Well-designed gold nanoclusters–indocyanine green nanoprobes (Au NCs–INPs) have been developed by the conjugation of Au NC assemblies with indocyanine green (ICG) for the therapeutic real-time monitoring based on fluorescence resonance energy transfer (FRET). The synthesized Au NCs–INPs demonstrated the improved cellular uptake and effective tumor targeting because of the enhanced permeability and retention effect and the gp60-mediated secreted protein acidic and rich in cysteine combined transport pathway, suggesting excellent dual-modal near-infrared fluorescence and photoacoustic imaging. Moreover, the simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) of Au NCs–INPs exhibited higher cancer cell killing and tumor removal efficiency than those of PDT or PTT alone. More importantly, a promising therapeutic monitoring strategy was performed based on FRET between Au NCs and ICG, suggesting that Au NCs–INPs could be utilized to evaluate the therapeutic response by real-time monitoring the change in Au NCs in fluorescence intensity together with ICG supersession. Therefore, Au NCs–INPs as a novel photosensitizer have great potentials for combined tumor imaging, therapy, and therapeutic monitoring in real time.Keywords: fluorescence resonance energy transfer; gold nanoclusters; indocyanine green; near-infrared fluorescence imaging; photoacoustic imaging; real-time monitoring; synchronous therapy;

Photodynamic therapy (PDT) is a site-specific treatment of cancer using much lower optical power densities with minimal nonspecific damage to normal tissues. To improve the therapeutic efficiency of PDT, we fabricated a multifunctional theranostic nanoparticle system (DSSCe6@Fe3O4 NPs) by loading Fe3O4 nanoparticles in redox-responsive chlorin e6 (Ce6)-conjugated dextran nanoparticles for near-infrared (NIR)/magnetic resonance (MR) dual-modality imaging and magnetic targeting. The obtained DSSCe6@Fe3O4 NPs demonstrated a uniform nanospherical morphology consisting of Fe3O4 clusters. The fluorescence signal of Ce6 of this theranostic system could turn “ON” from a self-quenching state in a reductive intracellular environment. T2-Weighted MR imaging revealed a high transverse relaxivity (r2) measured to be 194.4 S−1 mM−1, confirming that it was also a distinctive contrast agent in T2-weighted MR imaging. Confocal images and flow cytometry results showed that the cellular uptake of DSSCe6@Fe3O4 NPs was enhanced effectively under an extra magnetic field, which resulted in promoted PDT therapeutic efficiency. In vivo MR imaging showed that DSSCe6@Fe3O4 NPs effectively accumulated in tumors under an extra magnetic field. These results illustrated that the DSSCe6@Fe3O4 NPs could be a promising theranostic system for both NIR/MR imaging-guided PDT precision therapy.

The inadequate oxygen supply in solid tumor causes hypoxia, which leads to drug resistance and poor chemotherapy outcomes. To solve this problem, a cancer cell membrane camouflaged nanocarrier is developed with a polymeric core encapsulating hemoglobin (Hb) and doxorubicin (DOX) for efficient chemotherapy. The designed nanoparticles (DHCNPs) retain the cancer cell adhesion molecules on the surface of nanoparticles for homologous targeting and possess the oxygen-carrying capacity of Hb for O2-interfered chemotherapy. The results show that DHCNPs not only achieve higher tumor specificity and lower toxicity by homologous targeting but also significantly reduce the exocytosis of DOX via suppressing the expressions of hypoxia-inducible factor-1α, multidrug resistance gene 1, and P-glycoprotein, thus resulting in safe and high-efficient chemotherapy. This work presents a new paradigm for targeted oxygen interference therapy by conquering hypoxia-involved therapeutic resistance and achieves effective treatment of solid tumors.

As one of near-infrared (NIR) fluorescent (FL) nanoprobes, gold nanoclusters (Au NCs) are delicated to passive-targeting tumors for NIR FL imaging, but which easily cleared by the kidneys for the small size (<1.5 nm). Herein, the well-defined gold clusters nanoassembly (Au CNA) was synthesized by the self-assembly of Au NCs based on protein cross-linking approach. The as-prepared Au CNA demonstrated highly effective cellular uptake and precise tumor targeting compared to that of Au NCs. Moreover, with the irradiation of 660 nm laser, Au CNA generated largely reactive oxygen species (ROS) for photodynamic therapy (PDT). In vitro and in vivo PDT revealed that Au CNA exhibited largely cell death and significantly tumor removal at a low power density of 0.2 W/cm2. It could be speculated that the laser-excited Au CNA produced photon energy, which further obtained electron from oxygen to generate radical species. Therefore, Au CNA as a photosensitizer could realize NIR FL imaging and NIR laser induced PDT.Download high-res image (259KB)Download full-size imageThe well-defined gold clusters nanoassembly (Au CNA) were employed for near-infrared (NIR) fluorescent (FL) imaging and photodynamic therapy (PDT) in vitro/vivo.

A combination of chemotherapy and photothermal treatment has already become a promising strategy for cancer treatment. Hence, it is highly desirable to develop a safe and effective delivery system. In the present study, we have developed bovine serum albumin-loaded nano-selenium (SeNPs)/indocyanine green (ICG) nanoparticles (BSINPs) that were generated by a programmed assembly method. They could simultaneously deliver SeNPs (a chemotherapeutic agent) and ICG (a photothermal agent) to tumor regions for combined chemo-photothermal therapy. BSINPs presented good monodispersity, a suitable size, fluorescence stability, and characteristic spectral features in comparison with free ICG. Moreover, the BSINPs displayed a longer retention time in tumors and a higher temperature response under laser irradiation. In addition, the process of subcellular location in vitro and the distribution of BSINPs in vivo could be monitored. The combined therapy offered by the BSINPs with laser irradiation synergistically induced the death of U87L glioma cells, and completely inhibited U87L tumor growth in vivo compared with chemo or photothermal therapy alone. Outstandingly, no tumor recurrence or treatment-induced toxicity was observed after a single-dose of BSINPs with laser irradiation. The results indicate that the well-defined BSINPs are highly desirable for cancer treatment with chemo-photothermal therapy.

Targeted phototherapy and multi-modal imaging can effectively improve the therapeutic efficacy and reduce the side effects of theranostics. Herein, we constructed novel biocompatible cyanine dye IR808-conjugated hyaluronic acid nanoparticles (HAIR NPs) for photothermal therapy (PTT) with near-infrared fluorescence (FL) and photoacoustic (PA) dual-modal imaging. The nanoparticles formed stable nanostructures under aqueous conditions with uniform size distribution. The HAIR NPs were rapidly taken up by the human lung cancer cells A549 via CD44 (the hyaluronic acid receptor on the surface of tumor cells) receptor-mediated endocytosis. Upon laser irradiation, the HAIR NPs enabled good near-infrared fluorescence imaging and photoacoustic imaging in tumor-bearing mice. In addition, the tight nanostructure arising from the covalent link between HA and IR808 could significantly improve the light-thermal conversion efficiency of IR808. Under a low dose of laser power, the HAIR NPs presented more effective photothermal therapy for the suppression of tumor growth than free IR808 in vitro and in vivo. Overall, these results indicate that the HAIR NPs may be an extremely promising nanoplatform in cancer theranostics for targeted PTT under FL and PA dual-modal imaging.

Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(L-lysine)-b-poly(L-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around −30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR+) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR+ HeLa and FR− A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD-NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy.

We designed and synthesized new kinds of near-infrared catechol-based multidentate polymers which were intended to yield compact NIR-active iron oxide nanoparticles with excellent stability and biocompatibility. The resulted multifunctional nanoprobes showed great potential as multimodal contrast agents for NIRF/PA/MR trimodal imaging in vivo.

A series of functional quantum dots (QDs) with widely tunable near-infrared fluorescence emission (620–750 nm) and lifetime (30–160 ns) were synthesized via lattice strain and showed excellent photo, colloid, pH, and lifetime stabilities. The well-defined targeting QDs were first developed for a living cell multilifetime encoding strategy to track and recognize specified tumor cell clusters dependent on lifetime distribution using fluorescence lifetime imaging microscopy.

We here report smart hyaluronidase-actived theranostic nanoparticles based on hyaluronic acid (HA) coupled with chlorin e6 (Ce6) via adipic dihydrazide (ADH) forming HA-ADH-Ce6 conjugates and self-assembling into HACE NPs. The resulting nanoparticles showed stable nano-structure in aqueous condition with uniform size distribution and can be actively disassembled in the presence of hyaluronidase (over-expressed in tumor cells), exhibiting hyaluronidase-responsive “OFF/ON” behavior of fluorescence signal. The HACE NPs were rapidly taken up to human lung cancer cells A549 via CD44 (the HA receptor on the surface of tumor cells) receptor mediated endocytosis. Upon laser irradiation, the HACE NPs realized good near-infrared fluorescence imaging and photoacoustic imaging in the tumor bearing mice, which showed 5-fold higher fluorescence intensity and 3-fold higher photoacoustic (PA) intensity than free Ce6, respectively. In addition, under low dose of laser power, the HACE NPs presented more effective photodynamic therapy to suppression of tumor growth than free Ce6 in vitro and in vivo. Overall, these results suggest that the well-defined HACE NPs is a biocompatible theranostic nanoplatform for in vivo dual-modal tumor imaging and phototherapy simultaneously.

An active cell membrane–camouflaged nanoparticle, owning to membrane antigens and membrane structure, can achieve special properties such as specific recognition, long blood circulation, and immune escaping. Herein, we reported a cancer cell membrane–cloaked nanoparticle system as a theranostic nanoplatform. The biomimetic nanoparticles (indocyanine green (ICG)-loaded and cancer cell membrane-coated nanoparticles, ICNPs) exhibit a core–shell nanostructure consisting of an ICG-polymeric core and cancer cell membrane shell. ICNPs demonstrated specific homologous targeting to cancer cells with good monodispersity, preferable photothermal response, and excellent fluorescence/photoacoustic (FL/PA) imaging properties. Benefited from the functionalization of the homologous binding adhesion molecules from cancer cell membranes, ICNPs significantly promoted cell endocytosis and homologous-targeting tumor accumulation in vivo. Moreover, ICNPs were also good at disguising as cells to decrease interception by the liver and kidney. Through near-infrared (NIR)-FL/PA dual-modal imaging, ICNPs could realize real-time monitored in vivo dynamic distribution with high spatial resolution and deep penetration. Under NIR laser irradiation, ICNPs exhibited highly efficient photothermal therapy to eradicate xenografted tumor. The robust ICNPs with homologous properties of cancer cell membranes can serve as a bionic nanoplatform for cancer-targeted imaging and phototherapy.Keywords: biomimetic nanoparticle; cancer cell membrane; dual-modal imaging; homologous targeting; photothermal therapy

A chelator-free doping method is developed for constructing a Ni-integrated CuS nanostructure as a novel PA/MRI contrast agent. It exhibits tunable near-infrared absorption. Moreover, the hybrid nanostructure has demonstrated a dramatically enhanced T1 relaxivity compared with Ni ions. Due to these unique properties, chelator-free nanoparticles have been successfully applied for in vivo PA/MRI dual-modal imaging.

pH-responsive doped quantum dots with an ultrasmall size (∼3.5 nm), near-infrared emission (∼720 nm) and long lifetime (∼1 μs), which exhibit a linear response range from pH 5.5 to 7.0 with the maximum change in the fluorescence lifetime up to ∼600 nm, were synthesized as lifetime-based pH nanosensors for in vivo imaging.

Smac-conjugated nanoparticle (Smac-NP) was designed to induce the apoptosis of cancer cells and as a drug carrier for combination therapy. It contained three parts, a SmacN7 peptide which could induce apoptosis of cancer cells by interacting with XIAPs, the cell penetrating domain rich in arginine, and four hydrophobic tails for self-assembled Smac-NP. We demonstrated that Smac-NPs exerted an antitumor effect in breast cancer cell MDA-MB-231 and nonsmall lung cancer (NSCLC) cell H460, which efficiently inhibited cancer cells proliferation without influencing normal liver cell lines LO2. Smac-NPs also significantly induced apoptosis of MDA-MB-231 and H460 cells through activating pro-caspase-3, down-regulating the expression of antiapoptotic protein Bcl-2 and up-regulating the pro-apoptotic protein Bax. Furthermore, Smac-NPs could be explored as a drug delivery system to load hydrophobic drug such as DOX for combination therapy. The DOX-loaded nanoparticles (DOX-Smac-NPs) exhibited higher cellular uptake efficiency and antitumor effect. Our work provided a new insight into therapeutic peptides integrated with drug simultaneously in one system for cancer combination treatment.Keywords: combination therapy; drug delivery; Smac; therapeutic peptides;

Multifunctional theranostic materials with good biocompatibility are desirable for cancer imaging and therapy. In this paper, a glioma-specific theranostic agent is prepared using Chlorotoxin fusion protein GST-CTX (gCTX) as a template to direct the synthesis of Au nanoclusters (NCs). By trapping the Au NCs in the gCTX, the prepared Au@gCTX NCs show ultrasmall size with hydrodynamic diameter of ∼2.2 nm and exhibit red-emitting fluorescence with a quantum yield of approximately 6.5%. The investigation from confocal fluorescent microscopy reveals the bright fluorescence and high specificity of the Au@gCTX NCs to label glioma cells through binding to membrane-bound matrix metalloproteinase 2 (MMP-2). Gelatin Zymography, MTT cell viability assay and flow cytometry studies further demonstrate that the Au@gCTX NCs can inhibit the enzymatic activity of MMP-2 and cancer proliferation by elevating intracellular ROS levels, and without harming normal cells. Our results suggest an efficient method for the synthesis of multifunctional theranostic agents for the treatment of cancer.

Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA–NP) significantly reduced metastasis in the lung. When DOX and siRNA were co-delivered by the nanocarriers (siRNA–DOX–NP), a synergistic therapeutic effect was observed, resulting in dramatic inhibition of tumor growth in a H460 xenograft model. These results demonstrated that the siRNA–NP or siRNA–DOX–NP complex targeting ZEB1 could be developed into a new therapeutic approach for non-small cell lung cancer (NSCLC) treatment.

We have developed a microwave assisted one-pot approach to fabricate a novel hybrid nano-composite composed of two-dimensional chemically exfoliated layered hexagonal boron nitride (h-BN) and embedded silver nanoparticles (SNP). Atomic layered h-BN exfoliated using chemical liquid showed strong in-plane bonding and weak van der Waals interplanar interactions, which is utilized for chemically interfacing SNP, indicating their ability to act as excellent nano-scaffolds. The SNP/h-BN optical response, in particular band gap, is strongly dependent on the concentration of the metallic particles. In order to gain further insight into this behavior we have also carried out ab initio density functional theory (DFT) calculations on modeled structures, demonstrating that the bandgap value of SNP/h-BN hybrids could be significantly altered by a small percentage of OH− groups located at dangling B and N atoms. Our results showed that these novel SNP/h-BN nanohybrid structures exhibited excellent thermal stability and they are expected to be applied as devices for thermal oxidation-resistant surface enhanced Raman spectroscopy (SERS). The SNP/h-BN membrane showed remarkable antibacterial activity, suggesting their potential use in water disinfection and food packaging.

pH is an important control parameter for maintenance of cell viability and tissue functions. pH monitoring provides valuable information on cell metabolic processes and the living environment. In this study, we prepared dual pH-sensitive, fluorescent dye-loaded polypeptide nanoparticles (DPNs) for ratiometric sensing of pH changes in living cells. DPNs contain two types of dyes: N-(rhodamine B) lactam cystamine (RBLC), an acid activatable fluorescent dye with increased fluorescence in an acidic environment, and fluorescein isothiocyanate (FITC), a base activatable fluorescent dye with enhanced fluorescence in an alkaline environment. Hence, DPNs exhibited a dual response signal with strong red fluorescence and weak green fluorescence under acidic conditions; in contrast, they showed strong green fluorescence and almost no red fluorescence under alkaline and neutral conditions. The favorable inverse pH responses of the two fluorescent dyes resulted in ratiometric pH determination for DPNs with an optimized pH-sensitive range of pH 4.5–7.5. Quantitative analysis of the intracellular pH of intact MCF-7 cells has been successfully demonstrated with our nanosensor. Moreover, single acid activatable fluorescent dye doped polypeptide nanoparticles that only contained RBLC can distinguish tumor tissue from normal tissue by monitoring the acidic extracellular environment.

Folic acid (FA)-targeted indocyanine green (ICG)-loaded nanoparticles (NPs) (FA-INPs) were developed to a near-infrared (NIR) fluorescence theranostic nanoprobe for targeted imaging and photothermal therapy of cancer. The FA-INPs with good monodispersity exhibited excellent size and fluorescence stability, preferable temperature response under laser irradiation, and specific molecular targeting to MCF-7 cells with FA receptor overexpression, compared to free ICG. The FA-INPs enabled NIR fluorescence imaging to in situ monitor the tumor accumulation of the ICG. The cell survival rate assays in vitro and photothermal therapy treatments in vivo indicated that FA-INPs could efficiently targeted and suppressed MCF-7 cells and xenograft tumors. Hence, the FA-INPs are notable theranostic NPs for imaging-guided cancer therapy in clinical application.Keywords: cancer imaging; folic acid; indocyanine green; photothermal therapy; theranostic nanoparticles;

A new FRET model using near-infrared quantum-dots (NIR-QDs) and oxidized carbon nanoparticles (OCNPs) as the energy donor and acceptor was constructed and designed for insulin detection in complex human plasma.

Photodynamic therapy (PDT) has emerged as an effective treatment for tumor with minimal nonspecific damage to adjacent healthy tissues. Herein, redox-responsive self-quenching polysaccharide-based theranostic nanoparticles (DEX-SS-Ce6 NPs) were developed for tumor imaging and photodynamic therapy. The dextran–chlorin e6 conjugates (DEX-SS-Ce6) could self-assemble into nanoparticles with uniform sphere shape in aqueous solution and exhibit cellular redox-responsive “OFF/ON” behavior of a fluorescence signal. In addition, the DEX-SS-Ce6 NPs demonstrated an effective cellular uptake property and high phototoxicity upon near-infrared (NIR) laser irradiation. More importantly, DEX-SS-Ce6 NP treated mice presented enhanced tumor targeting ability and improved photodynamic therapeutic efficiency in an in vivo study, compared with free Ce6 treated mice. These results suggest that the DEX-SS-Ce6 NP is a great potential system for tumor imaging and photodynamic therapy.

Highly pathogenic avian influenza A viruses are emerging pandemic threats in human beings. Monitoring the in vivo dynamics of avian influenza viruses is extremely important for understanding viral pathogenesis and developing antiviral drugs. Although a number of technologies have been applied for tracking viral infection in vivo, most of them are laborious with unsatisfactory detection sensitivity. Herein we labeled avian influenza H5N1 pseudotype virus (H5N1p) with near-infrared (NIR)-emitting QDs by bioorthogonal chemistry. The conjugation of QDs onto H5N1p was highly efficient with superior stability both in vitro and in vivo. Furthermore, QD-labeled H5N1p (QD-H5N1p) demonstrated bright and sustained fluorescent signals in mouse lung tissues, allowing us to visualize respiratory viral infection in a noninvasive and real-time manner. The fluorescence signals of QD-H5N1p in lung were correlated with the severity of virus infection and significantly attenuated by antiviral agents, such as oseltamivir carboxylate and mouse antiserum against H5N1p. The biodistribution of QD-H5N1p in lungs and other organs could be easily quantified by measuring fluorescent signals and cadmium concentration of virus-conjugated QDs in tissues. Hence, virus labeling with NIR QDs provides a simple, reliable, and quantitative strategy for tracking respiratory viral infection and for antiviral drug screening.Keywords: bioorthogonal chemistry; in vivo dynamic imaging; live virus labeling; near-infrared quantum dots; viral infection

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a light-activated local treatment modality that is under intensive preclinical and clinical investigations for cancer. To enhance the treatment efficiency of phototherapy and reduce the light-associated side effects, it is highly desirable to improve drug accumulation and precision guided phototherapy for efficient conversion of the absorbed light energy to reactive oxygen species (ROS) and local hyperthermia. In the present study, a programmed assembly strategy was developed for the preparation of human serum albumin (HSA)-indocyanine green (ICG) nanoparticles (HSA-ICG NPs) by intermolecular disulfide conjugations. This study indicated that HSA-ICG NPs had a high accumulation with tumor-to-normal tissue ratio of 36.12 ± 5.12 at 24 h and a long-term retention with more than 7 days in 4T1 tumor-bearing mice, where the tumor and its margin, normal tissue were clearly identified via ICG-based in vivo near-infrared (NIR) fluorescence and photoacoustic dual-modal imaging and spectrum-resolved technology. Meanwhile, HSA-ICG NPs efficiently induced ROS and local hyperthermia simultaneously for synergetic PDT/PTT treatments under a single NIR laser irradiation. After an intravenous injection of HSA-ICG NPs followed by imaging-guided precision phototherapy (808 nm, 0.8 W/cm2 for 5 min), the tumor was completely suppressed, no tumor recurrence and treatments-induced toxicity were observed. The results suggest that HSA-ICG NPs generated by programmed assembly as smart theranostic nanoplatforms are highly potential for imaging-guided cancer phototherapy with PDT/PTT synergistic effects.Keywords: indocyanine green; photoacoustic imaging; photodynamic therapy; photothermal therapy; synergistic effect; theranostics;

PEGylation has been applied as an effective strategy of surface functionalization to improve the stability and reduce non-specific binding of quantum dots (QDs). However, its effects on the proinflammatory properties of QDs and the underlying mechanism have not been well elucidated yet. Herein, the proinflammatory effects of PEGylated CdSe/ZnS QDs with an amphiphilic polymer coating (PEG-pQDs) were investigated in human pulmonary epithelial cells and macrophages by evaluating the cytokine/chemokine production. The results showed that the proinflammatory effects of PEG-pQDs were strongly associated with the functional groups (–COOH, –NH2, –OH, and –OCH3) at the end of PEG chain. COOH-PEG-pQDs demonstrated the most proinflammatory effects followed by NH2-PEG-pQDs and HO-PEG-pQDs with CH3O-PEG-pQDs exhibiting the least proinflammatory effects. The proinflammatory effects of PEG-pQDs relied on lipid raft- and class A scavenger receptor (SRA)-dependent endocytic pathways as well as the downstream NF-κB and MAPK signaling cascades. COOH-PEG-pQDs were selectively internalized by lipid raft- and SRA-mediated endocytosis, which consequently activated NF-κB signaling pathway. On the other hand, NH2-PEG-pQDs and HO-PEG-pQDs were mostly internalized via lipid raft-mediated endocytosis, thereby activating p38 MAPK/AP-1 signaling cascades. These data revealed a critical role of terminal functional group-associated endocytic pathways in the proinflammatory responses induced by PEGylated QDs in human pulmonary epithelial cells and macrophages.

Multimodal imaging is highly desirable for accurate diagnosis because it can provide complementary information from each imaging modality. In this study, we prepared hybrid gold–gadolinium nanoclusters (NCs), which are ultrasmall, stable, biocompatible, and suitable for triple-modal NIRF/CT/MRI imaging. Upon intravenously injected, the hybrid NCs are effectively accumulated in tumor tissues and quickly clear by renal excretion, indicating their capacity of tumor targeting and low body residues. Notably, the ultrasmall hybrid NCs would penetrate into the solid tumor for capturing its heterostructure and do not induce potential toxicity in vivo. Hence, the well-defined hybrid gold–gadolinium NCs provide a versatile nanoprobe for cancer targeted imaging and diagnosis in vivo.

Indocyanine green (ICG) nanoparticles were developed via electrostatic interactions of ICG and dextran based block copolymers (PEG–dextran(–SS–NH2)) as near-infrared (NIR) theranostic nanoparticles. The nanoparticles could be activated from “OFF” to “ON” of NIR fluorescence in an intracellular environment and used for NIR imaging and photothermal therapy.

We developed a facile one-step method to produce ready-to-use quantum dots based on a peptide sequence containing a hexahistidine(his6-tag), poly(ethylene glycol) (PEG), and a functional group, which lead to stable and customized peptide–QDs conjugates that could serve as fluorescent nanoprobes for biological imaging and detection.

Modern subunit vaccines with purified or recombinant antigens are important alternatives to the traditional vaccines. However, there remains a big challenge to elicit potent antibody production and CD8 T cell response. Nanoparticle-based antigen delivery systems have emerged as an innovative strategy to improve the efficacy of subunit vaccines. The present study reported self-assembled cationic micelles based on poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-leucine) (PEG-PLL-PLLeu) hybrid polypeptides as a simple and potent vaccine delivery system. The results showed that the PEG-PLL-PLLeu micelles spontaneously encapsulated OVA antigens with great loading capacity (LC = 55%) and stability. More importantly, the polypeptide micelle formulations robustly enhanced vaccine-induced antibody production by 70–90 fold, which could be due to their capability of inducing dendritic cell maturation, enhancing antigen uptake and presentation, as well as promoting germinal center formation. Furthermore, the polypeptide micelles could simultaneously encapsulate OVA and polyriboinosinic: polyribocytidylic acid (PIC), a TLR3 agonist, to synergistically augment tumor specific cytotoxic-T-lymphocyte (CTL) response. Hence, the polypeptide micelle-based antigen delivery system could be a robust adjuvant to enhance vaccine-induced immune responses.Polypeptide micelle-based vaccine delivery system could not only promote antibody responses, but also co-encapsulate antigens (e.g. OVA) and immunopotentiators (e.g. PIC), thereby synergistically augmenting CD8 T cell-mediated tumor cell lysis.

Although polysaccharide nanogels have emerged as a novel antigen delivery system for vaccine development, whether modulating the redox sensitivity of nanogels could improve vaccine efficacy remains unclear. In the present study, we generated bioreducible cationic alginate-polyethylenimine (PEI) nanogels as a novel vaccine delivery system. Briefly, nanogels were prepared by the electrostatic interaction of negatively charged alginate sodium with branched PEI2k, followed by disulfide cross-linking to generate bioreducible nanogels (AP-SS). The AP-SS nanogels demonstrated great antigen-loading capacity and minimal cytotoxicity. The in vitro study showed that reducible AP-SS nanogels not only facilitated antigen uptake by mouse bone marrow dendritic cells (BMDCs), but also promoted intracellular antigen degradation and cytosolic release. Moreover, AP-SS nanogels significantly enhanced both MHC class I and II antigen presentation by BMDCs. Compared with the non-reducible nanogels, AP-SS nanogels more potently enhanced vaccine-induced antibody production and CD8+ T cell-mediated tumor cell lysis. Hence, the bioreducible alginate-PEI nanogels could serve as a potent adjuvant to improve vaccine-elicited humoral and cellular immune responses.The bioreducible alginate-PEI nanogels not only enhance intracellular antigen degradation and cytosolic release, but also promote antigen presentation to T lymphocytes, thereby augmenting downstream antibody production and cytoxic T-cell responses.

Multidrug resistance (MDR) is one of the critical reasons for the failure of cancer chemotherapy. To overcome MDR, we have developed redox-responsive doxorubicin prodrug (DEX-PEI(-SS-DOX)) micelles based on dextran-poly(ethylene imine) copolymers (DEX-PEI). The DEX-PEI(-SS-DOX) conjugates were conveniently prepared by grafting PEI to dextran, and then the anticancer drug doxorubicin (DOX) was conjugated to DEX-PEI through redox-responsive cleavable disulfide linkers. The amphiphilic DOX prodrug self-assembled into micelles in aqueous solution and the micelles showed an average size of 100–140 nm with a uniform spherical morphology. In vitro drug release studies showed that the prodrug micelles accomplished rapid drug release under reducing conditions. Confocal images revealed that the micelles enhance the cellular accumulation of DOX and achieve endosomal escape in human breast carcinoma multidrug resistant (MCF-7/ADR) cells. The therapeutic efficacy of the self-assembled DOX prodrug micelles against MCF-7/ADR cells in vitro was evaluated through the MTT assay. The results showed that the therapeutic efficacy of DOX prodrug micelles against MCF-7/ADR cells was remarkably enhanced compared with free DOX. These results indicate that the redox-responsive DOX prodrug micelles could be a promising delivery system for overcoming MDR.

Nanomedcine holds great potential in cancer therapy due to its flexibility on drug delivery, protection, releasing, and targeting. Epigenetic drugs, such as 2′-deoxy-5-azacytidine (DAC), are able to cause reactive expression of tumor suppressor genes (TSG) in human cancers and, therefore, might be able to enhance the sensitivity of cancer cells to chemotherapy. In this report, we fabricated a lipid–polymer nanoparticle for codelivery of epigenetic drug DAC and traditional chemotherapeutic drug (DOX) to cancer cells and monitored the growth inhibition of the hybrid nanoparticles (NPs) on cancer cells. Our results showed that NPs encapsulating DAC, DOX, or both, could be effectively internalized by cancer cells. More importantly, incorporating DAC into NPs significantly enhanced the sensitivity of cancer cells to DOX by inhibiting cell growth rate and inducing cell apoptosis. Further evidence indicated that DAC encapsulated by NPs was able to rescue the expression of silenced TSG in cancer cells. Overall our work clearly suggested that the resulting lipid–polymer nanoparticle is a potential tool for combining epigenetic therapy and chemotherapy.Keywords: cancer therapy; chemotherapeutic drug; combined therapy; drug delivery; epigenetic drug;

Gadolinium-functionalized CdHgTe–ZnS core–shell quantum dots with ultrasmall particle size and tunable near-infrared emission were synthesized as a dual-modal nanoprobe for in vivo fluorescence and magnetic resonance imaging.

Indocyanine green (ICG) is a near-infrared (NIR) fluorescence dye for extensive applications; however, it is limited for further biological application due to its poor aqueous stability in vitro, concentration-dependent aggregation, rapid elimination from the body, and lack of target specificity. To overcome its limitations, ICG was encapsulated in the core of a polymeric micelle, which self-assembled from amphiphilic PEG-polypeptide hybrid triblock copolymers of poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu), with PLLeu as the hydrophobic core and PEG as the hydrophilic shell. The ICG was associated with the hydrophobic core via hydrophobic interaction and also the hydrophilic heads through electrostatic attractive interaction. Compared with free ICG, PEG-PLL-PLLeu-ICG micelles significantly improved quantum yield and fluorescent stability. The cellular uptake experiments showed that PEG-PLL-PLLeu-ICG micelles have a high cellular uptake rate. And the in vivo experiments revealed the excellent passive tumor targeting ability and long circulation time of PEG-PLL-PLLeu-ICG. The above results indicated the broad prospects of PEG-PLL-PLLeu-ICG application in the fields of tumor diagnosis and imaging. In addition, temperature measurements under NIR laser irradiation and in vitro photothermal ablation studies proved the potential application of PEG-PLL-PLLeu-ICG in tumor photothermal therapy.

Theranostics is a concept that integrated imaging and therapy. As an emerging field, it embraces multiple techniques to arrive at an individualized treatment purpose. Indocyanine green (ICG) is a near infrared dye that has been approved by Food and Drug Administration (FDA) in USA for the use in indicator-dilution studies in humans. ICG nanoparticles (NPs) have attracted much attention for its potential applications in cancer theranostics. This review focuses on the preparation, application of ICG NPs for in vivo imaging (fluorescent imaging and photoacoustic imaging) and therapeutics (photothermal therapy, photodynamic therapy and photoacoustic therapy), and future directions based on recent developments in these areas. It is hoped that this review might provide new impetus to understand ICG NPs for cancer theranostics.

A combination of chemotherapy and photothermal therapy has emerged as a promising strategy for cancer therapy. To ensure the chemotherapeutic drug and photothermal agent could be simultaneously delivered to a tumor region to exert their synergistic effect, a safe and efficient delivery system is highly desirable. Herein, we fabricated doxorubicin (DOX) and indocyanine green (ICG) loaded poly(lactic-co-glycolic acid) (PLGA)–lecithin–polyethylene glycol (PEG) nanoparticles (DINPs) using a single-step sonication method. The DINPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the DINPs showed higher temperature response, faster DOX release under laser irradiation, and longer retention time in tumor. In the meantime, the fluorescence of DOX and ICG in DINPs was also visualized for the process of subcellular location in vitro and metabolic distribution in vivo. In comparison with chemo or photothermal treatment alone, the combined treatment of DINPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive MCF-7 and DOX-resistant MCF-7/ADR cells, and suppressed MCF-7 and MCF-7/ADR tumor growth in vivo. Notably, no tumor recurrence was observed after only a single dose of DINPs with laser irradiation. Hence, the well-defined DINPs exhibited great potential in targeting cancer imaging and chemo-photothermal therapy.Keywords: chemotherapy; doxorubicin; indocyanine green; multidrug resistance; photothermal therapy

We synthesized a new class of mutifunctional multidentate-imidazole polymer ligands by one-step reaction to produce conjugation-ready QDs with great stability and compact size. Furthermore, combined with strain-promoted click chemistry, we developed a general strategy for efficient labeling of living-viruses with QD probes.

This work presents a method to visualize the degradation of exogenous DNA in living cells using a novel type of activatable fluorescence imaging probe. Deoxyribonuclease (DNase)-activatable fluorescence probes (DFProbes) are composed of double strands deoxyribonucleic acid (dsDNA) which is labeled with fluorophore (ROX or Cy3) and quencher on the end of one of its strands, and stained with SYBR Green I. In the absence of DNase, DFProbes produce the green fluorescence signal of SYBR Green I. In the presence of DNase, SYBR Green I is removed from the DFProbes and the labeled fluorophore is separated from the quencher owing to the degradation of DFProbes by DNase, resulting in the decrease of the green fluorescence signal and the occurrence of a red fluorescence signal due to fluorescence resonance energy transfer (FRET). DNase in biological samples was detected using DFProbes and the fluorescence imaging in living cells was performed using DFprobe-modified Au nanoparticles. The results show that DFProbes have good responses to DNase, and can clearly visualize the degradation of exogenous DNA in cells in real time. The well-designed probes might be useful in tracing the dynamic changes of exogenous DNA and nanocarriers in vitro and in vivo.

Fluorescence signal amplification by cation exchange in aptamer-conjugated CdSe nanoclusters, a biological self-assembly of CdSe quantum dots, was developed as a novel method for cancer cell detection.

Developing safe and effective nonviral gene vector is highly crucial for successful gene therapy. In the present study, we designed a series of biodegradable micelles based on hybrid polypeptide copolymers of poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) for efficient gene delivery. A group of amphiphilic PEG-PLL-PLLeu hybrid polypeptide copolymers were synthesized by ring-opening polymerization of N-carboxyanhydride, and the chemical structure of each copolymer was characterized by 1H NMR and FT-IR spectroscopy measurement. The PEG-PLL-PLLeu micelles were positively charged with tunable sizes ranging from 40 to 90 nm depending on the length of PLL and PLLeu segment. Compared with PEG-PLL copolymers, PEG-PLL-PLLeu micelles demonstrated significantly higher transfection efficiency and less cytotoxicity. Furthermore, the transfection efficiency and biocompatibility of the micelles can be simultaneously improved by tuning the length of PLL and PLLeu segments. The transfection efficiency of PEG-PLL-PLLeu micelles in vivo was two to three times higher than that of PEI25k, which was attributable to their capability of promoting DNA condensation and cell internalization as well as successful lysosome escape. Hence well-defined PEG-PLL-PLLeu micelles would serve as highly effective nonviral vectors for in vivo gene delivery.

Cationic liposomes have emerged as a novel adjuvant and antigen delivery system to enhance vaccine efficacy. However, the role of surface charge density in cationic liposome-regulated immune responses has not yet been elucidated. In the present study, we prepared a series of DOTAP/DOPC cationic liposomes with different surface densities by incorporating varying amounts of DOPC (a neutral lipid) into DOTAP (a cationic lipid). The results showed that DOTAP/DOPC cationic liposome-regulated immune responses relied on the surface charge density, and might occur through ROS signaling. The liposomes with a relatively high charge density, such as DOTAP/DOPC 5:0 and 4:1 liposomes, potently enhanced dendritic cell maturation, ROS generaion, antigen uptake, as well as the production of OVA-specific IgG2a and IFN-γ. In contrast, low-charge liposomes, such as DOTAP/DOPC 1:4 liposome, failed to promote immune responses even at high concentrations, confirming that the immunoregulatory effect of cationic liposomes is mostly attributable to their surface charge density. Moreover, the DOTAP/DOPC 1:4 liposome suppressed anti-OVA antibody responses in vivo. Overall, maintaining an appropriate surface charge is crucial for optimizing the adjuvant effect of cationic liposomes and enhancing the efficacy of liposome-based vaccines.

Highly luminescent near-infrared (NIR) emitting CdTe/CdSe quantum dots (QDs) were prepared through a fast and convenient method, and a new type of multivalent polymer ligands was used as the surface substituents to prepare highly stable hydrophilic QDs with small sizes. The well-defined CdTe/CdSe QDs were characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), energy dispersive X-ray (EDX) spectroscopy and photoluminescence (PL) spectroscopy, respectively. The as-prepared CdTe/CdSe QDs were photostable with high PL quantum yields (QYs) (up to 66% at room temperature), low toxicity to cells at experimental dosages, and the QDs' fluorescence emissions were tunable between 700 and 820 nm. Furthermore, fluorescence imaging using CdTe/CdSe QDs conjugated with the AS1411 aptamer (targeting nucleolin) probe in cancer cells was reported, and the CdTe/CdSe QDs were also successfully applied for the fluorescence imaging of living animals. Our preliminary results illustrated that the CdTe/CdSe NIR-QDs with small sizes would be an alternative probe for ultrasensitive, multicolor, and multiplex applications, especially for in vivo imaging applications.

Porous silicon microcavities (PSM) optical crystals consisting of a Fabry-Perot microcavity embedded between two distributed Bragg reflectors have been fabricated by electrochemical etching. Scanning electron microscopy (SEM) clearly depicted their physical sandwich construction. The optical feature of the PSM structure was tuned by varying the anodization parameters. Through proper thermal oxidation and surface chemical modifications, the resulting structures were employed as optical sensors for the detection of environmental pollutants including volatile organic vapors (i.e. acetonitrile, toluene, cyclohexane, chloroform, acetone and ethanol) and interior decoration gases (i.e. toluene, ammonia and formaldehyde). Fourier transform infrared spectroscopy (FTIR) spectra confirmed the effective thermal annealing and surface modification chemistry, and the sensing process was accompanied by recording the modified structures’ optical responses when exposed to target analytes. The PSM optical sensors showed good stability, sensitivity and selectivity, implying promising applications in gas sensing and environmental monitoring.

In this paper, we report a new homogeneous assay for rapid, highly selective and sensitive detection of Hg2+ in aqueous solution based on the induced photoluminescence (PL) quenching of BSA-modified gold nanoclusters (BSA-Au NCs). There was a linear correlation between the expression (I0 − I)/I0 and the concentrations of Hg2+ over the ranges of 0.4–43.2 μM, and the corresponding limit of detection (LOD) was 80 nM. The relative standard deviation of 5 replicate measurements was 1.4% for 1.0 × 10−5 mol L−1 Hg2+. Moreover, this method has excellent selectivity over metal ions and anions. The feasibility of the BSA-Au NCs sensor for Hg2+ in different aqueous samples was demonstrated with satisfactory results. Moreover, the possible sensing Hg2+ mechanism was also discussed.

Photodynamic therapy (PDT) is a noninvasive and effective approach for cancer treatment. The main bottlenecks of clinical PDT are poor selectivity of photosensitizer and inadequate oxygen supply resulting in serious side effects and low therapeutic efficiency. Herein, a thermal-modulated reactive oxygen species (ROS) strategy using activatable human serum albumin-chlorin e6 nanoassemblies (HSA-Ce6 NAs) for promoting PDT against cancer is developed. Through intermolecular disulfide bond crosslinking and hydrophobic interaction, Ce6 photosensitizer is effectively loaded into the HSA NAs, and the obtained HSA-Ce6 NAs exhibit excellent reduction response, as well as enhanced tumor accumulation and retention. By the precision control of the overall body temperature instead of local tumor temperature increasing from 37 °C to 43 °C, the photosensitization reaction rate of HSA-Ce6 NAs increases 20%, and the oxygen saturation of tumor tissue raise 52%, significantly enhancing the generation of ROS for promoting PDT. Meanwhile, the intrinsic fluorescence and photoacoustic properties, and the chelating characteristic of porphyrin ring can endow the HSA-Ce6 NAs with fluorescence, photoacoustic and magnetic resonance triple-modal imaging functions. Upon irradiation of low-energy near-infrared laser, the tumors are completely suppressed without tumor recurrence and therapy-induced side effects. The robust thermal-modulated ROS strategy combined with albumin-based activatable nanophotosensitizer is highly potential for multi-modal imaging-guided PDT and clinical translation.

Targeted phototherapy and multi-modal imaging can effectively improve the therapeutic efficacy and reduce the side effects of theranostics. Herein, we constructed novel biocompatible cyanine dye IR808-conjugated hyaluronic acid nanoparticles (HAIR NPs) for photothermal therapy (PTT) with near-infrared fluorescence (FL) and photoacoustic (PA) dual-modal imaging. The nanoparticles formed stable nanostructures under aqueous conditions with uniform size distribution. The HAIR NPs were rapidly taken up by the human lung cancer cells A549 via CD44 (the hyaluronic acid receptor on the surface of tumor cells) receptor-mediated endocytosis. Upon laser irradiation, the HAIR NPs enabled good near-infrared fluorescence imaging and photoacoustic imaging in tumor-bearing mice. In addition, the tight nanostructure arising from the covalent link between HA and IR808 could significantly improve the light-thermal conversion efficiency of IR808. Under a low dose of laser power, the HAIR NPs presented more effective photothermal therapy for the suppression of tumor growth than free IR808 in vitro and in vivo. Overall, these results indicate that the HAIR NPs may be an extremely promising nanoplatform in cancer theranostics for targeted PTT under FL and PA dual-modal imaging.

Photodynamic therapy (PDT) is a site-specific treatment of cancer using much lower optical power densities with minimal nonspecific damage to normal tissues. To improve the therapeutic efficiency of PDT, we fabricated a multifunctional theranostic nanoparticle system (DSSCe6@Fe3O4 NPs) by loading Fe3O4 nanoparticles in redox-responsive chlorin e6 (Ce6)-conjugated dextran nanoparticles for near-infrared (NIR)/magnetic resonance (MR) dual-modality imaging and magnetic targeting. The obtained DSSCe6@Fe3O4 NPs demonstrated a uniform nanospherical morphology consisting of Fe3O4 clusters. The fluorescence signal of Ce6 of this theranostic system could turn “ON” from a self-quenching state in a reductive intracellular environment. T2-Weighted MR imaging revealed a high transverse relaxivity (r2) measured to be 194.4 S−1 mM−1, confirming that it was also a distinctive contrast agent in T2-weighted MR imaging. Confocal images and flow cytometry results showed that the cellular uptake of DSSCe6@Fe3O4 NPs was enhanced effectively under an extra magnetic field, which resulted in promoted PDT therapeutic efficiency. In vivo MR imaging showed that DSSCe6@Fe3O4 NPs effectively accumulated in tumors under an extra magnetic field. These results illustrated that the DSSCe6@Fe3O4 NPs could be a promising theranostic system for both NIR/MR imaging-guided PDT precision therapy.

A new FRET model using near-infrared quantum-dots (NIR-QDs) and oxidized carbon nanoparticles (OCNPs) as the energy donor and acceptor was constructed and designed for insulin detection in complex human plasma.

Indocyanine green (ICG) nanoparticles were developed via electrostatic interactions of ICG and dextran based block copolymers (PEG–dextran(–SS–NH2)) as near-infrared (NIR) theranostic nanoparticles. The nanoparticles could be activated from “OFF” to “ON” of NIR fluorescence in an intracellular environment and used for NIR imaging and photothermal therapy.

Fluorescence signal amplification by cation exchange in aptamer-conjugated CdSe nanoclusters, a biological self-assembly of CdSe quantum dots, was developed as a novel method for cancer cell detection.

We have developed a microwave assisted one-pot approach to fabricate a novel hybrid nano-composite composed of two-dimensional chemically exfoliated layered hexagonal boron nitride (h-BN) and embedded silver nanoparticles (SNP). Atomic layered h-BN exfoliated using chemical liquid showed strong in-plane bonding and weak van der Waals interplanar interactions, which is utilized for chemically interfacing SNP, indicating their ability to act as excellent nano-scaffolds. The SNP/h-BN optical response, in particular band gap, is strongly dependent on the concentration of the metallic particles. In order to gain further insight into this behavior we have also carried out ab initio density functional theory (DFT) calculations on modeled structures, demonstrating that the bandgap value of SNP/h-BN hybrids could be significantly altered by a small percentage of OH− groups located at dangling B and N atoms. Our results showed that these novel SNP/h-BN nanohybrid structures exhibited excellent thermal stability and they are expected to be applied as devices for thermal oxidation-resistant surface enhanced Raman spectroscopy (SERS). The SNP/h-BN membrane showed remarkable antibacterial activity, suggesting their potential use in water disinfection and food packaging.

We developed a facile one-step method to produce ready-to-use quantum dots based on a peptide sequence containing a hexahistidine(his6-tag), poly(ethylene glycol) (PEG), and a functional group, which lead to stable and customized peptide–QDs conjugates that could serve as fluorescent nanoprobes for biological imaging and detection.

pH-responsive doped quantum dots with an ultrasmall size (∼3.5 nm), near-infrared emission (∼720 nm) and long lifetime (∼1 μs), which exhibit a linear response range from pH 5.5 to 7.0 with the maximum change in the fluorescence lifetime up to ∼600 nm, were synthesized as lifetime-based pH nanosensors for in vivo imaging.