Photonic and magnetic materials for on-demand local drug delivery.

Nanomedicine has been considered a promising tool for biomedical research and clinical practice in the 21st century because of the great impact nanomaterials could have on human health. The generation of new smart nanomaterials, which enable time- and space-controlled drug delivery, improve the limitations of conventional treatments, such as non-specific targeting, poor biodistribution and permeability. These smart nanomaterials can respond to internal biological stimuli (pH, enzyme expression and redox potential) and/or external stimuli (such as temperature, ultrasound, magnetic field and light) to further the precision of therapies. To this end, photonic and magnetic nanoparticles, such as gold, silver and iron oxide, have been used to increase sensitivity and responsiveness to external stimuli. In this review, we aim to report the main and most recent systems that involve photonic or magnetic nanomaterials for external stimulus-responsive drug release. The uniqueness of this review lies in highlighting the versatility of integrating these materials within different carriers. This leads to enhanced performance in terms of in vitro and in vivo efficacy, stability and toxicity. We also point out the current regulatory challenges for the translation of these systems from the bench to the bedside, as well as the yet unresolved matter regarding the standardization of these materials.

Targeted theranostics of lung cancer: PD-L1-guided delivery of gold nanoprisms with chlorin e6 for enhanced imaging and photothermal/photodynamic therapy.

Peptide modified nanoparticles have emerged as powerful tools for enhanced cancer diagnosis and novel treatment strategies. Here, human programmed death-ligand 1 (PD-L1) peptides were used for the first time for the modification of gold nanoprisms (GNPs) to enhance targeting efficiency. A multifunctional nanoprobe was developed that the GNPs@PEG/Ce6-PD-L1 peptide (GNPs@PEG/Ce6-P) was used for imaging-guided photothermal/photodynamic therapy by using the targeting effect of PD-L1. Both confocal imaging and flow cytometry experiments demonstrated a remarkable affinity of the as-prepared nanoprobes GNPs@PEG/Ce6-P to lung cancer cells (HCC827), which have a high PD-L1 expression. Subsequent in vitro and in vivo experiments further demonstrated that the nanoprobes GNPs@PEG/Ce6-P not only allowed for real-time visualization via fluorescence (FL) imaging and photoacoustic (PA) imaging, but also served as phototherapy agents for synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, treatments on human lung cancer cells-derived tumors demonstrated that the nanoprobes GNPs@PEG/Ce6-P could significantly suppress tumor growth through PTT and PDT from GNPs and Ce6, respectively. In conclusion, the as-prepared new nanoprobes show promising potential for nanomedicine with remarkable targeting ability for dual-mode imaging and enhanced PDT and PTT effects on lung cancer.

A plasmonic thermal sensing based portable device for lateral flow assay detection and quantification.

Point-of-care testing (POCT) is widely used for early diagnosis and monitoring of diseases. Lateral flow assay (LFA) is a successfully commercial tool for POCT. However, LFA often suffers from a lack of quantification and analytical sensitivity. To solve these drawbacks, we have previously developed a thermal LFA using plasmonic gold nanoparticles for thermal contrast into a portable device. Although this methodology significantly improves the analytical sensitivity compared with conventional visual detection, quantification problems are still remaining. In this study, we optimized the operating conditions for the device using conduction and radiation thermal sensing modes allowing the quantification of LFA. The limit of detection of the strips merely containing nanoparticles was decreased by 5-fold (conduction mode) and 12-fold (radiation mode) compared to traditional visual detection. The effect of the ambient temperature was studied for both methods of detection showing that the radiation mode was more affected by the ambient temperature than the conduction mode. To validate the thermal sensing method, human chorionic gonadotropin (HCG) biomarker was quantified using our LFA strips, obtaining a detection limit of 2.8 mIU/mL when using the radiation method of detection.

In vivo comparison of the biodistribution and long-term fate of colloids - gold nanoprisms and nanorods - with minimum surface modification.

Aim: To study the difference in biodistribution of gold nanoprisms (NPr) and nanorods (NR), PEGylated to ensure colloidal stability. Materials & methods: Surface changes were studied for nanoparticles in different media, while the biodistribution was quantified and imaged in vivo. Results: Upon interaction with the mouse serum, NR showed more abrupt changes in surface properties than NPr. In the in vivo tests, while NPr accumulated similarly in the spleen and liver, NR showed much higher gold presence in the spleen than in liver; together with some accumulation in kidneys, which was nonexistent in NPr. NPr were cleared from the tissues 2 months after administration, while NR were more persistent. Conclusion: The results suggest that the differential biodistribution is caused by size-/shape-dependent interactions with the serum.

A tumor microenvironment responsive biodegradable CaCO3/MnO2- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy.

The low efficiency of photodynamic therapy (PDT) is caused by tumor hypoxia and the adaptive immune resistance/evasion of tumor cells, while the currently emerging immune checkpoint therapy restores the intrinsic immune capacities but can't directly attack the tumor cells. Methods: Herein we report an integrated nanoplatform that combines PDT with immunotherapy to enhance photodynamic therapeutic effects and simultaneously inhibit tumor cells resistance/evasion. To achieve this, we fabricated Mn@CaCO3/ICG nanoparticles and loaded them with PD-L1-targeting siRNA. Results: Thanks to the protection of CaCO3 on the loaded ICG and the oxygen produced by MnO2, an enhanced photodynamic therapeutic effect in vitro was observed. In vivo experiments demonstrated that the nanoplatform could efficiently deliver the loaded drug to the tumor tissues and significantly improve tumor hypoxia, which further contributes to the therapeutic effect of PDT in vivo. Moreover, the synergistic benefits derived from the siRNA, which silenced the checkpoint gene PD-L1 that mediates the immune resistance/evasion, resulted in a surprising therapeutic effect to rouse the immune system. Conclusions: The combination treatment strategy has great potential to be developed as a new and robust method for enhanced PDT therapy with high efficiency and a powerful antitumor immune response based on PD-L1 blockade.

Oral pH sensitive GNS@ab nanoprobes for targeted therapy of Helicobacter pylori without disturbance gut microbiome.

How to eradicate Helicobacter pylori (H. pylori) in vivo with antibiotic resistance owns tremendous clinical requirement. Herein, gold nanostars were conjugated with acid-sensitive cis-aconitic anhydride modified anti-H. pylori polyclonal antibodies, resultant pH sensitive gold nanostars@H. pylori-antibodies nanoprobes (GNS@Ab) were employed for the theranostics of H. pylori in vivo. Photoacoustic imaging confirmed that prepared GNS@Ab could target actively H. pylori in the stomach. GNS@Ab nanoprobes could kill H. pylori in vivo in model animals under NIR laser irradiation, all GNS@Ab nanoprobes could be excreted out of gut within 7 days after oral administration. Gastric local lesion caused by H. pylori restored to normal status within one month. GNS@Ab nanoprobes within therapeutic doses did not damage intestinal bacteria imbalance. Forty clinical specimens of H. pylori with antibiotic resistance were verified validity of GNS@Ab nanoprobes. Prepared oral pH-sensitive GNS@Ab nanoprobes own clinical translational potential in the theranostics of H. pylori in near future.

Gastric Parietal Cell and Intestinal Goblet Cell Secretion: a Novel Cell-Mediated In Vivo Metal Nanoparticle Metabolic Pathway Enhanced with Diarrhea Via Chinese Herbs.

Up to date, the way in which metal nanoparticles are cleared in vivo has yet to be elucidated well. Herein, we report a novel intestinal goblet cell-mediated in vivo clearance pathway to remove metal nanoparticles. Typical metal nanoparticles such as triangular silver nanoplates, magnetic nanoparticles, gold nanorods, and gold nanoclusters were selected as representative examples. These metal nanoparticles were prepared, characterized, and injected via tail vein into a mice model with common bile duct (CBD) ligation. The feces and urines were collected for 7 days to be followed by the sacrifice of the mice and collection of the intestinal and gastric tissues for further analysis. The results showed that all four selected metal nanoparticles were located inside the goblet cells (GCs) of the whole intestinal tissue and were excreted into the gut lumen through the secretion of intestinal GC. Moreover, triangular silver nanoplates and gold nanorods were located inside the gastric parietal cells (PCs). Importantly, nanoparticles did not cause obvious pathological changes in intestinal tissues. In this study, we confirmed that the blood corpuscles are involved in the GCs secretion pathway. Furthermore, we found that the secretion of nanoparticles from intestinal GCs and PCs is accelerated by diarrhea induced via Chinese herbs. In conclusion, metal nanoparticles such as triangular silver nanoplates, magnetic nanoparticles, gold nanorods, and gold nanoclusters can be cleaned away by intestinal GCs and PCs. This novel pathway of in vivo clearance of metal nanoparticles has a great potential for future applications such as new drug design and development, nanoparticle-based labeling and in vivo tracking, and biosafety evaluation of in vivo nanoparticles.

Salivary Analysis Based on Surface Enhanced Raman Scattering Sensors Distinguishes Early and Advanced Gastric Cancer Patients from Healthy Persons.

Development of new methods to screen early gastric cancer patients has great clinical requirement. Ten amino acids in human saliva are identified as small metabolite biomarkers to distinguish early gastric cancer patients and advanced gastric cancer patients from healthy persons by using high performance liquid chromatography-mass spectrometry (HPLC-MS). Then, surface enhanced Raman scattering (SERS) sensors based on graphene oxide nanoscrolls wrapped with gold nanoparticles are developed to detect ten amino acids biomarkers in saliva. The distinctive graphene oxide nanoscrolls wrapped with gold nanoparticles are facilely prepared via ultrasonication without any organic stabilizer, and endow the SERS sensors with excellent uniformity, stability and SERS activity to adsorb and detect the biomarkers with 108 enhancement coefficient. The SERS sensors were confirmed to be feasible for distinguishing early gastric cancer patients and advanced gastric cancer patients from healthy persons by simulation samples and 220 clinical saliva samples with excellent performance (specificity >87.7% and sensitivity >80%). This non-invasive, cheap, fast and reliable salivary analysis method based on the SERS sensors provides a new strategy to screen out early gastric cancer patients and advanced gastric cancer patients from population, and owns clinical translational prospects.

Mitochondria-targeting near-infrared light-triggered thermosensitive liposomes for localized photothermal and photodynamic ablation of tumors combined with chemotherapy.

Lonidamine, an anticancer drug that acts on mitochondria, has poor water solubility. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Hence, a mitochondria-targeting drug delivery system loaded with Lonidamine and a ROS-produced photosensitizer could improve the bioavailability of Lonidamine and maximize photodynamic therapeutic efficiency. Here we report, for the first time, new IR-780 and Lonidamine encapsulated mitochondria-targeting thermosensitive liposomes (IL-TTSL). DSPE-PEG2000-NH2 was coupled with triphenylphosphine to form DSPE-PEG2K-TPP. The liposomes (IL-TTSL) were self-assembled from DPPC, DSPC, DSPE-PEG2K-TPP, cholesterol, IR-780 and Lonidamine. Coupled linker modified triphenylphosphine (TPP) is cationic and can selectively accumulate several hundred-fold within mitochondria. Once the liposomes are located inside mitochondria, 808 nm laser irradiation could trigger photosensitizer IR-780 to elevate the local temperature, which could be utilized in photothermal therapy and induce the release of Lonidamine from the thermosensitive liposomes. Meanwhile, IR-780 could release ROS for photodynamic therapy in mitochondria and increase photodynamic therapeutic efficiency. Our results showed that the surface modification of the liposomes with triphenylphosphine cations had good mitochondria-targeting ability. The liposomes exhibited good biocompatibility and all components of the empty liposomes were safe to be used in humans. Few reports were related to IR-780 being used in photodynamic therapy and we proved this function of IR-780. Overall, the stealth liposomes provide a promising new strategy to realize mitochondria-targeting thermosensitive chemo-, photodynamic and photothermal combination therapy with a single light source for lung cancer.

Tumor-triggered drug release from calcium carbonate-encapsulated gold nanostars for near-infrared photodynamic/photothermal combination antitumor therapy.

Different stimulus including pH, light and temperature have been used for controlled drug release to prevent drug inactivation and minimize side-effects. Herein a novel nano-platform (GNS@CaCO3/ICG) consisting of calcium carbonate-encapsulated gold nanostars loaded with ICG was established to couple the photothermal properties of gold nanostars (GNSs) and the photodynamic properties of indocyanine green (ICG) in the photodynamic/photothermal combination therapy (PDT/PTT). In this study, the calcium carbonate worked not only a drug keeper to entrap ICG on the surface of GNSs in the form of a stable aggregate which was protected from blood clearance, but also as the a pH-responder to achieve highly effective tumor-triggered drug release locally. The application of GNS@CaCO3/ICG for in vitro and in vivo therapy achieved the combined antitumor effects upon the NIR irradiation, which was superior to the single PDT or PTT. Meanwhile, the distinct pH-triggered drug release performance of GNS@CaCO3/ICG implemented the tumor-targeted NIR fluorescence imaging. In addition, we monitored the bio-distribution and excretion pathway of GNS@CaCO3/ICG based on the NIR fluorescence from ICG and two-photon fluorescence and photoacoustic signal from GNSs, and the results proved that GNS@CaCO3/ICG had a great ability for tumor-specific and tumor-triggered drug release. We therefore conclude that the GNS@CaCO3/ICG holds great promise for clinical applications in anti-tumor therapy with tumor imaging or drug tracing.

Nanoparticles for multi-modality cancer diagnosis: Simple protocol for self-assembly of gold nanoclusters mediated by gadolinium ions.

It is essential to develop a simple synthetic strategy to improve the quality of multifunctional contrast agents for cancer diagnosis. Herein, we report a time-saving method for gadolinium (Gd3+) ions-mediated self-assembly of gold nanoclusters (GNCs) into monodisperse spherical nanoparticles (GNCNs) under mild conditions. The monodisperse, regular and colloidal stable GNCNs were formed via selectively inducing electrostatic interactions between negatively-charged carboxylic groups of gold nanoclusters and trivalent cations of gadolinium in aqueous solution. In this way, the Gd3+ ions were chelated into GNCNs without the use of molecular gadolinium chelates. With the co-existence of GNCs and Gd3+ ions, the formed GNCNs exhibit significant luminescence intensity enhancement for near-infrared fluorescence (NIRF) imaging, high X-ray attenuation for computed tomography (CT) imaging and reasonable r1 relaxivity for magnetic resonance (MR) imaging. The excellent biocompatibility of the GNCNs was proved both in vitro and in vivo. Meanwhile, the GNCNs also possess unique NIRF/CT/MR imaging ability in A549 tumor-bearing mice. In a nutshell, the simple and safe GNCNs hold great potential for tumor multi-modality clinical diagnosis.

ROS-Responsive Mitochondria-Targeting Blended Nanoparticles: Chemo- and Photodynamic Synergistic Therapy for Lung Cancer with On-Demand Drug Release upon Irradiation with a Single Light Source.

Mitochondria in cancer cells maintain a more negative membrane potential than normal cells. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Thus, the strategy of targeting mitochondria can maximize the photodynamic therapeutic efficiency for cancer. Here we report, for the first time, synthesis of a new mitochondria-targeting drug delivery system, ZnPc/CPT-TPPNPs. To synthesize this novel compound, polyethylene glycol was functionalized with thioketal linker-modified camptothecin (TL-CPT) and triphenylphosphonium to form the block copolymer, TL-CPT-PEG1K-TPP. The ZnPc/CPT-TPPNPs was constructed for delivery of the photosensitizer Zinc phthalocyanine (ZnPc) by blending the block copolymer TL-CPT-PEG1K-TPP with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)] (DSPE-PEG).Triphenylphosphine can accumulate selectively several hundred-fold within mitochondria. The thioketal linker is ROS-responsive and CPT can be released upon ROS cleavage. We also show that the ZnPc loaded in ZnPc/CPT-TPPNPs absorbed the 633 nm laser to produce ROS, which could be utilized both in photodynamic therapy and to cleave the thioketal linker thereby releasing camptothecin for chemotherapy. Thus, the mitochondria-targeting nanoparticles could elevate photodynamic therapeutic efficacy. Our results showed that surface modification of the nanoparticles with triphenylphosphine cations facilitated efficient subcellular delivery of the photosensitizer to mitochondria. The nanoparticles had a good ROS-responsive effect to release CPT, which could transfer to the nucleus and interfere with DNA replication as a topoisomeraseⅠinhibitor. Thus, the blended nanoparticles provide a new promising approach as a mitochondria-targeting ROS-activated chemo- and photodynamic therapy with a single light source for lung cancer.

Gold nanoprism-nanorod face off: comparing the heating efficiency, cellular internalization and thermoablation capacity.

AIM: This work compares the synthesis, heating capability, cellular internalization and thermoablation capacity of two different types of anisotropic gold nanoparticles: gold nanorods (NRs) and nanoprisms (NPrs). METHODS: Both particles possess surface plasmon resonance absorption bands in the near-IR, and their heating efficiency upon irradiation with a continuous near-IR laser (1064 nm) was evaluated. The cellular internalization, location and toxicity of these PEG-stabilized NPrs and NRs were then assessed in the Vero cell line by transmission electron microscopy and inductively coupled plasma mass spectrometry analysis, and their ability to induce cell death upon laser irradiation was then evaluated and compared. RESULTS & CONCLUSION: Although both nanoparticles are highly efficient photothermal converters, NRs possessed a more efficient heating capability, yet the in vitro thermoablation studies clearly demonstrated that NPrs were more effective at inducing cell death through photothermal ablation due to their greater cellular internalization.

Breath Analysis Based on Surface-Enhanced Raman Scattering Sensors Distinguishes Early and Advanced Gastric Cancer Patients from Healthy Persons.

Fourteen volatile organic compound (VOC) biomarkers in the breath have been identified to distinguish early gastric cancer (EGC) and advanced gastric cancer (AGC) patients from healthy persons by gas chromatography-mass spectrometry coupled with solid phase microextraction (SPME). Then, a breath analysis approach based on a surface-enhanced Raman scattering (SERS) sensor was developed to detect these biomarkers. Utilizing hydrazine vapor adsorbed in graphene oxide (GO) film, the clean SERS sensor is facilely prepared by in situ formation of gold nanoparticles (AuNPs) on reduced graphene oxide (RGO) without any organic stabilizer. In the SERS sensor, RGO can selectively adsorb and enrich the identified biomarkers from breath as an SPME fiber, and AuNPs well dispersed on RGO endow the SERS sensor with an effective detection of adsorbed biomarkers. Fourteen Raman bands associated with the biomarkers are selected as the fingerprints of biomarker patterns to distinguish persons in different states. The approach has successfully analyzed and distinguished different simulated breath samples and 200 breath samples of clinical patients with a sensitivity of higher than 83% and a specificity of more than 92%. In conclusion, the VOC biomarkers and breath analysis approach in this study can not only diagnose gastric cancer but also distinguish EGC and AGC. This work has great potential for clinical translation in primary screening diagnosis and stage determination of stomach cancer in the near future.

Near-Infrared Light Triggered ROS-activated Theranostic Platform based on Ce6-CPT-UCNPs for Simultaneous Fluorescence Imaging and Chemo-Photodynamic Combined Therapy.

Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6-CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future.