specifically for TRPV1-postive cancer cells. Multiple transient activation of TRPV1 channels is essential to induce such a cell death both in vitro and in vivo because both free Cap and simple Cap-encapsulated nanoparticles fail to do so. The photothermally triggered release also ensures a high local concentration of the TRPV1 agonist at tumor site, permitting specific cancer cell therapy at a low systemic administration dosage. Our study thus demonstrates the first example of ion-channel-specific and remote-controlled drug-delivery system for cancer cell therapy.

Enhanced Cellular Ablation by Attenuating Hypoxia Status and Reprogramming Tumor-Associated Macrophages via NIR Light-Responsive Upconversion Nanocrystals

Near-infrared (NIR) light-mediated photodynamic therapy (PDT), especially based on lanthanide-doped upconversion nanocrystals (UCNs), have been extensively investigated as a promising strategy for effective cellular ablation owing to their unique optical properties to convert NIR light excitation into multiple short-wavelength emissions. Despite the deep tissue penetration of NIR light in living systems, the therapeutic efficiency is greatly restricted by insufficient oxygen supply in hypoxic tumor microenvironment. Moreover, the coexistent tumor-associated macrophages (TAMs) play critical roles in tumor recurrence during the post-PDT period. Herein, we developed a unique photosensitizer-loaded UCNs nanoconjugate (PUN) by integrating manganese dioxide (MnO2) nanosheets and hyaluronic acid (HA) biopolymer to improve NIR light-mediated PDT efficacy through attenuating hypoxia status and synergistically reprogramming TAMs populations. After the reaction with overproduced H2O2 in acidic tumor microenvironment, the MnO2 nanosheets were degraded for the production of massive oxygen to greatly enhance the oxygen-dependent PDT efficiency upon 808 nm NIR light irradiation. More importantly, the bioinspired polymer HA could effectively reprogram the polarization of pro-tumor M2-type TAMs to anti-tumor M1-type macrophages to prevent tumor relapse after PDT treatment. Such promising results provided the great opportunities to achieve enhanced cellular ablation upon NIR light-mediated PDT treatment by attenuating hypoxic tumor microenvironment, and thus facilitated the rational design of new generations of nanoplatforms toward immunotherapy to inhibit tumor recurrence during post-PDT period.

Upconversion Nanoparticles for Bioimaging

Rare earth lanthanide-doped upconversion nanoparticles (UCNPs), which can nonlinearly convert long wavelength near-infrared (NIR) light illumination into multiplex emissions, have been widely used in biomedical applications for in vitro and in vivo biolabeling and optical data storage based on their controllable multicolor emission properties. Compared to the traditional used downconversion fluorescence imaging strategies, such NIR light-excited luminescence of UCNPs displays low cytotoxicity and high photostability with little background auto-fluorescence. In this way, it therefore allows for deep tissue penetration, making them attractive as promising contrast agents for biological sensing, biomedical imaging, and diseases theranostics. In this chapter, we mainly place our attention on the recent development of new type of lanthanide-doped UCNP nanomaterials for their in vitro and in vivo bioimaging applications and we also highlight some key challenges for future biomedical studies.

Nanoformulation of metal complexes: Intelligent stimuli-responsive platforms for precision therapeutics

Precision medicine is a potential effective therapeutic for various human diseases. Currently, metal complex-based drugs are being successfully used in clinical applications owing to diverse properties such as multiple redox states, photo-induced ligand exchange, and preferential ligand and coordination numbers, which facilitate drug design and development. However, drawbacks such as toxicity, lack of specificity, and severe side effects have hampered their therapeutic outcome. Therefore, innovative strategies for improving the specificity and pharmacokinetics of conventional metal complex-based therapeutic agents are required. Recently, nanotechnology, which provides a unique toolbox for developing effective and safer medicine, has attracted considerable attention, mainly because of their ability to reduce side effects and enhance drug loading efficiency and pharmacokinetics. Considering the promising chemical and physical properties of diverse nanostructures, nanoformulation of metal complexes can be used to effectively address the problems associated with current metallodrug complexes, especially those based on stimuli-responsive therapeutic strategies, with excellent spatial, temporal, and dosage control. In this review, we have mainly focused on the specificity and environment-responsiveness of metallodrug nanoformulations as therapeutics, and summarized the recent strategies being used for developing metal complex-functionalized intelligent nanoplatforms, which respond to various types of stimuli, including endogenous signals (pH, redox conditions, and enzyme activities) or external triggers (light irradiation and magnetic field manipulations). In addition, we have also discussed the potential challenges associated with use of metallodrugs and their nanoformulations as effective precision therapy with improved specificity and minimal side effects.

Near-infrared light-mediated rare-earth nanocrystals: recent advances in improving photon conversion and alleviating the thermal effect

With the rapid development of nanotechnology, the unique rare-earth lanthanide-doped upconversion nanocrystals (UCNs), which can convert tissue-penetrable near-infrared (NIR) photonic irradiation into ultraviolet, visible, and NIR emissions, have a significant potential in bioimaging, diagnosis, and therapy, as well as in photovoltaic systems and optical data storage. Despite the promising achievements made in the past decade, critical challenges associated with low upconversion efficiencies and the overheating effect induced by NIR laser-irradiation still remain in the biomedical fields. In high demand are more well-defined material design and unique structural modifications that are capable of solving these technical concerns and promoting such promising NIR light-mediated upconversion nanocrystals for their further application in the medical sciences. Recent advances in upconversion nanomaterials have witnessed a tremendous development towards enhancing their photon conversion efficiency, which provides great opportunities in expanding the potential of the UCNs in bioimaging diagnosis and anticancer therapy. Hence, this review is mainly focused on summarizing the fundamental principles and strategies that improve upconversion luminescence and the approaches to reduce the local thermal effect on the basis of a rational design of UCNs. In addition, the future perspectives in the development of UCNs for biomedical applications are also proposed.Nanocrystals: helping bright bioprobes keep their coolRare-earth elements and organic dyes are improving the safety and efficiency of innovative fluorescent probes designed to diagnose tumors and other disorders deep inside living tissue. Upconversion nanocrystals are microscopic particles that can release a broad range of infrared, visible, and ultraviolet light after activation by laser irradiation. Bengang Xing from Nanyang Technological University in Singapore and colleagues review how these nanomaterials may be engineered to achieve brighter luminescence while minimizing laser-related heating. Although researchers normally impregnate upconversion nanocrystals with small amounts of rare earths, new findings show that boosting rare earth levels with ions such as neodymium enables the tuning of laser excitations to biologically compatible frequencies, and emission outputs to specific colors. Adding organic molecules capable of broadband light adsorption to the nanocrystals offers opportunities for targeted, ultra-bright imaging and activation of biomolecules.With the rapid development of nanotechnology, the unique rare earth lanthanide-doped upconversion nanocrystals (UCNs), which can convert tissue-penetrable near-infrared (NIR) photonic irradiation into ultraviolet, visible and NIR emissions, have found significant potential in bioimaging, diagnosis, therapy, as well as photovoltaics and optical data storage. Despite the promising achievements made in the past decade, critical challenges associated with low upconversion efficiencies and overheating effect induced by NIR laser-irradiation remain in the biomedical fields. More well-defined material design and unique structural modification are highly demanded that are capable of solving these technical concerns and promoting such promising NIR light mediated upconversion nanocrystals for their further practice in medical sciences. Recent advances in upconversion nanomaterials have witnessed the tremendous development towards enhancing the photon converted efficiency, which provides great opportunities in expanding the UCNs potential in bioimaging diagnosis and anticancer therapy. Hence, this review is mainly focusing on summarizing the fundamental principles and strategies to improve the upconversion luminescence and the approaches to reduce the local thermal effect on the basis of rational design of UCNs. In addition, the future perspectives in the development of UCNs for biomedical applications are also proposed.

pH-sensitive and biodegradable charge-transfer nanocomplex for second near-infrared photoacoustic tumor imaging

The emerging technique of photoacoustic imaging, especially in the near infra-red (NIR) window, permits high resolution, deep-penetration, clinically reliable sensing. However, few contrast agents are available that can specifically respond to intricate biological environments, and which are biodegradable and biocompatible. Herein, we introduce a new class of pH-sensitive organic photoacoustic contrast agent that operates in the second NIR window (NIR-II, 960–1,700 nm), which is derived from the self-assembled charge-transfer nanocomplex (CTN) by 3,3’,5,5’-tetramethylbenzidine (TMB) and its dication structure (TMB++). The unique NIR-II-responsive CTN can specifically respond to pH change in the physiological range and allows noninvasive and sensitive visualization of the tumor acidic microenvironment (e.g. at pH 5) in mice with higher signal-to-noise ratio. The CTN is biodegradable under physiological conditions (e.g. pH 7.4), which alleviates the biosafety concern of nanoparticle accumulation in vivo. These results clearly show the potential of the TMB/TMB++-based CTN as a promising pH-activated and biodegradable molecular probe for specific tumor photoacoustic imaging in the NIR-II region.