Fengping Tan

Photosensitizer-Loaded pH-Responsive Hollow Gold Nanospheres for Single Light-Induced Photothermal/Photodynamic Therapy.

Novel photoinduced triple-response antitumor therapeutic system based on hollow gold nanospheres (HAuNS), pH (low) insertion peptide (pHLIP), and Chlorin e6 (Ce6), was reported for the first time. The system was able to intracellularly deliver the nanocarriers by the transmembrane ability of pHLIP at the condition of pH 6.2. Ce6 and pHLIP were then released from the surface of the carriers due to the weakening electrostatic interaction with HAuNS under the photoirradiation. Herein, HAuNS performed two different functions: (1) as a nanocarrier because of the excellent loading capability; (2) experienced the photothermal therapy (PTT) effect as a photothermal coupling agent (PTCA), thus enhancing the photodynamic therapy (PDT) effect of Ce6.

Smart IR780 Theranostic Nanocarrier for Tumor-Specific Therapy: Hyperthermia-Mediated Bubble-Generating and Folate-Targeted Liposomes

The therapeutic effectiveness of chemotherapy was hampered by dose-limiting toxicity and was optimal only when tumor cells were subjected to a maximum drug exposure. The purpose of this work was to design a dual-functional thermosensitive bubble-generating liposome (BTSL) combined with conjugated targeted ligand (folate, FA) and photothermal agent (IR780), to realize enhanced therapeutic and diagnostic functions. This drug carrier was proposed to target tumor cells owing to FA-specific binding, followed by triggering drug release due to the decomposition of encapsulated ammonium bicarbonate (NH4HCO3) (generated CO2 bubbles) by being subjected to near-infrared (near-IR) laser irradiation, creating permeable defects in the lipid bilayer that rapidly release drug. In vitro temperature-triggered release study indicated the BTSL system was sensitive to heat triggering, resulting in rapid drug release under hyperthermia. For in vitro cellular uptake experiments, different results were observed on human epidermoid carcinoma cells (KB cells) and human lung cancer cells (A549 cells) due to their different (positive or negative) response to FA receptor. Furthermore, in vivo biodistribution analysis and antitumor study indicated IR780-BTSL-FA could specifically target KB tumor cells, exhibiting longer circulation time than free drug. In the pharmacodynamics experiments, IR780-BTSL-FA efficiently inhibited tumor growth in nude mice with no evident side effect to normal tissues and organs. Results of this study demonstrated that the constructed smart theranostic nanocarrier IR780-BTSL-FA might contribute to establishment of tumor-selective and effective chemotherapy.

MoS2 Quantum Dot@Polyaniline Inorganic–Organic Nanohybrids for in Vivo Dual-Modal Imaging Guided Synergistic Photothermal/Radiation Therapy

In this study, we introduce a versatile nanomaterial based on MoS2 quantum dot@polyaniline (MoS2@PANI) inorganic-organic nanohybrids, which exhibit good potential to not only enhance photoaccoustic (PA) imaging/X-ray computed tomography (CT) signal but also perform efficient radiotherapy (RT)/photothermal therapy (PTT) of cancer. Upon the intravenous injection of MoS2@PANI hybrid nanoparticles, the in vivo tumor could be precisely positioned and thoroughly eliminated under the PA/CT image-guided combination therapy of PTT/RT. This versatile nanohybrid could show good potential to facilitate simultaneously dual-modal imaging and synergetic PTT/RT to realize better anticancer efficiency.

Dual-targeting nanocarrier system based on thermosensitive liposomes and gold nanorods for cancer thermo-chemotherapy.

The primary challenge of cancer therapy was the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious systemic side effects. We designed a tumor-targeting accumulated and locally triggered-release nanocarrier system to increase the intratumoral drug concentration and thus the efficacy of chemotherapy, based on gold nanorods (GNRs) and thermosensitive liposomes (TSLs). PEGylated GNRs could not only make nanocarriers to co-accumulate in tumors depending on enhanced permeability and retention (EPR) effect, but also generated heat locally under near-infrared (NIR) stimulation. CO2 bubbles were generated by the encapsulated ammonium bicarbonate (ABC) under hyperthermia, thus the co-encapsulated drug was released and local drug concentration was increased along with the disintegration of liposomal membrane. On the other hand, this dual-targeting system prevented the drug leakage in blood circulation or other organs while facilitated most of the active agents delivered to tumors. In vitro and in vivo experiments revealed high cytotoxicity and good affinity of HTSL to MDA-MB-435 cells when used synergistically with GNRs, but low toxicity to normal cells at the same condition. When combined with thermotherapy, the smart nanocarrier system held significant promise for future cancer treatment for their markedly improved therapeutic efficacy and decreased systemic toxicity.

Rapamycin/DiR Loaded Lipid-Polyaniline Nanoparticles for Dual-Modal Imaging Guided Enhanced Photothermal and Antiangiogenic Combination Therapy

Imaging-guided photothermal therapy (PTT) has promising application for treating tumors. Nevertheless, so far imaging-guided photothermal drug-delivery systems have been developed with limited success for tumor chemo-photothermal therapy. In this study, as the proof-of-concept, a stimuli-responsive tumor-targeting rapamycin/DiR loaded lipid-polyaniline nanoparticle (RDLPNP) for dual-modal imaging-guided enhanced PTT efficacy is reported for the first time. In this system, polyaniline (PANI) with π-π electronic conjugated system and effective photothermal efficiency is chosen as the appropriate model receptor of fluorescence resonance energy transfer (FRET), and loaded cyanine probe (e.g., 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide, DiR) acts as the donor of near-infrared fluorescence (NIRF). In addition, rapamycin (RAPA), which is used as the antiangiogenesis chemotherapeutic drug, can cutdown the tumor vessels and delay tumor growth obviously. After intravenous treatment of RDLPNPs into Hela tumor bearing mice, fluorescent (from DiR) and enhanced photoacoustic (from DLPNPs) signals were found in tumor site over time, which reached to peak at the 6h time point. After irradiating with an NIR laser, a good anti-tumor effect was observed owing to the enhanced photothermal and antiangiogenic effect of RDLPNPs. These results show that the multifunctional nanoparticle can be used as a promising imaging-guided photothermal drug delivery nanoplatform for cancer therapy.

Indocyanine Green-Loaded Silver Nanoparticle@Polyaniline Core/Shell Theranostic Nanocomposites for Photoacoustic/Near-Infrared Fluorescence Imaging-Guided and Single-Light-Triggered Photothermal and Photodynamic Therapy

Photoacoustic (PA)/near-infrared fluorescence (NIRF) dual-modal imaging-guided phototherapy has been wide explored very recently. However, the development of high-efficiency and simplified-performed theranostic system for amplifying imaging-guided photothermal therapy/photodynamic therapy (PTT/PDT) is still a great challenge. Herein, a single-light-triggered indocyanine green (ICG)-loaded PEGylation silver nanoparticle core/polyaniline shell (Ag@PANI) nanocomposites (ICG-Ag@PANI) for PA/NIRF imaging-guided enhanced PTT/PDT synergistic effect has been successfully constructed. In this study, the synthesized Ag@PANI nanocomposites are utilized not only as the promising photothermal agent but also as potential nanovehicles for loading photosensitizer ICG via π-π stacking and hydrophobic interaction. The as-prepared ICG-Ag@PANI possesses many superior properties such as strong optical absorption in the near-infrared (NIR) region, enhanced photostability of ICG, as well as outstanding NIR laser-induced local hyperthermia and reactive oxygen species (ROS) generation. In the in vivo study, PA/NIRF dual-modal imaging confirms the accumulation and distribution of ICG-Ag@PANI in the tumor region via enhanced permeability and retention (EPR) effect. Moreover, the PTT effect of ICG-Ag@PANI rapidly raised the tumor temperature to 56.8 °C within 5 min. It is also demonstrated that the cytotoxic ROS generation ability of ICG is well maintained after being loaded onto Ag@PANI nanocomposites. Remarkably, in comparison with PTT or PDT alone, the single 808 nm NIR laser-triggered combined PTT/PDT therapy exhibits enhanced HeLa cells lethality in vitro and tumor growth inhibition in vivo.

An efficient dual-loaded multifunctional nanocarrier for combined photothermal and photodynamic therapy based on copper sulfide and chlorin e6.

The therapeutic effectiveness of photodynamic therapy (PDT) was hampered by the poor water solubility and instability in physiological conditions of the photosensitizers. Here, we designed folate conjugated thermosensitive liposomes (TSL) as the nanocarrier to improve the solubility, stability and biocompatibility of photosensitizer Chlorin e6 (Ce6). Based on the photothermal effect, we combined copper sulfide (CuS) as the photothermal agent to realize heat-triggered Ce6 release as well as synergistic effect of photothermal and photodynamic therapy. In vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that Ce6-CuS-TSL had low dark toxicity, while performed excellent phototoxicity under the combined 660 and 808 nm laser irradiation compared to any single laser irradiation alone. Moreover, in vivo combination therapy study revealed that Ce6-CuS-TSL inhibited tumor growth to a great extent without evident side effect under the laser irradiation. All detailed evidence demonstrated a considerable potential of Ce6-CuS-TSL for synergistic cancer treatment.

Dual-Modal Imaging-Guided Theranostic Nanocarriers Based on Indocyanine Green and mTOR Inhibitor Rapamycin.

The development of treatment protocols that resulted in a complete response to photothermal therapy (PTT) was usually hampered by uneven heat distribution and low effectiveness. Here, we reported an NIR fluorescence and photoacoustic dual-modal imaging-guided active targeted thermal sensitive liposomes (TSLs) based on the photothermal therapy agent Indocyanine green (ICG) and antiangiogenesis agent Rapamycin (RAPA) to realize enhanced therapeutic and diagnostic functions. As expected, the in vitro drug release studies exhibited the satisfactory result of drug released from the TSLs under hyperthermia conditions induced by NIR stimulation. The in vitro cellular studies confirmed that the FA-ICG/RAPA-TSLs plus NIR laser exhibited efficient drug accumulation and cytotoxicity in tumor cells and epithelial cells. After 24 h intravenous injection of FA-ICG/RAPA-TSLs, the margins of tumor and normal tissue were accurately identified via the in vivo NIR fluorescence and photoacoustic dual-modal imaging. In addition, FA-ICG/RAPA-TSLs combined with NIR irradiation treated tumor-bearing nude mice inhibited tumor growth to a great extent and possessed much lower side effects to normal organs. All detailed evidence suggested that the theranostic TSLs which were capable of enhancing the therapeutic index might be a suitable drug delivery system for dual-modal imaging-guided therapeutic tools for diagnostics as well as the treatment of tumors.

Photosensitizer loaded PEG-MoS2–Au hybrids for CT/NIRF imaging-guided stepwise photothermal and photodynamic therapy

In this study, we developed X-ray computed tomography (CT)/near-infrared fluorescence (NIRF) imaging for visually guiding the photothermal therapy (PTT)/photodynamic therapy (PDT) of antitumor nanocomposites (PEG-MoS2-Au-Ce6), by adsorbing chlorin e6 (Ce6) to the gold nanoparticle (AuNPs)-decorated molybdenum disulfide (PEG-MoS2) nanosheets. The NIR photosensitizer Ce6 was adsorbed onto the PEG-MoS2-Au hybrids viaπ-π stacking and hydrophobic interactions, where Ce6 remained in its quenched state due to the surface plasmon resonance (SPR) capacity of AuNPs, as well as the coupling interaction with PEG-MoS2 nanosheets. However, Ce6 was dequenched and boosted strong NIR fluorescence signals after being released from the surface of PEG-MoS2-Au hybrids upon heat generation, thus producing the PDT effect for anti-tumor therapy. Moreover, the PEG-MoS2 nanosheets and Ce6 in the PEG-MoS2-Au-Ce6 nanocomposites could be further used for CT and NIRF dual-modal imaging, respectively. In vitro NIR-triggered drug release studies indicated that the PEG-MoS2-Au-Ce6 nanocomposites rapidly release the drug around the tumor site under the photothermal effect. Therefore, this dual-modality nanosystem simultaneously enables precise cancer diagnosis and therapy.

In vitro/in vivo characterization of nanoemulsion formulation of metronidazole with improved skin targeting and anti-rosacea properties

Topical skin treatment was limited due to the lack of suitable delivery system with significant cutaneous localization and systemic safety. The aim of this study was to develop and optimize a nanoemulsion (NE) to enhance targeting localization of metronidazole (MTZ) in skin layers. In vitro studies were used to optimize NE formulations, and a series of experiments were carried in vitro and in vivo to validate the therapeutic efficacy of MTZ-loaded optimal NE. NE type selection and D-optimal design study were applied to optimize NE formulation with maximum skin retention and minimum skin penetration. Three formulation variables: Oil X1 (Labrafil), Smix X2 (a mixture of Cremophor EL/Tetraethylene glycol, 2:1 w/w) and water X3 were included in D-design. The system was assessed for skin retention Y1, cumulative MTZ amount after 24 h Y2 and droplet size Y3. Following optimization, the values of formulation components (X1, X2 and X3) were 4.13%, 16.42% and 79.45%, respectively. The optimized NE was assessed for viscosity, droplet size, morphological study and in vitro permeation in pig skin. Distributions of MTZ were validated by confocal laser scanning microscopy (CLSM). Active agent of NE transferred into deeper skin and localized in epidermal/dermal layers after 24 h, which showed significant advantages of the optimal NE over Gel. The skin targeting localization and minimal systemic escape of optimal NE was further proved by in vivo study on rat skin. Current in vitro-in vivo correlation (IVIVC) enabled the prediction of pharmacokinetic profile of MTZ from in vitro permeation results. Further, the in vivo anti-rosacea efficacy of optimal formulation was investigated by pharmacodynamics study on mice ear.