Erratum: Nanosonosensitizers for Highly Efficient Sonodynamic Cancer Theranostics: Erratum.

[This corrects the article DOI: 10.7150/thno.29569.].

Novel Multifunctional Nanoagent for Visual Chemo/Photothermal Therapy of Metastatic Lymph Nodes via Lymphatic Delivery.

Breast cancer is one of the major diseases that threaten women's health. Lymph node (LN) metastasis is the most common metastatic path of breast cancer. Finding a simple, effective, and safe strategy to eliminate metastatic tumors in LNs is highly desired for clinical use. Carbon nanoparticles (CNs), as an LN tracer, have been widely used in the clinical setting. In addition, previous experiments have confirmed that CNs have good photoacoustic imaging and photothermal effects. In this study, we used CNs as a photothermal conversion material and drug carrier, poly(lactic-co-glycolic acid) (PLGA) as a film-forming material, and docetaxel as a chemotherapy drug to prepare multifunctional nanoparticles (DOC-CNPs). The prepared DOC-CNPs present as a black solution, which shows smooth spherical particles under light microscopy and transmission electron microscopy (TEM), and they have a good ability for liquid-gas phase transition, good dispersibility, high drug-loading capacity, and low cytotoxicity. In vitro, they can release drugs and inhibit tumor cells after laser irradiation. The photoacoustic (PA) signal intensity and the photothermal conversion efficiency increased with an increase in the concentration of DOC-CNPs. In vivo, after administration, the DOC-CNPs reached the LNs. After laser irradiation, the DOC-CNPs absorbed laser energy, and the temperature of the LNs increased high enough to achieve photothermal therapy under PA and ultrasound monitoring. Fracture of the DOC-CNPs was caused by the liquid-gas phase transition with the increased temperature, and the ruptured DOC-CNPs released docetaxel to achieve targeted chemotherapy. These findings suggested that DOC-CNPs can achieve precise treatment for metastatic LNs of breast cancer with PA and ultrasound visualization.

Cell penetrating peptide-modified nanoparticles for tumor targeted imaging and synergistic effect of sonodynamic/HIFU therapy.

BACKGROUND: Theranostics based on multifunctional nanoparticles (NPs) is a promising field that combines therapeutic and diagnostic functionalities into a single nanoparticle system. However, the major challenges that lie ahead are how to achieve accurate early diagnosis and how to develop efficient and noninvasive treatment. Sonodynamic therapy (SDT) utilizing ultrasound combined with a sonosensitizer represents a novel noninvasive modality for cancer therapy. Different ultrasound frequencies have been used for SDT, nevertheless, whether the effect of SDT can enhance synergistic HIFU ablation remains to be investigated. MATERIALS AND METHODS: We prepared a nanosystem for codelivery of a sonosensitizer (methylene blue, MB) and a magnetic resonance contrast agent (gadodiamide, Gd-DTPA-BMA) based on hydrophilic biodegradable polymeric NPs composed of poly (lactic-co-glycolic acid) (PLGA). To enhance accumulation and penetration of the NPs at the tumor site, the surface of PLGA NPs was decorated with a tumor-homing and penetrating peptide-F3 and polyethylene glycol (PEG). The physicochemical, imaging and therapeutic properties of F3-PLGA@MB/Gd and drug safety were thoroughly evaluated both in vitro and in vivo. F3-PLGA@MB/Gd was evaluated by both photoacoustic and resonance imaging. RESULTS: F3-PLGA@MB/Gd NPs exhibited higher cellular association than non-targeted NPs and showed a more preferential enrichment at the tumor site. Furthermore, with good drug safety, the apoptosis triggered by ultrasound in the F3-PLGA@MB/Gd group was greater than that in the contrast group. CONCLUSION: F3-PLGA@MB/Gd can work as a highly efficient theranostic agent, and the incorporation of targeted multimodal and combined therapy could be an encouraging strategy for cancer treatment.

Melanin-loaded biocompatible photosensitive nanoparticles for controlled drug release in combined photothermal-chemotherapy guided by photoacoustic/ultrasound dual-modality imaging.

Combined photothermal-chemotherapy guided by multimodal imaging is a promising strategy for cancer diagnosis and treatment. Multifunctional nanoparticles, such as those comprising organic and inorganic compounds, have been extensively investigated for combined photothermal-chemotherapy; however, their application is still limited by their potential long-term toxicity and lack of contrast properties. To solve these problems, in this study, a new type of multifunctional nanoparticle for combined photothermal-chemotherapy guided by dual-modality imaging was prepared with endogenous melanin by multistep emulsification to enhance tumor ablation. The nanoparticles were coated with poly(lactide-co-glycolic acid) (PLGA) and loaded with paclitaxel (PTX), encapsulated melanin and perfluoropentane (PFP). The materials in the nanoparticles were endogenous, ensuring high stability, biocompatibility, and biosafety. Nanoparticles irradiated with a laser, which induced their phase transformation into microbubbles, exhibited high photothermal conversion efficiency, thereby achieving photoacoustic (PA)/ultrasound (US) dual-modality imaging to determine tumor location, boundary, and size and to monitor drug distribution. Furthermore, optical droplet vaporization (ODV) of the nanoparticles could trigger the release of PTX; thus, these nanoparticles are a useful drug carrier. In vivo and in vitro experiments revealed that a strong synergistic antitumor effect was achieved by combining the photothermal properties of the nanoparticles with a chemotherapy drug. Importantly, the cavitation, thermoelastic expansion, and sonoporation caused by the phase transformation of the nanoparticles could directly damage the tumors. These processes also promoted the release, penetration and absorption of the drug, further enhancing the effect of combined photothermal-chemotherapy on tumor suppression. Therefore, the multifunctional nanoparticles prepared in this study provide a new strategy of using endogenous materials for controlled near-infrared (NIR)-responsive drug release and combined photothermal-chemotherapy guided by multimodal imaging.

PEG-coated and Gd-loaded fluorescent silica nanoparticles for targeted prostate cancer magnetic resonance imaging and fluorescence imaging.

Background: Multimodal imaging probes have become a powerful tool for improving detection sensitivity and accuracy, which are important in disease diagnosis and treatment. Methods: In this study, novel bifunctional magnetic resonance imaging (MRI)/fluorescence probes were prepared by loading gadodiamide into fluorescent silica nanoparticles (NPs) (Gd@Cy5.5@SiO2-PEG-Ab NPs) for targeting of prostate cancer (PCa). The physicochemical characteristics, biosafety and PCa cell targeting ability of the Gd@Cy5.5@SiO2-PEG-Ab NPs were studied in vitro and in vivo. Results: The Gd@Cy5.5@SiO2-PEG-Ab NPs had a spherical morphology with a relatively uniform size distribution and demonstrated high efficiency for Gd loading. In vitro and in vivo cell-targeting experiments demonstrated a high potential for the synthesized NPs to target prostate-specific membrane antigen (PSMA) receptor-positive PCa cells, enabling MRI and fluorescence imaging. In vitro cytotoxicity assays and in vivo hematological and pathological assays showed that the prepared NPs exhibited good biological safety. Conclusion: Our study demonstrates that the synthesized Gd@Cy5.5@SiO2-PEG-Ab NPs have great potential as MRI/fluorescence contrast agents for specific identification of PSMA receptor-positive PCa cells.

Magnetic-responsive and targeted cancer nanotheranostics by PA/MR bimodal imaging-guided photothermally triggered immunotherapy.

While theranostic nanoparticle (TNP)-based photothermal therapy (PTT) exhibits prominent promise for cancer therapy, metastatic cancers remain one of the main obstacles of effective PTT. Immunotherapy has been developed vigorously to inhibit metastatic cancers, but the heterogeneity of patients and the complexities of manufacturing cancer vaccines significantly hinder its further clinical applications. Herein, a photothermally triggered immunotherapeutic paradigm under imaging guidance was designed based on magnetic-responsive immunostimulatory nanoagents (MINPs) loaded with superparamagnetic iron oxide (SPIO) nanoparticles and cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). The fabricated MINPs with the clinically approved components acted not only as a contrast agent for photoacoustic (PA)/magnetic resonance (MR) bimodal imaging but also as a magnetic-targeting therapeutic agent for photothermally triggered immunotherapy. Under external magnetic fields, the MINPs showed a great magnetic-targeting ability, leading to high accumulation of the photoabsorber (SPIO) and the immunoadjuvant (CpG ODNs) in the tumors for precise bimodal imaging guidance. More importantly, the excellent photothermal conversion effect of the MINPs upon near-infrared (NIR) exposure enabled the effective photothermal destruction of the primary tumors, releasing tumor-associated antigens and showing 'autologous cancer vaccine'-like functions, thus activating robust antitumor immune responses, especially in the presence of CpG ODN-containing immunostimulatory nanoagents. Such generated immune responses can further attack the remaining tumors and distant metastatic tumors in mice. This work provides an imaging-guided photothermally triggered immunotherapeutic strategy based on multifunctional MINPs to effectively eliminate primary tumors and inhibit metastatic tumors simultaneously with high specificity, easy maneuverability and favorable biocompatibility. This strategy may potentially be applicable for precise individualized diagnosis and therapy of various tumors.

Silk Fibroin-Coated Nanoagents for Acidic Lysosome Targeting by a Functional Preservation Strategy in Cancer Chemotherapy.

Background: Premature drug leakage and inefficient cellular uptake are stand out as considerable hurdles for low drug delivery efficiency in tumor chemotherapy. Thus, we established a novel drug delivery and transportation strategy mediated by biocompatible silk fibroin (SF)-coated nanoparticles to overcome these therapeutic hurdles. Methods: we first synthesised a TME-responsive biocompatible nanoplatform constructed of amorphous calcium carbonate (ACC) cores and SF shells for enhanced chemotherapy by concurrently inhibiting premature drug release, achieving lysosome-targeted explosion and locally sprayed DOX, and monitoring via PAI, which was verified both in vitro and in vivo. Results: The natural SF polymer first served as a "gatekeeper" to inhibit a drug from prematurely leaking into the circulation was demonstrated both in vitro and in vivo. Upon encountering TMEs and targeting to the acidic pH environments of lysosomes, the sensitive ACC nanoparticles were gradually degraded, eventually generating a large amount of Ca2+ and CO2, resulting in lysosomal collapse, thus preventing both the efflux of DOX from cancer cells and the protonation of DOX within the lysosome, releasing multiple hydrolytic enzyme to cytoplasm, exhibiting the optimal therapeutic dose and remarkable synergetic therapeutic performance. In particular, CO2 gas generated by the pH response of ACC nanocarriers demonstrated their imaging capability for PAI, providing the potential for quantifying and guiding drug release in targets. Conclusion: In this work, we constructed TME-responsive biocompatible NPs by coating DOX-preloaded ACC-DOX clusters with SF via a bioinspired mineralization method for efficient therapeutics. This functional lysosome-targeted preservation-strategy-based therapeutic system could provid novel insights into cancer chemotherapy.

A light-controllable specific drug delivery nanoplatform for targeted bimodal imaging-guided photothermal/chemo synergistic cancer therapy.

Breast cancer is a severe threat to the health and lives of women due to its difficult early diagnosis and the unsatisfactory therapeutic efficacy of breast cancer treatments. The development of theranostic strategies to combat breast cancer with high accuracy and effectiveness is therefore urgently needed. In this study, we describe a near-infrared (NIR) light-controllable, targeted and biocompatible drug delivery nanoplatform (PFH-PTX@PLGA/SPIO-Her) for photoacoustic (PA)/ultrasound (US) bimodal imaging-guided photothermal (PTT)/chemo synergistic cancer therapy of breast cancer. Carboxyl-modified PEGylated poly (lactic-co-glycolic acid) (PLGA-PEG-COOH) constituted the skeleton of the nanoplatform. Especially, the antibody Herceptin was modified onto the surface of nanoplatform for active HER2-targing to facilitate the tumor accumulation of the nanoplatform. The encapsulated superparamagnetic iron oxide (SPIO) nanoparticles could be employed as an excellent PA imaging agent to guide tumor therapy. When exposed to NIR light, the SPIO also could transform NIR light into thermal energy for photothermal ablation of tumor. The NIR-induced thermal effect subsequently triggered the optical droplet vaporization (ODV) of perfluorohexane (PFH) to generate PFH gas bubbles, which not only achieved the US imaging enhancement, but also contributed to the release of loaded paclitaxel (PTX) from the nanoplatform for significantly improving PTT therapeutic efficacy. Our results demonstrated that the targeted tumor accumulation, accurate real-time bimodal imaging, and the abundant drug release at the tumor site were all closely associated with the PTT therapeutic efficacy. Therefore, the theranostic nanoplatform is a very promising strategy for targeted imaging-guided photothermal/chemo synergistic tumor therapy with high therapeutic efficacy and minimized side effects. STATEMENT OF SIGNIFICANCE: Breast cancer is the most frequent cancer in women. Herein, we successfully developed a light-controllable and HER2 targeted theranostic nanoparticels (PFH-PTX@PLGA/SPIO-Her) as a specific drug delivery nanoplatform to overcome the low accuracy of tumor detection and the low specificity of traditional chemo-therapeutic protocols. The study demonstrated that PFH-PTX@PLGA/SPIO-Her could actively target to breast cancer cells with positive HER2 expression. The biocompatible PFH-PTX@PLGA/SPIO-Her nanoparticles as both photoacoustic/ultrasound bimodal imaging agents, photothermal-conversion nanomaterials (photothermal hyperthermia) and controllable drug delivery nanoagents (optical droplet vaporization) have completely eradicated the tumor without severe side effects. The theranostic strategy not only integrates strengthens of traditional imaging or therapeutic modalities, but also paves a new way for the efficient cancer treatment by taking the advantage of quickly-developing nanomedicine.

Folate-receptor-targeted laser-activable poly(lactide-co-glycolic acid) nanoparticles loaded with paclitaxel/indocyanine green for photoacoustic/ultrasound imaging and chemo/photothermal therapy.

BACKGROUND: Cancer is one of the most serious threats to human health. Precision medicine is an innovative approach to treatment, as part of which theranostic nanomedicine has been studied extensively. However, the required biocompatibility and substantial cost for the approval of nanomedicines hinder their clinical translation. PURPOSE: We designed a novel type of theranostic nanoparticle (NP) folate-receptor-targeted laser-activatable poly(lactide-co-glycolic acid) (PLGA) NPs loaded with paclitaxel (Ptx)/indo-cyanine green (ICG)-folic acid-polyethylene glycol (PEG)-PLGA-Ptx@ICG-perfluorohexane (Pfh)- using safe and approved materials and drugs, which would facilitate clinical translation. With laser irradiation, highly efficient photothermal therapy can be achieved. Additionally, targeted NPs can be activated by near-infrared laser irradiation at a specific region, which leads to the sharp release of Ptx at areas of high folate-receptor expression and ensures a higher Ptx concentration within the tumor region, thereby leading to chemo/photothermal synergistic antitumor efficacy. Meanwhile, the NPs can be used as a dual-modality contrast agent for photoacoustic and ultrasound imaging. MATERIALS AND METHODS: FA-PEG-PLGA-Ptx@ICG-Pfh NPs were prepared by sonification method and characterized for physicochemical properties. Cytotoxicity and in vivo biocompatibility were evaluated respectively by CCK8 assay and blood analysis. NPs as dual-modality contrast agents were evaluated by photoacoustic/ultrasound imaging system in vitro and in vivo. In vitro anticancer effect and in vivo anticancer therapy was evaluated by CCK8 assay and MDA-MB231 tumor-bearing mice model. RESULTS: FA-PEG-PLGA-Ptx@ICG-Pfh NPs were in the size of 308±5.82 nm with negative zeta potential and showed excellent photothermal effect. The NPs could be triggered sharp release of Ptx by laser irradiation, and showed the good biocompatibility in vitro and in vivo. Through photoacoustic/ultrasound imaging, the NPs showed an excellent ability as dual-modality contrast agents in vitro and in vivo. FA-PEG-PLGA-Ptx@ICG-Pfh NPs with laser irradiation showed the best anticancer efficacy in vitro and in vivo. CONCLUSION: Such a biocompatible and novel theranostic NP is expected to integrate dual-modality imaging with improved therapeutic efficacy and provide a promising paradigm for cancer therapy.

PA/US dual-modality imaging to guide VEGFR-2 targeted photothermal therapy using ZnPc-/PFH-loaded polymeric nanoparticles.

Angiogenesis is a common pathological characteristic of many solid tumors and vulnerable atherosclerotic plaques. Photothermal therapy (PTT) is a promising method to reduce neovascularization. To increase the targeting ability and efficiency of PTT, a novel polymeric nanosystem that encapsulates phthalocyanine zinc (ZnPc) and perfluorohexane (PFH) was developed to target the new blood vessels of breast tumors. After being conjugated to the anti-VEGFR-2 antibody, the polymeric nanoparticles (NPs) targeted vascular endothelial cells efficiently. The photosensitizer (PS) in the NPs could convert laser energy into heat, generating local high temperatures to kill the surrounding cells under laser irradiation. In addition, the liquid-gas phase transition of PFH was induced, and an enhanced ultrasound (US) and photoacoustic (PA) image could be obtained. US/PA imaging enables visualization of the location of NPs, and laser irradiation position can be guided to the optimal location, resulting in fewer side effects than those from traditional treatments with a high targeting ability and an efficient synergistic effect from the PTT.

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound.

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release.

A laser-activated multifunctional targeted nanoagent for imaging and gene therapy in a mouse xenograft model with retinoblastoma Y79 cells.

Retinoblastoma (RB) is the most common intraocular malignancy of childhood that urgently needs early detection and effective therapy methods. The use of nanosized gene delivery systems is appealing because of their highly adjustable structure to carry both therapeutic and imaging agents. Herein, we report a folic acid (FA)-modified phase-changeable cationic nanoparticle encapsulating liquid perfluoropentane (PFP) and indocyanine green (ICG) (FA-CN-PFP-ICG, FCNPI) with good plasmid DNA (pDNA) carrying capacity, favorable biocompatibility, excellent photoacoustic (PA) and ultrasound (US) contrast, enhanced gene transfection efficiency and therapeutic effect. The liquid-gas phase transition of the FCNPI upon laser irradiation has provided splendid contrasts for US/PA dual-modality imaging in vitro as well as in vivo. More importantly, laser-mediated gene transfection with targeted cationic FCNPI nanoparticles demonstrated the best therapeutic effect compared with untargeted cationic nanoparticle (CN-PFP-ICG, CNPI) and neutral nanoparticle (NN-PFP-ICG, NNPI), both in vitro and in vivo. Such a multifunctional nanoagent is expected to combine dual-mode guided imaging with fewer side effects and proper therapeutic efficacy. These results establish an experimental foundation for the clinical detection of and therapy for RB. STATEMENT OF SIGNIFICANCE: We successfully constructed a multifunctional targeted cationic nanoparticle (FCNPI) and meticulously compared the variations in the plasmid loading capacity and binding to Y79 cells with NNPI, CNPI, and FCNPI. FCNPI exhibited favorable plasmid loading capability, splendid ability for targeting and only it could provide optimal US and PA contrast to background during a considerable long time. The FCNPI/pDNA + Laser system also exhibited the best therapeutic effect in vivo; this finding proposes a potential strategy for the evaluation of an efficient gene delivery nanocarrier for gene targeting therapy of RB tumor. Our study showed that there are great advantages of targeting FCNPI to provide PA/US imaging and to enlighten laser-mediated gene transfection. FCNPI is a very helpful multifunctional agent with potential.

Nanosonosensitizers for Highly Efficient Sonodynamic Cancer Theranostics.

Background: Multifunctional nanoplatforms with diagnostic-imaging and targeted therapeutic functionality (theranostics) are of great interest in the field of precision nanomedicine. The emerging sonodynamic therapy (SDT) combined with sonosensitizers under the guidance of photoacoustic (PA) imaging is highly expected to accurately eliminate cancer cells/tissue. Methods: Unique core/shell-structured theranostic FA-HMME-MNPs-PLGA nanoparticles (FHMP NPs, FA: folate, HMME: hematoporphyrin monomethyl ether, MNPs: melanin nanoparticles, PLGA: poly (lactic-co-glycolic) acid) were constructed by the integration of MNPs (for PA imaging) in the core and HMME in the shell for enhanced PA imaging-guided SDT, which were further functionalized with a tumor-targeting ligand, FA. The PA imaging-guided SDT was systematically and successfully demonstrated both in vitro and in vivo. The high biosafety of FHMP NPs was also systematically evaluated. Results: The synthesized FHMP NPs with a broad optical absorption not only possess high PA-imaging contrast enhancement capability but also exhibit significant SDT efficiency. Importantly, such a PLGA based nanoplatform improved light stability of HMME, enhancing sonodynamic performance and facilitated delivery of MNPs to the tumor region. Meanwhile, a combined effect between HMME and MNPs was discovered and verified. Furthermore, a sonosensitizer assisted by ultrasound irradiation engenders reactive oxygen species (ROS)-mediated cytotoxicity toward tumor cells/tissue. Both in vitro cell-level and systematic in vivo xenograft evaluations on tumor-bearing mice demonstrated that the selective killing effect of ROS on tumor cells was assisted by FHMP NPs, which played an active role in the suppression of tumor growth with high biosafety. Conclusion: A theranostic nanoplatform was successfully constructed, achieving PA imaging-guided SDT against breast cancer cells/tissue. More importantly, MNPs and HMME in one platform with combined effect for enhancing PA imaging was demonstrated. This unique theranostic nanoplatform with multiple capabilities paves a new way toward personalized medicine by rational utilization.

Drug release from core-shell PVA/silk fibroin nanoparticles fabricated by one-step electrospraying.

Silk fibroin (SF), a FDA-approved natural protein, is renowned for its great biocompatibility, biodegradability, and mechanical properties. SF-based nanoparticles provide new options for drug delivery with their tunable drug loading and release properties. To take advantage of the features of carrier polymers, we present a one-step electrospraying method that combines SF, polyvinyl alcohol (PVA) and therapeutic drugs without an emulsion process. A distinct core-shell structure was obtained with the PVA core and silk shell after the system was properly set up. The model drug, doxorubicin, was encapsulated in the core with a greater than 90% drug encapsulation efficiency. Controllable drug release profiles were achieved by alternating the PVA/SF ratio. Although the initial burst release of the drug was minimized by the SF coating, a large number of drug molecules remained entrapped by the carrier polymers. To promote and trigger drug release on demand, low intensity focused ultrasound (US) was applied. The US was especially advantageous for accelerating the drug diffusion and release. The apoptotic activity of MDA-MB-231 cells incubated with drug-loaded nanoparticles was found to increase with time. In addition, we also observed PVA/SF nanoparticles that could elicit a drug release in response to pH.

Phase-Transition Nanodroplets for Real-Time Photoacoustic/Ultrasound Dual-Modality Imaging and Photothermal Therapy of Sentinel Lymph Node in Breast Cancer.

Pathological status of lymph nodes (LNs) plays a critical role in staging and treatment for the patients with breast cancer. Sentinel lymph node biopsy has become the standard method in determining pathological status of axillary LNs. Therefore, the determination of sentinel lymph nodes (SLNs) and therapy of metastatic LNs are highly desirable in clinic. Herein, an unprecedented carbon nanoparticles (CNs)-incorporated liquid-gas phase-transition nanodroplets (CNPs) with strong near-infrared (NIR) absorption, good biocompatibility, excellent photoacoustic (PA) and ultrasound (US) contrast, and high photothermal-conversion efficiency are reported in this study. Upon laser irradiation, liquid-gas phase transition of the CNPs has been demonstrated to provide excellent contrasts for PA/US dual-modality imaging both in vitro and in vivo. Additionally, the CNPs are capable of staining lymph nodes, which can contribute significantly to the identification of LNs with naked eyes. With increased laser energy, the CNPs exhibit the high performance in killing the breast cancer cells both in vitro and in vivo, due to the photothermal effect induced from the CNs within CNPs. These results suggest that the developed multifunctional phase-transition nanodroplets have high potential to act as the theranostic agents in both SLNs detection and therapy of metastatic LNs.

The effects of MIBG on the invasive properties of HepG2 hepatocellular carcinoma cells.

The aim of the present study was to investigate the effects of meta-iodobenzylguanidine (MIBG) on the invasive properties of hepatocellular carcinoma (HCC) cells and examine whether these effects are due to the ability of MIBG to inhibit arginine-specific mono-ADP-ribosylation. Samples from patients with HCC were divided into 2 groups, a metastatic group and a non-metastatic group. Immunohistochemistry and RT-PCR were used to detect the protein and mRNA expression of arginine-specific adenosine diphosphate-ribosyltransferase 1 (ART1) and integrin α7 in the HCC tissues. In addition, the expression of ART1 was measured in HepG2 HCC cells by immunofluorescence. The inhibition of the metastasis of HepG2 cells by MIBG at various concentrations was measured by MTT assay. In addition, the effects of MIBG on HepG2 cell metastasis were measured using a scratch wound assay and a transwell invasion assay. Western blot analysis was used to detect the protein expression of ART1, integrin α7, focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K) and urokinase-type plasminogen activator (uPA) in the HepG2 cells. The mRNA and protein levels of ART1 and integrin α7 were higher in the metastatic HCC samples than in the non-metastatic HCC samples. ART1 expression was detected in the HepG2 cells. The half maximal inhibition concentration (IC50) of MIBG in the HepG2 cells was 200 µmol/l (P<0.05). Within a certain dose range, MIBG exerted inhibitory effects on HepG2 cell migration in a dose-dependent manner. Treatment with MIBG significantly inhibited the migration and invasion of the HepG2 cells relative to the control cells (P<0.05) and reduced the protein expression of ART1, integrin α7, FAK, PI3K and uPA (P<0.05). Our data demonstrate that ART1 and integrin α7 may be involved in the invasive and metastatic properties of HCC cells. MIBG inhibited the migration and invasion of HepG2 cells, possibly through the inhibition of arginine-specific single-adenosine diphosphate ribosylation and the suppression of the protein expression of integrin α7ß1, FAK and PI3K and the secretion of uPA, leading to reduced invasion by HepG2 cells.