DNA-Templated Ag@Pd Nanoclusters for NIR-II Photoacoustic Imaging-Guided Photothermal-Augmented Nanocatalytic Therapy.

Developing multifunctional nanozymes with photothermal-augmented enzyme-like reaction dynamics in the second near-infrared (NIR-II) biowindow is of significance for nanocatalytic therapy (NCT). Herein, DNA-templated Ag@Pd alloy nanoclusters (DNA-Ag@Pd NCs) are prepared as a kind of novel noble-metal alloy nanozymes by using cytosine-rich hairpin-shaped DNA structures as growth templates. DNA-Ag@Pd NCs exhibit high photothermal conversion efficiency (59.32%) under 1270 nm laser and photothermally augmented peroxidase-mimicking activity with synergetic enhancement between Ag and Pd. In addition, hairpin-shaped DNA structures on the surface of DNA-Ag@Pd NCs endow them with good stability and biocompatibility in vitro and in vivo, and enhanced permeability and retention effect at tumor sites. Upon intravenous injection, DNA-Ag@Pd NCs demonstrate high-contrast NIR-II photoacoustic imaging-guided efficient photothermal-augmented NCT of gastric cancer. This work provides a strategy to synthesize versatile noble-metal alloy nanozymes in a bioinspired way for highly efficient therapy of tumors.

Mitochondria-Targeting MoS2-Based Nanoagents for Enhanced NIR-II Photothermal-Chemodynamic Synergistic Oncotherapy.

The synergy of chemodynamic therapy (CDT) and photothermal therapy (PTT) can improve anticancer efficacy, while the limited diffusion distance and the short lifetime of •OH still greatly restrict the therapeutic efficacy of PTT-CDT. Herein, MoS2@PDA-Fe@PEG/TPP (MPFPT) nanosheets (NSs) with mitochondria-targeting ability were reported for enhanced PTT-CDT synergistic oncotherapy. MPFPT NSs were prepared by covalent modification of poly(ethylene glycol) (PEG) and triphenylphosphonium (TPP) on polydopamine (PDA)-Fe3+coated MoS2 NSs. Co-localization experiments showed that MPFPT NSs can efficiently target mitochondria via the direction of TPP. Moreover, MPFPT NSs have good photothermal performance in the second near-infrared (NIR-II) region and can greatly accelerate the Fenton reaction from H2O2 to generate more hydroxyl radicals (•OH). In vitro experimental results showed that MPFPT NSs have improved therapeutic efficacy to cancer cells than similar MoS2-based nanoagents without mitochondria-targeting units, which can be attributed to the short distance between mitochondria and MPFPT NSs and the efficient damage of mitochondria by in situ generated •OH. In the 4T1 tumor-bearing mice model, MPFPT NSs demonstrated significantly enhanced therapeutic efficacy by PTT-CDT, suggesting the superiority of the mitochondria-targeting strategy. This study reveals that mitochondria-targeting MPFPT NSs are promising nanoagents for oncotherapy.

A Smart "Sense-and-Treat" Nanoplatform Based on Semiconducting Polymer Nanoparticles for Precise Photothermal-Photodynamic Combined Therapy.

Integrated theranostic nanoplatforms with biomarker recognition and photothermal- and photodynamic (PTT/PDT) therapy is in high demand but remains challenging. Herein, a "sense-and-treat" nanoplatform based on semiconducting polymer nanoparticles (SPNs) for ratiometric bioimaging of phospholipase D (PLD) activity and PTT/PDT combined therapy was proposed. Semiconducting polymer nanoparticles (PSBTBT NPs) serve not only as photothermal agents but also as fluorescent quenchers of Rhodamine B (Rhod B) through a PLD-cleavable linker. Chlorin e6 (Ce6) was used as a photodynamic agent and fluorescence reference. The obtained nanoplatform (PSBTBT-Ce6@Rhod NPs) showed high PDT efficiency and photothermal performance upon single laser irradiation. The PTT/PDT combined therapy achieved more efficient tumor inhibition results as compared with single treatments. In addition, the overexpressed biomarker PLD in tumor tissue will cleave Rhod, leading to the fluorescence recovery of Rhod B and thus allowing the activatable fluorescence imaging of tumor and targeted phototherapy.

A photothermally-induced HClO-releasing nanoplatform for imaging-guided tumor ablation and bacterial prevention.

Photothermal therapy (PTT) is a cure that can inhibit tumor growth effectively and even remove tumor via photo-induced local hyperthermia. However, its shortcoming lies in the fact that excessive heat is most likely to lead to thermal injury at the epidermis of the tumor region and even the area of the surrounding tissue. As a consequence, the exposure of the thermally-induced wound would result in the increased risk of bacterial infection. To date, few PTT platforms have attached importance to the prevention of bacterial infection at the photothermally-induced wound. Herein, we reported a thermally-sensitive liposome nanosystem (Lipo-B-TCCA) containing aza-BODIPY and trichloroisocyanuric acid, which is conductive for the PTT of tumor and the prevention of bacteria. It is observed that the designed nanoplatform could exhibit remarkable stability, high photothermal conversion efficiency (31.4%), and efficient HClO-releasing ability in vitro and in vivo. Moreover, Lipo-B-TCCA is able to eliminate tumor efficiently via near infrared fluorescence and photothermal imaging guidance with low side effects. Most importantly, Lipo-B-TCCA could prevent the growth of S. aureus in the thermal wound during the process of PTT. The imaging-guided photothermally-induced HClO-releasing PTT nanoplatform for tumor ablation and bacterial prevention shows excellent performance and great potential for biomedical applications.

High peroxidase-mimicking activity of gold@platinum bimetallic nanoparticle-supported molybdenum disulfide nanohybrids for the selective colorimetric analysis of cysteine.

Herein, gold@platinum (Au@Pt) bimetallic nanoparticles with high catalytic ability were in situ decorated onto a molybdenum disulfide (MoS2) surface to obtain nanocomposites (MoS2-Au@Pt) with high peroxidase-mimicking activity, which were used to construct a colorimetric sensor for cysteine (Cys) detection. Interestingly, this sensor can efficiently distinguish Cys from homocysteine (Hcy), glutathione (GSH) and 19 other amino acids with high sensitivity. As expected, the colorimetric sensor can determine the Cys content in Cys supplement tablets due to its high stability and repeatability. Finally, the detection mechanism was studied.

Highly stable semiconducting polymer nanoparticles for multi-responsive chemo/photothermal combined cancer therapy.

Rationale: Structural stability and size controllability are critical issues to semiconducting polymer nanoparticles (SPNs), which currently show great potential for theranostic applications. Methods: Herein, multi-responsive semiconducting polymer semi-interpenetrating nanoparticles (PDPP3T@PNIPAMAA IPNs) with highly stable structure and uniform size have been successfully designed by semi-interpenetrating technique. Results: It is proposed for the first time that PDPP3T@PNIPAMAA IPNs were prepared with "reinforced concrete" particle structure, which is even resistant to organic solvent such as ethanol and THF. By adjusting the polymerization time, the obtained PDPP3T@PNIPAMAA IPNs exhibit uniform and controllable particle size with extremely low polydispersity index (~0.037) at 1 h of reaction time. The presence of pH/light/GSH multi-responsive semi-interpenetrating network in PDPP3T@PNIPAMAA IPNs dramatically increase their drug loading efficiency (92.64%), which is significantly higher than previously reported comparable SPNs-based drug delivery systems. Additionally, PDPP3T@PNIPAMAA-DOX IPNs further provide improved therapeutic efficacy by the combination of chemotherapy and photothermal therapy with controllably regulated release of doxorubicin (DOX). In vitro and in vivo results indicate that PDPP3T@PNIPAMAA-DOX IPNs are able to release drugs at controlled rate by pH/light/GSH regulation and offer PAI-guided chemo/photothermal combined therapy with excellent therapeutic efficacy. Conclusions: The semi-interpenetrating network method may be generally extended for the preparation of a wide range of organic polymer nanoparticles to achieve ultrahigh structural stability, precise particle size controllability and excellent drug loading capacity.

A lipase-responsive antifungal nanoplatform for synergistic photodynamic/photothermal/pharmaco-therapy of azole-resistant Candida albicans infections.

A lipase-triggered drug release nanoplatform (PGL-DPP-FLU NPs) for multi-modal antifungal therapy is developed. The lipases secreted by C. albicans can accelerate FLU release. The ROS and heat produced by PGL-DPP-FLU NPs make C. albicans more vulnerable to FLU, thereby PGL-DPP-FLU NPs exhibit high performance for combating azole-resistant C. albicans biofilms and wound infection.

Mussel-inspired functionalization of semiconducting polymer nanoparticles for amplified photoacoustic imaging and photothermal therapy.

A versatile and straightforward strategy for the encapsulation of semiconducting polymer nanoparticles (SPNs) using biocompatible polydopamine (PDA) as both the protection and versatile bioconjugation layer is proposed. In addition to providing stable functionalized SPNs, this approach provides SPNs with a flexible surface for further modification with various functional ligands. In this study, three representative surface modifiers including a small molecule (folic acid, FA), a peptide (cRGD) and a stealth polymer (SH-PEG) were conjugated onto the surface of SPNs. Specifically, PDA encapsulation can reliably form SPNs that are uniform in size (∼65 nm) and facilitate the rapid purification of SPN bioconjugates by centrifugation which is difficult to achieve using traditional methods for preparing SPN bioconjugates. Compared to pristine PSBTBT NPs, the synthesized PSBTBT@PDA NPs simultaneously showed more excellent structural stability, significantly enhanced PA brightness and amplified PTT efficacy. Benefiting from the outstanding PA and PTT performances, it is possible for the PSBTBT@PDA NPs to ablate tumors more effectively compared to PSBTBT NPs. Our study thus demonstrates that the PDA encapsulated SPNs should be a promising theranostic agent for PA imaging and PTT.

Hydrothermal synthesis of novel rhombic dodecahedral SnS nanocrystals for highly efficient photothermal therapy.

Novel rhombic dodecahedral SnS nanocrystals were prepared via a facile one-pot hydrothermal method for the first time, which exhibit a large extinction coefficient of 36.8 L g-1 cm-1 and a high photothermal conversion efficiency of 39.4% under irradiation with a 785 nm laser. Moreover, they show good performance for photothermal therapy of HeLa tumors.

Gold nanostars for cancer cell-targeted SERS-imaging and NIR light-triggered plasmonic photothermal therapy (PPTT) in the first and second biological windows.

Cancer cell-targeted imaging and efficient therapy are vital for tumor diagnosis and treatments. However, the development of multifunctional plasmonic nanoparticles with high-performance SERS-imaging and NIR light-triggered plasmonic photothermal therapy (PPTT) of cancer cells in both the first (NIR-I) and second (NIR-II) biological windows is still a big challenge. In the present work, gold nanostars which possess a broad NIR absorption band covering the NIR-I and NIR-II windows with good NIR SERS activity and photothermal effects were synthesized by a seed-mediated growth method, using gold chloride (HAuCl4), ascorbic acid (AA) and (1-hexadecyl) trimethylammonium chloride (CTAC) as growth solutions. The gold nanostars were further designed to be multifunctional nanoagents by labeling Raman molecules and then conjugating arginine-glycine-aspartic acid (RGD), which can serve as cancer cell-targeted SERS-imaging tags and photothermal nanoagents in both the NIR-I and NIR-II windows. The investigation of in vitro SERS-mapping and PPTT of the A549 human lung adenocarcinoma cells indicates that the proposed multifunctional gold nanostars have great potential for a wide spectrum of light-mediated applications, such as optical imaging and image-guided phototherapy in both the NIR-I and NIR-II biological windows.

Nanogel-Incorporated Injectable Hydrogel for Synergistic Therapy Based on Sequential Local Delivery of Combretastatin-A4 Phosphate (CA4P) and Doxorubicin (DOX).

Drug combination therapies employing dual-drug delivery systems offer an effective approach to reduce disadvantages of single-drug therapy, such as high dose and easy generation of drug resistance. Herein, a dual-drug delivery system based on nanogel-incorporated injectable hydrogel (NHG) was designed for sequential local delivery of combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) for antiangiogenesis and anticancer combination therapy. The injectable hydrogel was prepared for loading and quick release of hydrophilic drug CA4P, while the pH and redox stimuli-responsive nanohydrogels were incorporated into the injectable hydrogel by pH-responsive boronate ester bond for sustained long-term DOX delivery. The dual-drug-loaded NHG system released CA4P and DOX sequentially and exhibited high inhibitory activities on the cancer cell proliferation in vitro. It displayed superior therapeutic efficacy in vivo with only one single injection. Immunohistochemistry analyses suggested a synergistic therapeutic effect through tumor vascular collapse caused by CA4P and tumor cell apoptosis induced by DOX. The combination therapy of antiangiogenic and cytotoxic drugs using NHG delivery system offers a promising approach for improved cancer therapeutic efficacy. The nanogel-embedded injectable hydrogel can be employed as a universal drug carrier for local dual-drug delivery with sequential release behaviors by simple injection.

"Triple-Punch" Anticancer Strategy Mediated by Near-Infrared Photosensitizer/CpG Oligonucleotides Dual-Dressed and Mitochondria-Targeted Nanographene.

Nanomedicine-based combination therapy has sparked a growing interest in clinical disease treatment and pharmaceutical industry. In this study, a mitochondria-targeted and near-infrared (NIR) light-activable multitasking nanographene (i.e., GT/IR820/DP-CpG) was engineered to in situ trigger highly efficient "triple-punch" strategy of cancer photodynamic therapy, photothermal therapy, and immunotherapy. Modification of triphenylphosphonium on graphene made the vehicle specifically guide the NIR dye IR820 home to mitochondria, followed by lysosomes escape in a time-dependent manner. The photoactive nanocomplex generated an abundant reactive oxygen species as well as photothermal heat to ultimately kill cancer cells by inducing mitochondrial collapse and irreversible cell apoptosis upon the NIR laser irradiation. Further introduction of an immunostimulatory conjugate DP-CpG significantly promoted the secretion of proinflammatory cytokines (i.e., interleukin-6, tumor necrosis factor-α, and interferon-γ) and thus improved the immunogenicity of tumors. In vivo studies demonstrated that GT/IR820/DP-CpG remarkably inhibited tumor growth (tumor inhibition rate, ∼88%) resulting from the combinational phototherapeutic effect of IR820 and immunostimulatory activity of DP-CpG, thereby causing negligible toxic effects on mice. Our work provides a new paradigm of architecting organelle-targeted and stimulative nanocomplex for highly efficient cancer photoimmunotherapy.

A gold nanoflower-based traceable drug delivery system for intracellular SERS imaging-guided targeted chemo-phototherapy.

Accurate and effective drug delivery in tumor cells significantly improves the curative effect with high drug delivery efficiency, low toxicity and side effects and has become an urgent demand for anticancer therapy. In this paper, a novel traceable and targeted drug delivery nanosystem (i.e. AuNF-nanocarriers) with high drug encapsulation and pH-controlled release was prepared based on gold nanoflowers (AuNFs) for efficient intracellular SERS imaging-guided chemo-phototherapy. SERS-active flower-like gold nanoparticles with large surface area were synthesized first and then modified with Raman and RGD molecules in sequence to prepare bright, traceable and targeted SERS tags of A549 human lung cancer cells. Furthermore, thiolated-PAA (PAA-SH) was synthesized and utilized for the first time to modify the SERS tags with a layer of negative charges for efficient pH-dependent loading and release of the anticancer drug doxorubicin. Based on the A549 human lung cancer cell model, the availability of the proposed AuNF-nanocarriers for efficient intracellular SERS imaging-guided chemo-phototherapy was studied and the results indicate that the AuNF-based drug delivery system exhibited attractive characteristics such as good stability, efficiency and pH-controlled drug loading and release, traceable and targeted delivery, as well as SERS imaging and chemo-phototherapy functions, and shows great potential for powerful SERS-imaging and as a theranostic candidate for precision nanomedicine that could achieve sensitive and accurate tumor detection and therapy.

RGD-QD-MoS2 nanosheets for targeted fluorescent imaging and photothermal therapy of cancer.

The fast-developing field of nanotechnology provides unprecedented opportunities for the increasing demands of biomedicine, especially for cancer diagnostics and treatment. Here, novel multifunctional zero-dimensional-two-dimensional (0D-2D) RGD-QD-MoS2 nanosheets (NSs) with excellent fluorescence, photothermal conversion, and cancer-targeting properties were successfully prepared by functionalizing single-layer MoS2 NSs with fluorescent quantum dots (QDs) and arginine-glycine-aspartic (RGD) containing peptides. By using RGD-QD-MoS2 NSs as a multifunctional theranostic agent, targeted fluorescent imaging and photothermal therapy (PTT) of human cervical carcinoma (HeLa) cells were achieved. Moreover, HeLa tumors in mouse models can be fluorescently imaged and completely eradicated by photothermal irradiation using a low power NIR laser, due to the effective accumulation of RGD-QD-MoS2 NSs at the tumor sites through the RGD-integrin targeting and the enhanced penetration and retention (EPR) effect. Without exhibiting any appreciable toxicity to treated cells or animals, RGD-QD-MoS2 NSs have been demonstrated as promising multifunctional theranostic agents for cancer imaging and therapy.

Aqueous phase preparation of ultrasmall MoSe2 nanodots for efficient photothermal therapy of cancer cells.

Photothermal therapy (PTT) is a promising cancer treatment with both high effectiveness and fewer side effects. However, an ideal PTT agent not only needs strong absorption of near-infrared (NIR) light and high photothermal conversion efficiency, but also needs good biocompatibility, stability, and small size, which makes the design and preparation of a novel PTT agent a great challenge. In this work, we developed an ultrasonication-assisted liquid exfoliation method for the direct preparation of ultrasmall (2-3 nm) MoSe2 nanodots (NDs) in aqueous solution and demonstrated their superior properties as a PTT agent. The as-prepared MoSe2 NDs have strong absorption of NIR light and high photothermal conversion efficiency of about 46.5%. In vitro cellular experiments demonstrate that MoSe2 NDs have negligible cytotoxicity and can efficiently kill HeLa cells (human cervical cell line) under NIR laser (785 nm) irradiation.

Photosensitizer-assembled PEGylated graphene-copper sulfide nanohybrids as a synergistic near-infrared phototherapeutic agent.

OBJECTIVES: Stimulative nanostructures play a crucial role in developing the smart nanomedicine for high therapeutic efficacy with minimum adverse effects. Herein, a near-infrared (NIR) light-responsive nanohybrids p-nanographene oxide (GO)-copper sulfide (CuS)/indocyanine green (ICG) comprised of GO, CuS nanoparticles and photosensitizer ICG was fabricated to couple the photothermal property of CuS and photodynamic effect of ICG in one system in order to achieve the synergistic phototherapy. METHODS: pGO-CuS/ICG was constructed by self-assembling ICG on pGO-CuS nanostructure. Its physicochemical, photothermal and photodynamic properties were studied by spectroscopic methods. The in vitro cellular uptake, cytotoxicity, the single/combined photothermal therapeutic (PTT) and photodynamic therapeutic (PDT) effects were investigated with biological techniques. RESULTS: pGO-CuS/ICG exhibited high efficacy of photothermal conversation and singlet oxygen generation under NIR laser excitation. It entered into the target cancer cells probably via passive transmembrane pathway and exerted obvious PTT and PDT effect against the tumor cells upon irradiation with the respective 940 and 808 nm lasers. In particular, the tremendous synergistic efficacy of PDT and PTT had been demonstrated by tuning the NIR laser combined irradiation. CONCLUSIONS: This study promises the future applications of pGO-CuS/ICG as a NIR light activable theranostic nanodrug for deep-seated cancer noninvasive phototherapy.

Self-assembly of poly-adenine-tailed CpG oligonucleotide-gold nanoparticle nanoconjugates with immunostimulatory activity.

Synthetic unmethylated cytosine-guanine (CpG) oligodeoxynucleotides (CpG ODNs) possess high immunostimulatory activity and have been widely used as a therapeutic tool for various diseases including infection, allergies, and cancer. A variety of nanocarriers have been developed for intracellular delivery of CpG ODNs that are otherwise nonpermeable through the cellular membrane. For example, previous studies showed that gold nanoparticles (AuNPs) could efficiently deliver synthetic thiolated CpG ODNs into cultured cells and induce expression of proinflammatory cytokines. Nevertheless, the necessity of using thiolated CpG ODNs for the modification of AuNPs inevitably complicates the synthesis of the nanoconjugates and increases the cost. A new approach is demonstrated for facile assembly of AuNP-CpG nanoconjugates for cost-effective drug delivery. It is found that non-thiolated, diblock ODNs containing a CpG motif and a poly-adenine (polyA) tail can readily self-assemble on the surface of AuNPs with controllable and tunable density. Such nanoconjugates are efficiently delivered into RAW264.7 cells and induce immune response in a Toll-like receptor 9 (TLR9)-dependent manner. Under optimal conditions, polyA-CpG-AuNPs show significantly higher immunostimulatory activity than their thiolated counterpart. In addition, the immunostimulatory activity of CpG-AuNPs can be modulated by varying the length of the polyA tail. In vivo induction of immune responses in mice is demonstrated by using polyA-tailed CpG-AuNP nanoconjugates.