NIR-II-triggered doxorubicin release for orthotopic bladder cancer chemo-photothermal therapy.

Intravesical instillation has been widely utilized for bladder cancer treatment in clinic. However, due to the bladder mucosal barrier, its poor penetration efficiency and drug utilization limit the clinical therapeutic effectiveness and result in a high recurrence rate. Therefore, designing an efficient and controllable drug delivery nanoplatform is of great significance for bladder cancer treatment. Non-invasive therapy based on near-infrared-II (NIR-II) photothermal therapy (PTT) conduces to overcome bladder mucosal barrier and enhance drug delivery. Also, the photothermal nanomaterials, Au Hollow Nanorods (AuHNRs), demonstrate strong photothermal properties and drug loading capacity. Herein, a quaternized chitosan N-(2-hydroxyl)propyl-3-trimethyl ammonium chitosan chloride (HTCC)-modified nanocarrier Dox/NH4HCO3@AuHNRs-HTCC (DNAH) was designed for controlled drug release and enhanced penetration. The drug loading capacity of DNAH reached 117.20%. Also, the thermal decomposition of NH4HCO3 realized NIR-II-triggered gas-driven drug burst release, and the doxorubicin release was 2.79 times higher within 1 h after NIR-II irradiation. Also, the HTCC-modified nanocarriers significantly enhanced the bladder mucosal permeability as well as long-term drug retention, and the penetration efficiency of DNAH increased by 144%. In the orthotopic bladder cancer model, the tumor suppression rate and mouse survival time were significantly improved. DNAH showed potent inhibition of the orthotopic bladder tumor growth owing to the enhanced penetration and drug delivery. This work presents a potential drug delivery nanocarrier, which is promising for optimized bladder mucosal permeability and controlled drug burst release.

A Two-Pronged Strategy for Enhanced Deep-Tumor Penetration and NIR-II Multimodal Imaging-Monitored Photothermal Therapy.

The second near-infrared (NIR-II)-induced photothermal therapy (PTT) has attracted a great deal of attention in recent years due to its non-invasiveness and because it uses less energy. However, the penetration of photothermal agents into solid tumors is seriously impeded by the dense-tumor extracellular matrix (ECM) containing cross-linked hyaluronic acid (HA), thereby compromising the ultimate therapeutic effects. Herein, acid-labile metal-organic frameworks were employed as nanocarriers to efficiently mineralize hyaluronidase (HAase) and encapsulate Ag2S nanodots by a one-pot approach under mild conditions. The obtained nanocomposites (AHZ NPs) maintained enzyme activity and changed in size to prolong blood circulation and complete delivery of the cargo to the tumor. Moreover, the released HAase could specifically break out the HA to loosen ECM and enable the Ag2S nanodots to breeze through the tumor matrix space and gain access to the deep tumor. Under near-infrared laser irradiation, the AHZ NPs displayed remarkable fluorescence, outstanding photoacoustic signals, and excellent photothermal properties in the whole tumor. This work offers a promising two-pronged strategy via a decrease in nanoparticle size and the degradation of dense ECM for NIR-II multimodal imaging-guided PTT of deep tumors.

Activation of TRPV1 by capsaicin-loaded CaCO3 nanoparticle for tumor-specific therapy.

Capsaicin is a natural non-toxic small molecular organic substance, which is often used clinically to reduce inflammation and pain. Here, we report an acid-responsive CaCO3 nanoparticle loaded with capsaicin that can specifically activate TRPV1 channels and trigger tumor calcium ion therapy. The excellent acid responsiveness of calcium carbonate enables it to precisely target the tumor sites. The released capsaicin can specifically activate TRPV1 channel, overloading the intracellular calcium ion concentration and causing cell apoptosis, which provides a new safer and cheaper treatment. We proved that the naturalness and non-toxicity of capsaicin make the CaCO3@CAP nanoparticles have excellent biocompatibility, which has good development prospects and clinical application potential.

Tea Polyphenol Liposomes Overcome Gastric Mucus to Treat Helicobacter Pylori Infection and Enhance the Intestinal Microenvironment.

Infection with Helicobacter pylori (Hp) is one of the leading causes of stomach cancer. The ability to treat Hp infection is hampered by a lack of stomach gastric acid environment. This work introduces a nanoliposome that can rapidly adjust the gastric acid environment to ensure a drug's optimal efficacy. We introduce CaCO3@Fe-TP@EggPC nanoliposomes (CTE NLs) that are composed of Fe3+ and tea polyphenols (TPs) forming complexes on the surface of internal CaCO3 and then with lecithin producing a phospholipid bilayer on the polyphenols' outer surface. Through the action of iron-TP chelate, the phospholipid layer can fuse with the bacterial membrane to eliminate Hp. Furthermore, CaCO3 can promptly consume the excessive gastric acid, ensuring an ideal operating environment for the chelate. TPs, on the other hand, can improve the inflammation and gut microbes in the body. The experimental results show that CTE NLs can quickly consume protons in the stomach and reduce the bacterial burden by 1.2 orders of magnitude while reducing the inflammatory factors in the body. The biosafety evaluation revealed that nanoliposomes have good biocompatibility and provide a new strategy for treating Hp infection.

Photothermally triggered nitric oxide nanogenerator targeting type IV pili for precise therapy of bacterial infections.

Nitric oxide (NO) is an important biological messenger involved in the treatment of bacterial infections, but its controlled and targeted release in bacterial infections remains a major challenge. Herein, an intelligent NO nanogenerator triggered by near-infrared (NIR) light is constructed for targeted treatment of P. aeruginosa bacterial infection. Since maleimide can recognize and attach to the pilus of T4P of P. aeruginosa, we adopt this strategy to achieve the accurate release of therapeutic drugs at the infection site, i.e., after maleimide targets Gram-negative bacteria, the SNP@MOF@Au-Mal nanogenerator will release NO and generate ROS in situ from the inorganic photosensitizer gold nanoparticles under NIR irradiation to achieve synergistic antibacterial effect. In vivo experiments proved that the bacterial burden on the wound was reduced by 97.7%. Additionally, the nanogenerator was shown to promote the secretion of growth factors, which play a key role in regulating inflammation and inducing angiogenesis. This strategy has the advantage of generating a high concentration of NO in situ to promote the transfer of more NO and its derivatives (N2O3, ONOO-) to bacteria, thereby significantly improving the antibacterial effect. The multifunctional antibacterial platform has been demonstrated as a good carrier for gas therapy because of its simple and efficient gas release performance, indicating its great potential for the treatment of drug-resistant bacterial infections.

Enzyme induced molecularly imprinted polymer on SERS substrate for ultrasensitive detection of patulin.

We designed a new type of MIP-SERS substrate for specific and label-free detection of patulin (PAT), by combining molecular imprinting polymer (MIP) selectivity and SERS technology sensitivity. Initially, the solid substrate of PDMS/AAO was prepared using poly dimethylsiloxane (PDMS) concreted anodized aluminum oxide (AAO) template. Then moderate Au was sputtered on the surface of PDMS/AAO to obtain Au/PDMS/AAO SERS substrate. Based on the HRP enzyme initiated in situ polymerization on the Au/PDMS/AAO, the MIP-SERS substrate was successfully synthesized with selective polymer and high tense of SERS "hot spots". The new MIP-SERS substrate showed strong SERS enhancement effect and good selectivity for PAT. Besides, the results showed that the method owned a linear range from 5 × 10-10 to 10-6 M with the limit of detection (LOD) of 8.5 × 10-11 M (S/N = 3) for PAT. The proposed method also exhibited acceptable reproducibility (relative standard deviation, RSD = 4.7%)，good stability (Raman intensity is above 80% after two weeks) and recoveries from 96.43% to 112.83% with the average RSD of 6.3%. The substrate is easy to use without complex sample pretreatment, which makes it a potential candidate as a rapid and sensitive detection method in food samples.

Au Hollow Nanorods-Chimeric Peptide Nanocarrier for NIR-II Photothermal Therapy and Real-time Apoptosis Imaging for Tumor Theranostics.

The strategy that combines photodynamic therapy (PDT) and photothermal therapy (PTT) is widely used to achieve strong antitumor efficiency. Since light in the NIR-II window possesses ideal penetration ability, developing NIR-II PTT and NIR-II light triggered photosensitizer release for combined PDT and PTT is very promising in nanomedicine. Methods: We develop a novel nanocarrier (termed AuHNRs-DTPP) by conjugating photosensitizer contained chimeric peptide (DTPP) to Au hollow nanorods (AuHNRs). AuHNRs was obtained by a Te-templated method with the assistance of L-cysteine. The chimeric peptide PpIX-PEG8-GGK(TPP)GRDEVDGC (DTPP) was obtained through a solid-phase peptide synthesis (SPPS) method. Results: Under the 1064 nm laser irradiation, the nanocarrier can accumulate heat quickly for efficient PTT, and then release activated photosensitizer for real-time apoptosis imaging. Thereafter, supplementary PDT can be conducted to kill tumor cells survived from the PTT, and meanwhile the normal tissue can be protected from photo-toxicity. Conclusion: This designed AuHNRs-DTPP nanocarrier with remarkable therapy effect, real-time apoptosis imaging ability and reduced skin damage is of great potential in nanomedicine application.

One Stone with Two Birds: Functional Gold Nanostar for Targeted Combination Therapy of Drug-Resistant Staphylococcus aureus Infection.

The development of new antibacterial agents to deal with the emergence and spread of antibiotic resistance in Gram-positive bacterial pathogens has become an increasing problem. Here, a new strategy is developed for the effective targeting and killing of Gram-positive bacteria based on vancomycin (Van)-modified gold nanostars (AuNSs). Our work has demonstrated that the Van-modified AuNSs (AuNSs@Van) can not only selectively recognize methicillin-resistant Staphylococcus aureus (MRSA) but also kill MRSA under near-infrared laser irradiation in vitro. Additionally, AuNSs@Van shows satisfactory biocompatibility and antibacterial activity in treating bacterial infection in vivo. The attractive trait of AuNSs@Van is attributed to the physical effect of its antibacterial activity, with less potential for resistance development. The aforementioned advantages indicate the potential of AuNSs@Van as a photothermal antibacterial agent for effectively combating Gram-positive bacteria in the field of health care.

Design of Gold Hollow Nanorods with Controllable Aspect Ratio for Multimodal Imaging and Combined Chemo-Photothermal Therapy in the Second Near-Infrared Window.

Gold nanoparticles (AuNPs) exhibit great potential for biological applications due to their good biocompatibility and tunable localized surface plasmon resonance (LSPR) properties. Currently, although tuning the aspect ratio of a solid structure or designing a hollow structure has been performed to regulate the LSPR properties of AuNPs, the method of preparing hollow anisotropic AuNPs has rarely been reported. In this study, we designed gold hollow nanorods (AuHNRs) with controllable aspect ratios by a Se-doping Te nanorod-templated method with the assistance of l-cysteine. UV-vis-NIR spectra showed that AuHNRs with an aspect ratio of about 3 could have a LSPR peak in the second near-infrared (NIR-II) window, which is only half of the value required by traditional Au nanorods. Moreover, AuHNRs are nontoxic and capable of loading drugs. In vivo experiment revealed that AuHNRs can be used as contrast agents in multimodal imaging, including photothermal imaging, photoacoustic imaging, and computed tomography imaging, as well as in chemo-photothermal combined therapy of tumor in the NIR-II window. Because light in the NIR-II window has remarkable advantages over that in the first near-infrared (NIR-I) window in biomedical applications, AuHNRs can be used as promising NIR-II-window-responsive multifunctional nanoagents.

Tumor-triggered transformation of chimeric peptide for dual-stage-amplified magnetic resonance imaging and precise photodynamic therapy.

Despite the great success in clinical magnetic resonance imaging (MRI), Gd3+-based contrast agents still suffer from low proton relaxation efficiency, rapid metabolic clearance as well as poor sensitivity. In this work, we designed a matrix metalloproteinase-2 (MMP-2) responsive chimeric peptide for dual-stage-amplified MRI and precise photodynamic therapy. Both in vitro and in vivo studies indicated that this chimeric peptide could self-assembly into spherical nanoparticles at physiological condition with r1 value of 28.17 mM-1s-1. Meanwhile, the spherical shape endowed chimeric peptide with efficient tumor accumulation via enhanced penetration and retention (EPR) effect. Importantly, the overexpressed MMP-2 in tumor region could specifically hydrolyze chimeric peptide, leading to sphere-to-fiber transformation. This transformation enhanced both the tumor accumulation and the relaxivity of contrast agent. Consequently, the r1 value was remarkably elevated to 51.52 mM-1s-1, which guided precise photodynamic therapy. This tumor microenvironment-triggered transformable strategy should show great potential for tumor-targeted imaging and phototherapy.

Precisely Striking Tumors without Adjacent Normal Tissue Damage via Mitochondria-Templated Accumulation.

Ignored damage in adjacent normal tissue is fatal especially in some specific tumor therapy such as brain tumors, but it remains a great challenge to conquer due to random drug diffusion and tumor complexity. Herein, we show that hyperthermia in mitochondria, an interparticle plasmonic coupling effect activated nanoevent, selectively strikes tumor tissues without damaging adjacent normal tissues. Spherical gold nanoparticles with a mitochondria-targeting moiety, triphenyl phosphonium, preferentially accumulated inside tumor mitochondria and reached the threshold to activate interparticle plasmonic coupling effect among gold nanoparticles, realizing selective light-thermal conversion and mitochondrial dysfunction in tumor, whereas little hyperthermia and mitochondrial dysfunction were observed in adjacent normal tissues. In vivo study revealed that the temperature increment in tumor tissue with irradiation was nearly 4-fold that in adjacent normal tissue. This subcellular organelle-templated accumulation strategy provides a therapeutic model for highly selective tumor therapy with negligible local side effects.

Steric shielding protected and acidity-activated pop-up of ligand for tumor enhanced photodynamic therapy.

Tumor targeted drug delivery in vivo remains a significant challenge in tumor therapy. In this article, we fabricated a steric shielding protected/tumor acidity-activated chimeric peptide for tumor targeted photodynamic therapy. This amphiphilic chimeric peptide could form spherical nanoparticles at neutrally physiological environment with the shielding of biotin molecule (tumor target ligand). When in tumor acidic microenvironment, acidity-sensitive dimethylmaleic amide was rapidly hydrolyzed, resulting in subsequent liberation of (Lys)8 and the recovery of intramolecular electrostatic interaction between (Lys)8 and (Glu)8. Then (Glu)8 folded (Lys)8 and biotin molecule was popped up to the surface of nanoparticles. Both in vitro and in vivo studies indicated that this steric shielding protected/tumor acidity-activated pop-up strategy demonstrated here could remarkably enhance tumor specific accumulation/internalization of chimeric peptide, improve photodynamic therapy efficacy and minimize the side effects. This strategy should not only be used for phototherapy, but also open a window to endow nanocarriers with effective tumor target ability.

Ru(bpy)32+-Silica@Poly-L-lysine-Au as labels for electrochemiluminescence lysozyme aptasensor based on 3D graphene.

In this work, the feasibility of a novel sensitive electrochemiluminescence aptasensor for the detection of lysozyme using Ru(bpy)32+-Silica@Poly-L-lysine-Au (RuSiNPs@PLL-Au) nanocomposites labeling as an indicator was demonstrated. The substrate electrode of the aptasensor was prepared by depositing gold nanoparticles (AuNPs) on 3D graphene-modified electrode. The lysozyme binding aptamer (LBA) was attached to the 3D graphene/AuNPs electrode through gold-thiol affinity, hybridized with a complementary single-strand DNA (CDNA) of the lysozyme aptamer labeled by RuSiNPs@PLL-Au as an electrochemiluminescence intensity amplifier. Thanks to the synergistic amplification of the 3D graphene, the AuNPs and RuSiNPs@PLL-Au NPs linked to Ru(bpy)32+-ECL further enhanced the ECL intensity of the aptasensor. In presence of lysozyme, the CDNA segment of the self-assembled duplex was displaced by the lysozyme, resulting in decreased electrochemiluminescence signal. Under the optimized conditions, the decrease in electrochemiluminescence intensity varied proportionally with the logarithmic concentration of the lysozyme from 2.25 × 10-12 to 5.0 × 10-8 mol L-1, and the detection limit was estimated to 7.5 × 10-13 mol L-1. The aptasensor was further tested in real samples and found reliable for the detection of lysozyme, thus holding great potential application in food safety researches and bioassay analysis.

Folic Acid-Targeted and Cell Penetrating Peptide-Mediated Theranostic Nanoplatform for High-Efficiency Tri-Modal Imaging-Guided Synergistic Anticancer Phototherapy.

A novel nanomaterial with precisely-defined size and shape, biocompatible composition, and excellent stability, which can integrate multi modal targeted imaging and therapy into a single system for visualized therapeutics, has recently attracted significant research interest. Here, we developed a multifunctional nanoplatform based on silica-coated 4-mercaptobenzoic acid-modified gold nanorods (Au NRs) decorated with gold nanoclusters rich in the photosensitizer Ce6 (Au-Ce6 NCs). The nanoparticles also comprised folic acid and cell penetrating peptide molecules anchored on the surface, obtaining the Au@SiO2@Au-cell penetrating peptide nanocomposite. The Au-Ce6 NCs enhanced the photophysical stability, provided numerous bonding sites and offered a large surface-area and interior space to achieve a high drug loading efficiency (up to 55%). The anchored folic acid and cell penetrating peptide synergistically enhanced the efficiency of uptake of nanocomposites by HeLa cells (up to 70.7%) and improved therapeutic efficacy. The nanocomposite also has good water-solubility, excellent biocompatibility, and long-term stability against illumination and exposure to pH 3-12, thus facilitating their bioapplications in cancer theranostics. Here, the nanocomposite was established for high-resolution and noninvasive tri-modal surface-enhanced Raman spectrum/dark-field/fluorescence imaging-guided high-efficiency synergistic photodynamic/photothermal therapy of cancer. Our studies demonstrate that the multifunctional nanocomposite has the potential as a novel and sensitive contrast agent for complementary and synergistic theranostics in the clinic.

Targeted Near-Infrared Fluorescent Turn-on Nanoprobe for Activatable Imaging and Effective Phototherapy of Cancer Cells.

A novel and green multifunctional nanoplatform as a nanocarrier for drug delivery, cell imaging, and phototherapy has been engineered. The nanoplatform is composed of stabilized carbon spheres (CSs) as cores, a coated polydopamine (PDA) shell, targeted folic acid (FA), and the loaded anticancer drug indocyanine green (ICG), obtaining CSs@PDA-FA@ICG nanocomposites (NCs). The biocompatible PDA shell provided a high fluorescence quenching efficiency and a surface rich in functional groups for anchoring FA for targeting cancer cells. Aromatic ICG could be effectively loaded into the CSs@PDA-FA system via hydrophobic interactions and π-π stacking with a loading efficiency of 58.9%. Notably, the activated NIR fluorescence in an intracellular environment made CSs@PDA-FA@ICG a sensitive "OFF" to "ON" nanoprobe that can be used for NIR imaging. Moreover, compared to ICG alone, the CSs@PDA-FA@ICG NCs could induce efficient photoconversion for simultaneous synergetic photodynamic therapy (PDT) and photothermal therapy (PTT) under a single NIR laser irradiation. The results demonstrated that CSs@PDA-FA@ICG NCs as a targeted and activated nanoplatform provide new opportunities to facilitate the accurate diagnosis of cancer and enhanced treatment efficacy. This work stimulates more interest in the design of the facile surface functionalization strategy to construct other multifunctional nanocomposites, such as nanotubes and nanorods.

Electrochemical determination of thiols at single-wall carbon nanotubes and PQQ modified electrodes.

The electrocatalytic oxidation of thiols has been observed at a glassy carbon (GC) electrode coated with a single-wall carbon nanotube (SWNT) film. Fourteen thiols including L-cysteine (CySH) and glutathione were tested using the SWNT/GC electrode, and the cyclic voltammetry (CV) showed that each thiol was oxidized at much less positive potential than those at other electrodes such as bare GC and diamond electrodes. The SWNT/GC electrode was also modified with pyrroloquinoline quinone (PQQ) which showed a further improvement of the catalytic behavior of the SWNT/GC electrode: e.g. the oxidation peak current of CySH was observed at 0.27 V vs. Ag/AgCl in pH 7.5 phosphate buffer. The amperometic responses at these electrodes showed a linear relationship with the substrate concentration in a 10(-6)-10(-3) M range and 10(-6)-10(-7) M detection limits for several thiols including CySH, L-homocysteine, N-acetyl-L-cysteine, L-penicillamine and glutathione. These electrodes show a response time of 2-3 s and storage stabilities over 3 weeks. A PQQ/SWNT/GC electrode has been successfully applied for the assay of both L-cysteine and N-acetyl-L-cysteine in the dietary supplement.