Lanthanide ion (Ln(3+))-based upconversion nano/micromaterials that emit higher-energy visible light when excited by low-energy NIR light have aroused considerable attention in the forefront of materials science and biomedical fields, which stems from their unique optical and chemical properties including minimum photodamage to living organisms, low autofluorescence, high signal-to-noise ratio and detection sensitivity, and high penetration depth in biological or environmental samples. Thus, Ln(3+)-based upconversion materials are rising new stars and are quickly emerging as potential candidates to revolutionize novel biomedical applications. In this review article, we mainly focus on the recent progress in various chemical syntheses of Ln(3+)-based upconversion nanomaterials, with special emphasis on their application in stimuli-response controlled drug release and subsequent therapy. Functional groups that are introduced into the stimuli-responsive system can respond to external triggers, such as pH, temperature, light, and even magnetic fields, which can regulate the movement of the pharmaceutical cargo and release the drug at a desired time and in a desired area. This is crucial to boost drug efficacy in cancer treatment while minimizing the side effects of cytotoxic drugs. Many multifunctional (magnetic/upconversion luminescence and porous) composite materials based on Ln(3+) have been designed for controlled drug delivery and multimodal bioimaging. Finally, the challenges and future opportunities for Ln(3+)-based upconversion materials are discussed.

Controlling anticancer drug activity and release on demand is very significant in cancer therapy. The photoactivated platinum(IV) pro-drug is stable in the dark and can be activated by UV light. In this study, we develop a multifunctional drug delivery system combining upconversion luminescence/magnetic resonance/computer tomography trimodality imaging and NIR-activated platinum pro-drug delivery. We use the core-shell structured upconversion nanoparticles to convert the absorbed NIR light into UV to activate the trans-platinum(IV) pro-drug, trans,trans,trans-[Pt(N3)2(NH3)(py)(O2CCH2CH2COOH)2]. Compared with using the UV directly, the NIR has a higher tissue penetration depth and is less harmful to health. Meanwhile, the upconversion nanoparticles can effectively deliver the platinum(IV) pro-drugs into the cells by endocytosis. The mice treated with pro-drug-conjugated nanoparticles under near-infrared (NIR) irradiation demonstrated better inhibition of tumor growth than that under direct UV irradiation. This multifunctional nanocomposite could be used as multimodality bioimaging contrast agents and transducers by converting NIR light into UV for control of drug activity in practical cancer therapy.

In this study, we report a new controlled release system based on up-conversion luminescent microspheres of NaYF(4):Yb(3+)/Er(3+) coated with the smart hydrogel poly[(N-isopropylacrylamide)-co-(methacrylic acid)] (P(NIPAM-co-MAA)) (prepared using 5 mol % of MAA) shell. The hybrid microspheres show bright up-conversion fluorescence under 980 nm laser excitation, and turbidity measurements show that the low critical solution temperature of the polymer shell is thermo- and pH-dependent. We have exploited the hybrid microspheres as carriers for Doxorubicin hydrochloride (DOX) due to its stimuli-responsive property as well as good biocompatibility via MTT assay. It is found that the drug release behavior is pH-triggered thermally sensitive. Changing the pH to mildly acidic condition at physiological temperature deforms the structure of the shell, causing the release of a large number of DOX from the microspheres. The drug-loaded microspheres exhibit an obvious cytotoxic effect on SKOV3 ovarian cancer cells. The endocytosis process of drug-loaded microspheres is observed using confocal laser scanning microscopy and up-conversion luminescence microscopy. Meanwhile, the as-prepared NaYF(4):Yb(3+)/Er(3+)@SiO(2)@P(NIPAM-co-MAA) microspheres can be used as a luminescent probe for cell imaging. In addition, the extent of drug release can be monitored by the change of up-conversion emission intensity. These pH-induced thermally controlled drug release systems have potential to be used for in vivo bioimaging and cancer therapy by the pH of the microenvironment changing from 7.4 (normal physiological environment) to acidic microenvironments (such as endosome and lysosome compartments) owing to endocytosis.

YVO(4) nano/microcrystals with multiform morphologies, such as nanoparticles, microdoughnut, micropancake, pillar structure, and microflower, have been synthesized via a facile hydrothermal route. A series of controlled experiments indicate that the shape and size of as-prepared architectures can be tuned effectively by controlling the reaction conditions, such as reaction time, vanadium sources, different organic additives, and the molar ratio of organic additive trisodium citrate (Cit(3-)):Y(3+). It is found that Cit(3-) as a ligand and shape modifier has the dynamic effect by adjusting the growth rate of different facets under different experimental conditions, resulting in the formation of various geometries of the final products. The possible formation mechanisms for products with diverse architectures have been presented in detail. Additionally, we systematically investigate the luminescent properties of the YVO(4):Ln(3+) (Ln = Eu, Dy, Sm, and Er). Because of an efficient energy transfer from vanadate groups to dopants, YVO(4):Ln(3+) (Ln = Eu, Dy, Sm, and Er) phosphors showed their strong characteristic emission under ultraviolet excitation and low-voltage electron beam excitation. The ability to generate YVO(4) nano/microstructures with diverse shapes, multicolor emission, and higher quantum efficiency provides a great opportunity for systematically evaluating their luminescence properties, as well as fully exploring their applications in many types of color display fields.

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A novel approach for the fabrication of multifunctional microspheres integrating several advantages of mesoporous, luminescence, and temperature responses into one single entity is reported. First, the hollow mesoporous silica capsules are fabricated via a sacrificial template route. Then, Gd2O3:Eu3+ luminescent nanoparticles are incorporated into the internal cavities to form rattle‐type mesoporous silica nanocapsules by an incipient‐wetness impregnation method. Finally, the rattle‐type capsules serve as a nanoreactor for successfully filling temperature‐responsive hydrogel via photoinduced polymerization to form the multifunctional composite microspheres. The organic–inorganic hybrid microspheres show a red emission under UV irradiation due to the luminescent Gd2O3:Eu3+ core. The in vitro cytotoxicity tests show that the samples have good biocompatibility, which indicates that the nanocomposite could be a promising candidate for drug delivery. In addition, flow cytometry and confocal laser scanning microscopy (CLSM) confirm that the sample can be effectively taken up by SKOV3 cells. For in vitro magnetic resonance imaging (MRI), the sample shows the promising spin‐lattice relaxation time (T1) weighted effect and could potentially apply as a T1‐positive contrast agent. This composite drug delivery system (DDS) provides a positive temperature controlled “on‐off”drug release pattern and the drug, indomethacin (IMC), is released fast at 45 °C (on phase) and completely shut off at 20 °C (off phase). Meanwhile Gd2O3:Eu3+ plays an important role as the luminescent tag for tracking the drug loading and release process by the reversible luminescence quenching and recovery phenomenon. These results indicate that the obtained multifunctional composite has the potential to be used as a smart DDS for biomedical applications.

CoreÀshell structured up-conversion luminescent and mesoporous NaYF 4 :Yb 3+ /Er 3+ @nSiO 2 @mSiO 2 nanospheres were prepared by coating mesoporous SiO 2 layers with different thicknesses on NaYF 4 :Yb 3+ / Er 3+ nanoparticles via a simple two-step solÀgel process. The obtained sample shows a typical mesoporous structure and well-dispersed spherical morphology with a narrow size distribution. The nanospheres exhibit little cytotoxicity (via MTT assay), and ibuprofen (IBU) was used as a model drug to access the release properties of the system in detail. The amount of IBU adsorbed in mesoporous channels increases with the thickness of the ordered mesoporous silica shell coated on the NaYF 4 :Yb 3+ /Er 3+ nanoparticles. The in vitro release study of IBU reveals a release profile in two steps: an initial diffusion-controlled release, followed by a slower release rate. Furthermore, upon excitation by a 980 nm near-infrared laser, the nanospheres emit green ( 2 H 11/2 and 4 S 3/2 f 4 I 15/2 ) and red ( 4 F 9/2 f 4 I 15/2 ) fluorescence of Er 3+ even after the loading of IBU. Interestingly, the emission intensity of Er 3+ in the bifunctional (mesoporous and luminescence) drug carrier increases with an increase of the cumulative released amount of the model drug (IBU). Thus, the extent of drug release can be easily identified, tracked, and monitored based on the change of the up-conversion luminescence. These results suggest that the coreÀshell structured NaYF 4 :Yb 3+ /Er 3+ @nSiO 2 @m-SiO 2 nanospheres are a promising material for controlled drug release.

LaCO(3)OH nano/microcrystals with a variety of morphologies/sizes including nanoflakes, microflowers, nano/microrhombuses, two-double microhexagrams sandwichlike microspindles, and peach-nucleus-shaped microcrystals have been synthesized via a facile homogeneous precipitation route under mild conditions. A series of controlled experiments indicate that the pH values in the initial reaction systems, carbon sources, and simple ions (NH(4)(+) and Na(+)) were responsible for the shape determination of the LaCO(3)OH products. A possible formation mechanism for these products with diverse architectures has been presented. After annealing at suitable temperatures, LaCO(3)OH was easily converted to La(2)O(2)CO(3) and La(2)O(3) with the initial morphologies. A systematic study on the photoluminescence and cathodoluminescence properties of Eu(3+)- or Tb(3+)-doped La(2)O(2)CO(3)/La(2)O(3) samples has been performed in detail. The excitation and site-selective emission spectra were recorded to investigate the microstructure, site symmetry, and difference in the (5)D(0) → (7)F(2) transition of Eu(3+) ions in La(2)O(2)CO(3) and La(2)O(3) host lattices. In addition, the dependence of the luminescent intensity on the morphology for the as-prepared La(2)O(2)CO(3)/La(2)O(3):Ln(3+) (Ln = Eu, Tb) samples has been investigated. The ability of generating diverse morphologies and multiemitting colors for different rare-earth activator ion (Ln = Eu, Tb) doped La(2)O(2)CO(3)/La(2)O(3) nano/microstructures provides a great opportunity for the systematic evaluation of morphology-dependent luminescence properties, as well as the full exploration of their application in many types of color display fields.