Multi-shell structured upconversion nanocarriers that combine IDO inhibitor-induced immunotherapy with NIR-triggered photodynamic therapy for deep tumors.

Combination therapies for cancer have attracted substantial research interest as an emerging treatment strategy that can reduce the chance of cancer resistance to chemotherapy and deal effectively with cancer cell heterogeneity. In this study, we designed novel nanocarriers that combine immunotherapy, which attacks tumors by stimulating the immune system, with photodynamic therapy (PDT), a non-invasive phototherapy that can selectively destroy only cancer cells. Multi-shell structured upconversion nanoparticles (MSUCNs) with good photoluminescence (PL) strength were synthesized for a combination therapy of near-infrared (NIR) light-induced PDT and immunotherapy using a specific immune checkpoint inhibitor. By optimizing the doping content of ytterbium ions (Yb3+) and forming a multi-shell structure, MSUCNs able to emit light at multiple wavelengths with the PL efficiency improved by 260-380 times compared to core particles were synthesized. Then, the surfaces of the MSUCNs were modified with folic acid (FA) as a tumor-targeting ligand, Ce6 as a photosensitizer (PS), and 1-methyl-tryptophan (1MT) as an indoleamine 2,3-dioxygenase (IDO) inhibitor. The FA-, Ce6-, and 1MT-conjugated MSUCNs (F-MSUCN3-Ce6/1MT) exhibited targeted cellular uptake by active targeting against HeLa cells, which are FA receptor-positive cancer cells. Upon irradiation with NIR at 808 nm, the F-MSUCN3-Ce6/1MT nanocarriers produced reactive oxygen species, which caused apoptosis of the cancer cells, and activated CD8+ T cells, which enhanced the immune response by binding with immune checkpoint inhibitory proteins and blocking the IDO pathway. Therefore, these F-MSUCN3-Ce6/1MT nanocarriers could be potential candidate materials for synergistic anticancer therapy that combines IDO inhibitor-based immunotherapy with enhanced NIR-triggered PDT.

Synthesis of near-infrared-responsive hexagonal-phase upconversion nanoparticles with controllable shape and luminescence efficiency for theranostic applications.

Over the past few decades, photodynamic therapy has been studied as a therapeutic method by generating singlet oxygen through activation of a photosensitizer (PS) to kill cancer cells. However, the light within the activating wavelength range of commercial photosensitizers has a low penetration depth. In this study, we designed multifunctional upconversion nanoparticles (UCNs) that can emit high-energy light by absorbing low-energy near-infrared (NIR) light with excellent tissue permeability through a fluorescence resonance energy transfer procedure. This process can produce reactive oxygen species by activating the PS. We aimed to optimize the thermal decomposition synthesis procedure to produce lanthanide-doped UCNs with a uniform size and improve the photoluminescence efficiency for an NIR-regulated theranostic system. It was confirmed that the morphologies of UCNs can be controlled by varying the reaction time, reaction temperature, and feed molar ratio of the solvent and reactant. The crystalline morphology of the synthesized UCNs showed a thermodynamically stable hexagonal phase. The photoluminescence efficiency of the UCNs also was influenced by size, surface area, crystalline property, and stability in aqueous solution. Furthermore, the surface-modified UCNs with a folic acid-conjugated block copolymer and PS exhibited enhanced singlet oxygen generation and significantly improved aqueous solubility and photoluminescence efficiency.

Design of an Electro-Stimulated Hydrogel Actuator System with Fast Flexible Folding Deformation under a Low Electric Field.

Soft actuators have recently been widely studied due to their significant advantages including light weight, continuous deformability, high environment adaptability, and safe human-robot interactions. In this study, we designed electrically responsive poly(sodium 4-vinylbenzenesulfonate/2-hydroxyethylmethacrylate/acrylamide) (P(VBS/HEMA/AAm)) and poly(sodium 4-vinylbenzenesulfonate/2-hydroxyethyl methacrylate/acrylic acid) (P(VBS/HEMA/AAc)) hydrogels. A series of P(VBS/HEMA/AAm) and P(VBS/HEMA/AAc) hydrogels were prepared by adjusting the monomer composition and cross-linking density to systemically analyze various factors affecting the actuation of hydrogels under an electric field. All hydrogels exhibited more than 65% gel fraction and a high equilibrium water content (EWC) of more than 90%. The EWC of hydrogels gradually increased with decreasing cross-linker content and was also influenced by the monomer composition. The mechanical properties of hydrogels were proportional to the cross-linking density. Particularly, hydrogels showed bending deformation even at low voltages below 10 V, and the electrically responsive bending actuation of hydrogels can be modulated by cross-linking density, monomer composition, applied voltage, ion strength of the electrolyte solution, and geometrical parameters of the hydrogel. By controlling these factors, hydrogels showed a fast response with a bending of more than 100° within a minute. In addition, hydrogels did not show significant cytotoxicity in a biocompatibility test and exhibited more than 84% cell viability. These results indicate that P(VBS/HEMA/AAm) and P(VBS/HEMA/AAc) hydrogels with fast response properties even under a low electric field have the potential to be used in a wide range of soft actuator applications.

NIR Photoregulated Theranostic System Based on Hexagonal-Phase Upconverting Nanoparticles for Tumor-Targeted Photodynamic Therapy and Fluorescence Imaging.

Although photodynamic therapy (PDT) is an effective, minimally invasive therapeutic modality with advantages in highly localized and specific tumor treatments, large and deep-seated cancers within the body cannot be successfully treated due to low transparency to visible light. To improve the therapeutic efficiency of tumor treatment in deep tissue and reduce the side effects in normal tissue, this study developed a near-infrared (NIR)-triggered upconversion nanoparticle (UCNP)-based photosensitizer (PS) carrier as a new theranostics system. The NaYF4:Yb/Er UCNPs were synthesized by a hydrothermal method, producing nanoparticles of a uniformly small size (≈20 nm) and crystalline morphology of the hexagonal phase. These UCNPs were modified with folic acid-conjugated biocompatible block copolymers through a bidentate dihydrolipoic acid linker. The polymer modified hexagonal phase UCNPs (FA-PEAH-UCNPs) showed an improved dispersibility in the aqueous solution and strong NIR-to-vis upconversion fluorescence. The hydrophobic PS, pheophorbide a (Pha), was then conjugated to the stable vectors. Moreover, these UCNP-based Pha carriers containing tumor targeting folic acid ligands exhibited the significantly enhanced cellular uptake efficiency as well as PDT treatment efficiency. These results suggested that this system could extend the excitation wavelength of PDT to the NIR region and effectively improve therapeutic efficiency of PSs.

Targeted Photodynamic Therapy Activities of Surface-Enhanced Raman Scattering-Active Theranostic System Based on Folate/Hyaluronic Acid-Functionalized Gold Nanochains.

Light-based diagnostics and therapies have become indispensable tools in the field of cancer medicine. Nanotheranostics, namely the integration of diagnostic elements with therapeutic agents into a single nanosized-regimen, have been the recent focus of intense exploration with the aim to develop more specific, individualized therapies and to combine diagnostics and therapeutic capabilities into a single agent. In this study, gold nanochains (AuNCs) with worm-like nanostructures were developed as a light-triggered theranostic system for effective multiplex detection and photodynamic therapy (PDT). We fabricated the AuNC system through assembling of citrate-stabilized gold nanoparticles using hyaluronic acid-hydrocaffeic acid (HA-HCA) conjugates as templates. Raman reporters, photosensitizers (PSs), and active tumor targeting ligands were also conjugated onto the surfaces of the AuNCs. The length of the AuNCs could be controlled by the HCA composition ratio in the HA-HCA conjugates. The AuNCs with worm-like nanostructures exhibited significant surface-enhanced Raman scattering (SERS) properties, and their optical properties depended on their length. The AuNCs conjugated with a Raman reporter, PS, and active targeting ligand (HA-HCA2.0-Au-NPT-FA-Ce6) exhibited excellent selectivity and showed marked phototoxicity even at low concentration of PS compared with free PS after laser irradiation. This tumor-targeting HA-HCA2.0-Au-NPT-FA-Ce6 AuNC system could be a promising approach for applications in cancer theranostics, integrating SERS detection, fluorescence imaging, and PDT.

Gold nanorod-photosensitizer conjugates with glutathione-sensitive linkages for synergistic cancer photodynamic/photothermal therapy.

Recently, photodynamic therapy (PDT) has been intensively investigated as a useful modality for the treatment of various cancers. In addition, near infrared (NIR) photothermal therapy (PTT) using gold nanocarriers has attracted particular interest as a hyperthermia strategy. In this study, gold nanorod (AuNR)-photosensitizer conjugates with glutathione-sensitive linkages were designed for PDT and PTT. Several kinds of AuNRs with different aspect ratios were synthesized and modified with FA-conjugated block copolymers (FA-PEG-P(Asp)-DHLA) and Chlorin e6 (Ce6) as a photosensitizer. The surface-modified AuNRs showed excellent stability and solubility in aqueous solution. In particular, FA-PEG-P(Asp)-DHLA-AuNR100-SS-Ce6 with a 3.84 aspect ratio exhibited strong photothermal effects, enhanced singlet oxygen generation, and marked phototoxicity. Based on these results, we suggest that AuNR-photosensitizer conjugates with glutathione-sensitive linkages have potential application in PDT/PTT for effective clinical treatment of various cancers.