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Synthesis of Core-shell Lanthanide-doped Upconversion Nanocrystals for Cellular Applications

Lanthanide-doped upconversion nanocrystals (UCNs) have attracted much attention in recent years based on their promising and controllable optical ...

Nanyang Technological University

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.

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

Carbon dots (CDs) are remarkable nanocarriers due to their promising optical and biocompatible capabilities. However, their practical applicability in cancer therapeutics is limited by their insensitive surface properties to complicated tumor microenvironment in vivo. Herein, a tumor extracellular microenvironment-responsive drug nanocarrier based on cisplatin(IV) prodrug-loaded charge-convertible CDs (CDs-Pt(IV)@PEG-(PAH/DMMA)) was developed for imaging-guided drug delivery. An anionic polymer with dimethylmaleic acid (PEG-(PAH/DMMA)) on the fabricated CDs-Pt(IV)@PEG-(PAH/DMMA) could undergo intriguing charge conversion to a cationic polymer in mildly acidic tumor extracellular microenvironment (pH ∼ 6.8), leading to strong electrostatic repulsion and release of positive CDs-Pt(IV). Importantly, positively charged nanocarrier displays high affinity to negatively charged cancer cell membrane, which results in enhanced internalization and effective activation of cisplatin(IV) prodrug in the reductive cytosol. The in vitro experimental results confirmed that this promising charge-convertible nanocarrier possesses better therapeutic efficiency under tumor extracellular microenvironment than normal physiological condition and noncharge-convertible nanocarrier. The in vivo experiments further demonstrated high tumor-inhibition efficacy and low side effects of the charge-convertible CDs, proving its capability as a smart drug nanocarrier with enhanced therapeutic effects. The present work provides a strategy to promote potential clinical application of CDs in the cancer treatment.

Charge-Convertible Carbon Dots for Imaging-Guided Drug Delivery with Enhanced in Vivo Cancer Therapeutic Efficiency.

In this work, pH/redox dual-responsive carbon dots (CDs-RGD-Pt(IV)-PEG) were fabricated for tumor extracellular microenvironment triggered targeting and enhanced anticancer drug delivery. The system consists of fluorescent carbon dots as imaging-guided drug nanocarriers, cisplatin(IV) as prodrug, and RGD peptide as active targeting ligand, which is covered by monomethoxypolyethylene glycol (mPEG) through tumor extracellular pH (6.5-6.8) responsive benzoic-imine bond. The drug nanocarriers could be tracked by multicolor fluorescence of carbon dots. After the hydrolysis of benzoic-imine bond at the tumor extracellular pH to expose the inner targeting RGD peptide, the drug nanocarriers showed effective uptake by cancer cells through RGD-integrin αvβ3 (ligand-receptor) interaction. Upon the internalization, the loaded cisplatin(IV) prodrug was reduced to cytotoxic cisplatin in reductive cytosol of cancer cells to exhibit therapeutic effects. Confocal imaging, flow cytometry, and cell viability assays using CDs-RGD-Pt(IV)-PEG were performed to reveal the enhanced uptake and better therapeutic efficiency to cancer cells with high integrin αvβ3 expression at tumor extracellular pH than that in physiological condition. The developed CDs-RGD-Pt(IV)-PEG offers a new strategy to provide safe and effective therapeutic agents based on carbon dots for promising cancer therapy.

Dual-Responsive Carbon Dots for Tumor Extracellular Microenvironment Triggered Targeting and Enhanced Anticancer Drug Delivery.

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.

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

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.

Recent Advances of Light-Mediated Theranostics.

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.

Article	Year
In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics. Nature communications\| PubMed ID: 26786559	2016
Charge-Convertible Carbon Dots for Imaging-Guided Drug Delivery with Enhanced in Vivo Cancer Therapeutic Efficiency. ACS nano\| PubMed ID: 26997431	2016
Dual-Responsive Carbon Dots for Tumor Extracellular Microenvironment Triggered Targeting and Enhanced Anticancer Drug Delivery. ACS applied materials & interfaces\| PubMed ID: 27367152	2016
Near infrared light-mediated photoactivation of cytotoxic Re(i) complexes by using lanthanide-doped upconversion nanoparticles. Dalton transactions (Cambridge, England : 2003)\| PubMed ID: 27711690	2016
Recent Advances of Light-Mediated Theranostics. Theranostics\| PubMed ID: 27877246	2016
Remote Regulation of Membrane Channel Activity by Site-Specific Localization of Lanthanide-Doped Upconversion Nanocrystals. Angewandte Chemie (International ed. in English)\| PubMed ID: 28157258	2017

Xiangzhao Ai

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