Fujin Ai

Organocatalytic Asymmetric Synthesis of 1,1-Diarylethanes by Transfer Hydrogenation

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

A core-shell-shell nanoplatform upconverting near-infrared light at 808 nm for luminescence imaging and photodynamic therapy of cancer.

Upconversion nanoparticles (UCNPs) have been extensively explored for photodynamic therapy (PDT) and imaging due to their representative large anti-Stokes shifts, deep penetration into biological tissues, narrow emission bands, and high spatial-temporal resolution. Conventional UCNP-based PDT system, however, utilizes exitation at 980 nm, at which water has significant absorption, leading to a huge concern that the cell killing effect is from the irradiation due to overheating effect. Here we report an efficient nanoplatform using 808-nm excited NaYbF4:Nd@NaGdF4:Yb/Er@NaGdF4 core−shell−shell nanoparticles loaded with Chlorin e6 and folic acid for simultaneous imaging and PDT. At this wavelength, the absorption of water is minimized. High energy transfer efficiency is achieved to generate cytotoxic singlet oxygen. Our nanoplatform effectively kills cancer cells in concentration-, time-, and receptor-dependent manners. More importantly, our nanoplatform is still able to efficiently generate singlet oxygen beneath 15-mm thickness of muscle tissue but 980 nm excitation cannot, showing that a higher penetration depth is achieved by our system. These results imply that our nanoplatform has the ability to effectively kill intrinsic tumor or the center of large tumors through PDT, which significantly improves the anticancer efficacy using UCNP-based PDT system and broadens the types of tumors that could be cured.

An upconversion nanoprobe operating in the first biological window

Upconversion nanoparticles capable of converting low-energy excitation into higher-energy emission have been proved to be useful for sensitive biodetection due to the largely eliminated background autofluorescence and light scattering effects. However, the existing techniques have been constrained due to the absorption of excitation and emission light by water and hemoglobin in biological settings that typically result in low light penetration depth and potential thermal damage to biological samples. In this work, a core-shell-shell nanostructure is described to realize photon upconversion in the first biological spectral window (650-900 nm) where the absorption of water and the biological specimen is minimal. We synthesized core-shell-shell nanoparticles with small feature size (∼30 nm) that display dominant emission in the far red (660 nm) spectral region upon excitation at 808 nm. The as-synthesized core-shell-shell nanoparticles were further developed as optical bioprobes that offer sensitive biodetection in the presence of tissue wrapping.

Multimodal Upconversion Nanoplatform with a Mitochondria-Targeted Property for Improved Photodynamic Therapy of Cancer Cells.

Upconversion nanoparticles (UCNPs) with the capacity to emit high-energy visible or UV light under low-energy near-infrared excitation have been extensively explored for biomedical applications including imaging and photodynamic therapy (PDT) against cancer. Enhanced cellular uptake and controlled subcellular localization of a UCNP-based PDT system are desired to broaden the biomedical applications of the system and to increase its PDT effect. Herein, we build a multimodal nanoplatform with enhanced therapeutic efficiency based on 808 nm excited NaYbF4:Nd@NaGdF4:Yb/Er@NaGdF4 core-shell-shell nanoparticles that have a minimized overheating effect. The photosensitizer pyropheophorbide a (Ppa) is loaded onto the nanoparticles capped with biocompatible polymers, and the nanoplatform is functionalized with transcriptional activator peptides as targeting moieties. Significantly increased cellular uptake of the nanoparticles and dramatically elevated photocytotoxicity are achieved. Remarkably, colocalization of Ppa with mitochondria, a crucial subcellular organelle as a target of PDT, is proven and quantified. The subsequent damage to mitochondria caused by this colocalization is also confirmed to be significant. Our work provides a comprehensively improved UCNP-based nanoplatform that maintains great biocompatibility but shows higher photocytotoxicity under irradiation and superior imaging capabilities, which increases the biomedical values of UCNPs as both nanoprobes and carriers of photosensitizers toward mitochondria for PDT.

An upconversion nanoplatform for simultaneous photodynamic therapy and Pt chemotherapy to combat cisplatin resistance.

Platinum-based antineoplastic drugs are among the first-line chemotherapeutic agents against a variety of solid tumors, but toxic side-effects and drug resistance issues limit their clinical optimization. Novel strategies and platforms to conquer cisplatin resistance are highly desired. Herein, we assembled a multimodal nanoplatform utilizing 808 nm-excited and biocompatible core-shell-shell upconversion nanoparticles (UCNPs) [NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4] that were covalently loaded with not only photosensitizers (PSs), but also Pt(iv) prodrugs, which were rose bengal (RB) and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2], respectively. The UCNPs had the capability to convert near infrared (NIR) light to visible light, which was further utilized by RB to generate singlet oxygen. At the same time, the nanoplatform delivered the Pt(iv) prodrug into cancer cells. Thus, this upconversion nanoplatform was able to carry out combined and simultaneous photodynamic therapy (PDT) and Pt chemotherapy. The nanoplatform was well characterized and the energy transfer efficiency was confirmed. Compared with free cisplatin or UCNPs loaded with RB only, our nanoplatform showed significantly improved cytotoxicity upon 808 nm irradiation in both cisplatin-sensitive and -resistant human ovarian cancer cells. A mechanistic study showed that the nanoparticles efficiently delivered the Pt(iv) prodrug into cancer cells, resulting in Pt-DNA damage, and that the nanoplatform generated cellular singlet oxygen to kill cancer cells. We, therefore, provide a comprehensive strategy to use UCNPs for combined Pt chemotherapy and PDT against cisplatin resistance, and our nanoplatform can also be used as a theranostic tool due to its NIR bioimaging capacity.

A General Strategy for Ligand Exchange on Upconversion Nanoparticles

Lanthanide-doped upconversion nanoparticles with a suitable surface coating are appealing for biomedical applications. Because high-quality upconversion nanoparticles are typically prepared in an organic solvent and passivated by hydrophobic oleate ligands, a convenient and reliable method for the surface modification of upconversion nanoparticles is thus highly desired to satisfy downstream biological investigations. In this work, we describe a facile and versatile strategy for displacing native oleate ligands on upconversion nanoparticles with a diversity of hydrophilic molecules. The ligand-exchange procedure involves the removal of original oleate ligands followed by the attachment of new ligands in a separate step. The successful coating of relevant ligands was confirmed by Fourier transform infrared spectroscopy, thermogravimetry analysis, and ζ-potential measurement. The surface-modified nanoparticles display high stability and good biocompatibility, as revealed by electron microscopy, photoluminescence spectroscopy, and cytotoxicity assessment. Our study demonstrates that functional biomolecules such as biotin can be directly immobilized on the nanoparticle surface using this approach for the quick and effective detection of streptavidin.

A monofunctional platinum(II)-based anticancer agent from a salicylanilide derivative: Synthesis, antiproliferative activity, and transcription inhibition

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis-[Pt(NH3)2(N-donor)Cl](+) have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo. Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA-Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA-Pt was close to that of cisplatin. Mechanism studies revealed that SA-Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes.

Graphitic Carbon Nanocubes Derived from ZIF-8 for Photothermal Therapy.

Graphitic carbon nanocubes (GCNCs) were prepared by pyrolysis of ZIF-8 nanocubes. The GCNCs resemble the structure of N-doped graphite and exhibit a high photothermal conversion efficiency of 40.4%. In vitro tests demonstrate that the GCNCs are highly biocompatible and induce an effective photothermal therapy effect under 808 nm irradiation. Our study provides a facile strategy for preparing functional carbon nanomaterials of prescribed size, morphology, and porous structure for bioapplications.

An upconversion nanoplatform with extracellular pH-driven tumor-targeting ability for improved photodynamic therapy

Upconversion nanoparticles (UCNPs) are widely utilized for photodynamic therapy (PDT) due to their specific upconverting luminescence that utilizes near infrared (NIR) light to excite photosensitizers (PSs) for PDT. The efficiency of UCNP-based PDT will be improved if the cancer-targeting property of nanomedicine is enhanced. Herein, we employed the pH low insertion peptide (pHLIP), a cancer-targeting moiety, to functionalize an 808 nm excited UCNP-based nanoplatform that has a minimized over-heating effect to perform PDT. pHLIP can bring cargo specifically into cancer cells under an acidic environment, realizing the effective active-targeting abilities to cancer cells or tumor due to acidosis. The pHLIP-functionalized nanoplatform was assembled and well characterized. The nanoplatform shows an efficient NIR-irradiated PDT effect in cancer cells, especially under a slightly acidic condition that mimics the tumor microenvironment, and this effectiveness is attributed to the targeting properties of pHLIP to cancer cells under acidic conditions that favor the entry of the nanoplatform. Furthermore, the pHLIP-functionalized nanoplatform shows a favorable safety profile in mice with a high maximum tolerated dose (MTD), which may broaden the availability of administration in vivo. The efficient in vivo antitumor activity is achieved through intratumor injection of the nanoplatform followed by NIR irradiation on the breast tumor. The nanoparticles are largely accumulated in the tumor site, revealing the excellent tumor-targeting properties of the pHLIP-functionalized nanoplatform, which ensures efficient PDT in vivo. Moreover, the nanoparticles have a long retention time in the bloodstream, indicating their stability in vivo. Overall, we provide an example of a UCNP-based nanosystem with tumor-targeting properties to perform efficient PDT both in vitro and in vivo.

Upconversion in Nanostructured Materials: From Optical Tuning to Biomedical Applications

Photon upconversion that is characterized by high-energy photon emission followed by lower-energy excitation has been conventionally studied in bulk materials for several decades. This unique nonlinear luminescence process has become a subject of great attention since 2000 when upconverted emission was demonstrated in nanostructured crystals. In comparison with their bulk counterparts, nanostructured materials provide more room for optical fine-tuning by allowing flexible compositional integration and structural engineering. Moreover, the high colloidal stability of nanoparticles coupled with high amenability to surface functionalization opens up a number of new applications for upconversion, especially in the fields of biology and life science. In this focus review, we discuss recent developments in upconversion materials through nanostructural design and review emerging biomedical applications that involve these nanostructured upconversion materials. We also attempt to highlight challenging problems of these nanomaterials that constrain further progress in utilizing upconversion processes.