A Smart Multifunctional Nanoparticle for Enhanced Near-Infrared Image-Guided Photothermal Therapy Against Gastric Cancer.

BACKGROUND: Surgery is considered to be a potentially curative approach for gastric cancer. However, most cases are diagnosed at a very advanced stage for the lack of typical symptoms in the initial stage, which makes it difficult to completely surgical resect of tumors. Early diagnosis and precise personalized intervention are urgent issues to be solved for improving the prognosis of gastric cancer. Herein, we developed an RGD-modified ROS-responsive multifunctional nanosystem for near-infrared (NIR) imaging and photothermal therapy (PTT) against gastric cancer. METHODS: Firstly, the amphiphilic polymer was synthesized by bromination reaction and nucleophilic substitution reaction of carboxymethyl chitosan (CMCh) and 4-hydroxymethyl-pinacol phenylborate (BAPE). Then, it was used to encapsulate indocyanine green (ICG) and modified with RGD to form a smart multifunctional nanoparticle targeted to gastric cancer (CMCh-BAPE-RGD@ICG). The characteristics were determined, and the targeting capacity and biosafety were evaluated both in vitro and in vivo. Furthermore, CMCh-BAPE-RGD@ICG mediated photothermal therapy (PTT) effect was studied using gastric cancer cells (SGC7901) and SGC7901 tumor model. RESULTS: The nanoparticle exhibited suitable size (≈ 120 nm), improved aqueous stability, ROS-responsive drug release, excellent photothermal conversion efficiency, enhanced cellular uptake, and targeting capacity to tumors. Remarkably, in vivo studies suggested that CMCh-BAPE-RGD@ICG could accurately illustrate the location and margin of the SGC7901 tumor through NIR imaging in comparison with non-targeted nanoparticles. Moreover, the antitumor activity of CMCh-BAPE-RGD@ICG-mediated PTT could effectively suppress tumor growth by inducing necrosis and apoptosis in cancer cells. Additionally, CMCh-BAPE-RGD@ICG demonstrated excellent biosafety both in vitro and in vivo. CONCLUSION: Overall, our study provides a biocompatible theranostic nanoparticle with enhanced tumor-targeting ability and accumulation to realize NIR image-guided PTT in gastric cancer.

Inclusion of IR-820 into Soybean-Phosphatides-Based Nanoparticles for Near-Infrared-Triggered Release and Endolysosomal Escape in HaCaT Keratinocytes at Insignificant Cytotoxic Level.

PURPOSE: The degradation of drugs within endolysosomes has been widely addressed as a cause of poor bioavailability. One of the strategies to allow molecules to escape from a destructive fate is to introduce a photosensitizing moiety into a drug carrier enabling the permeabilization of endosomes and endolysosomes upon irradiation. This paper presents an alternative delivery nanosystem composed of cost-effective soybean phosphatides mixed with IR-820, a near-infrared (NIR) sensitizer, to load various active compounds and trigger an endolysosomal escape with a low cytotoxic effect. METHODS: IR-820-incorporated phosphatides-based nanoparticles were formulated using a thin-film hydration method to encapsulate different molecular probes and a drug model. The nanoparticles were characterized in vitro using dynamic light scattering, transmission electron microscopy, as well as ultraviolet-visible and fluorescence spectroscopy techniques. The NIR-corresponding generation of the photochemical products, the content release, and the cytotoxicity toward the HaCaT keratinocyte cell line were evaluated. The cellular internalization and endolysosomal escape were monitored using a cytochemical marker and fluorescent probes with a colocalization analysis. RESULTS: The IR-820-combined nanoparticles revealed the NIR-triggered changes in the singlet oxygen presence, nanoparticle architecture, and release rate without being cytotoxic. Additionally, the nanoplatform appeared to enhance cellular uptake of the macromolecules. The localization of the cytochemical marker and the colocalization analysis on the fluorescence signals of the encapsulated fluorophore and the lysosome-labeling reporter implied the transient endolysosomal escape of the cargo within the HaCaT cells after NIR irradiation. CONCLUSION: The inclusion of IR-820 into a soybean-phosphatides base ingredient provides NIR responsiveness, particularly the endolysosomal escape of the payload, to the formulated nanoparticles, while preserving the beneficial properties as a drug carrier. This alternative delivery nanomedicine system has future potential to provide high bioavailability of cytosolic drugs utilizing time- and spatial-controllable NIR triggerability as well as the synergistic therapeutic effects with NIR-biomodulation.

Near-infrared photothermal liposomal nanoantagonists for amplified cancer photodynamic therapy.

Photodynamic therapy (PDT) has been demonstrated to be a promising strategy for the treatment of cancer, while its therapeutic efficacy is often compromised due to excessive concentrations of glutathione (GSH) as a reactive oxygen species (ROS) scavenger in cancer cells. Herein, we report the development of near-infrared (NIR) photothermal liposomal nanoantagonists (PLNAs) for amplified PDT through through the reduction of intracellular GSH biosynthesis. Such PLNAs were constructed via encapsulating a photosensitizer, indocyanine green (ICG) and a GSH synthesis antagonist, l-buthionine sulfoximine (BSO) into a thermal responsive liposome. Under NIR laser irradiation at 808 nm, PLNAs generate mild heat via a ICG-mediated photothermal conversion effect, which leads to the destruction of thermal responsive liposomes for a controlled release of BSO in a tumor microenvironment, ultimately reducing GSH levels. This amplifies intracellular oxidative stresses and thus synergizes with PDT to afford an enhanced therapeutic efficacy. Both in vitro and in vivo data verify that PLNA-mediated phototherapy has an at least 2-fold higher efficacy in killing cancer cells and inhibiting tumor growth compared to sole PDT. This study thus demonstrates a NIR photothermal drug delivery nanosystem for amplified photomedicine.

Fluorescence imaging-guided multifunctional liposomes for tumor-specific phototherapy for laryngeal carcinoma.

Reliable diagnosis and efficient targeted therapy are important and may lead to the effective treatment of laryngeal carcinoma. Multifunctional nano-theranostic agents demonstrate great potential in tumor theranostic applications. Thus, herein, we report novel targeting multifunctional theranostic nanoparticles, internalized RGD (iRGD)-modified indocyanine green (ICG) encapsulated liposomes (iLIPICG), for imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) for the treatment of laryngeal carcinoma. The iRGD-PEG-DSPE lipid endowed iLIPICG with high affinity for tumor vascular targeting, tumor-penetration and tumor cell targeting. The in vivo results showed that iLIPICG exhibited excellent blood circulation and tumor accumulation. iLIPICG could be spatially and temporally controlled, simultaneously producing hyperthermia and reactive oxygen species as well as a fluorescence-guided effect through ICG to ablate laryngeal carcinoma cells under irradiation from an 808 nm laser. iLIPICG generated synergistic photodynamic-photothermal cytotoxicity against Hep-2 cells, resulting in the efficient ablation of laryngeal carcinoma. Thus, the iLIPICG system provides a promising strategy to improve the precision imaging and effective phototherapy for the treatment of laryngeal carcinoma.

Self-Assembly Nanoparticles for Overcoming Multidrug Resistance and Imaging-Guided Chemo-Photothermal Synergistic Cancer Therapy.

BACKGROUND AND PURPOSE: The development of multiple drug resistance (MDR) to chemotherapy and single modal therapy remains unsatisfied for the eradication of tumor, which are major obstacles in cancer therapy. This novel system with excellent characteristics for inhibition of P-glycoprotein (P-gp), and for near-infrared fluorescence (NIRF) imaging-guided chemo-photothermal therapy (PTT), has been identified as a promising way to MDR and achieve synergistic cancer therapy. METHODS: In this study, we successfully synthesized a multifunctional theranostic system, which was developed through FDA-approved self-assembling drugs, which contain anticancer drug doxorubicin (Dox), imaging and high photothermal conversion drug indocyanine green (ICG) and P-gp regulator TPGS (the system named T/Dox-ICG). We studied the characterization of T/Dox-ICG NPs, including the TEM, SEM, DLS, UV-vis-NIR, zeta potential, CLSM, in vitro FL imaging, in vitro photothermal effect, in vitro Dox and ICG release. We used CLSM to verify the location of intracellular distribution of Dox in SCG 7901/VCR cells, Western blot was performed to demonstrate the TPGS-mediated inhibition of P-gp. And, the cytotoxicity of materials against SCG 7901/VCR cells was studied by the MTT assay. RESULTS: The TEM showed the T/Dox-ICG NPs had good monodispersity with diameters of 19.03 nm, Dox and ICG could be released constantly from T/Dox-ICG NPs in vitro. In vitro cell experiments demonstrated higher Dox accumulation and retention in the nucleus. Western blot showed TPGS could obviously inhibit the expression of P-gp. In vitro cytotoxicity assay showed more significant cytotoxicity on MDR cells (SCG 7901/VCR) with only 8.75% of cells surviving. CONCLUSION: MDR cancer therapy indicates that it may be important to develop a safer system that can simultaneously inhibit the drug transporters and monitor the delivery of chemotherapeutic agents, and combination therapy have raised widespread concern on tumor treatment.

A novel treatment strategy using indocyanine green for transarterial chemoembolization in BCLC stage C hepatocellular carcinoma.

PURPOSE: The aim of our study was to propose a strategy based on indocyanine green (ICG) (SBI) to provide better clinical guidelines for transarterial chemoembolization (TACE) treatments for Barcelona clinic liver cancer (BCLC) stage C hepatocellular carcinoma (HCC) patients. MATERIALS AND METHODS: From October 2005 to December 2012, 112 BCLC stage C HCC patients initially treated with TACE were investigated, randomly divided into a training cohort (n = 79) and validation cohort (n = 33). In training group, the patients were grouped based on their 15 minutes ICG retention rate (ICG R15), different chemo drugs and dose of lipidol in TACE. Overall survival (OS) and progression-free survival (PFS) were analyzed in subgroups. Strategy based on ICG was built and verified in validation group. RESULTS: For those patients with ICG R15 values >10%, the lipiodol ≤10 mL group showed better survival than the lipiodol >10 mL group. For those patients with ICG R15 values ≤10%, the group that received triple-drug chemotherapy treatments with lipiodol diameter ratio values between 1 and 3 showed better survival than the other group. Patients who conformed with the SBI had better survival times than those who did not conform with the SBI, in both the training cohort (median OS 10.3 vs 5.1 months; P < .001; median PFS, 3.3 vs 2.1 months; P = .006) and the validation cohort (median OS 8.9 vs 7.1 months; P = .087; median PFS, 6.6 vs 2.3 months; P < .001). CONCLUSIONS: The SBI is suitable and may provide survival benefits for TACE treatments in BCLC stage C HCC patients.

Tissue Structure and Edema Fluid Events During Treatment of Lymphedema of Limbs with a Manual Pressure-Calibrated Device, Linforoll.

Background: Linforoll is a device composed of handpiece with roller and pressure sensor connected wireless to the computer displaying the pressure curve of the applied force. In a previous study, we proved it to regulate the applied force according to the hydromechanic conditions of the massaged tissues. Standardization of massage based on applied force was repeatable in the same patient; it decreased limb volume and provided evident increase in tissue elasticity. Methods and Results: In this study, we measured additional parameters useful for the understanding of tissue and fluid events and approval of the device for general practice. These were skin stiffness, subcutaneous tissue stiffness independent of skin, skin water concentration, changes in skin temperature, skin capillary blood flow, subcutaneous tissue fluid pressure, volume of the moved edema fluid, and visualization of movement on indocyanine green (ICG) lymphography. Measurements were done before and during the massage. The data were obtained from a group of 20 patients with obstructive lymphedema of lower limbs during the Linforoll massage. There was a lack of significant changes in skin stiffness, skin water concentration, skin surface temperature, and capillary blood flow, but evident increase in the subcutaneous tissue elasticity (tonometry) and lymphography-shown flow of the edema fluid. Conclusions: The skin tissue hydromechanic parameters remained normal proving lack of destructive changes under high massaging pressures. The obtained data evidently show that not the skin but the subcutis accumulated edema fluid that can successfully be moved proximally under pressures of 80-120 mmHg.

Cross-linked nanoparticles of silk fibroin with proanthocyanidins as a promising vehicle of indocyanine green for photo-thermal therapy of glioma.

Instability of silk fibroin nanoparticles (SFNPs) in physiologic condition hinders its application as drug delivery vehicle. Herein, indocyanine green (ICG) loaded silk fibroin nanoparticles (ICG-SFNPs) was firstly prepared and then crosslinked by proanthocyanidins to obtain the stable ICG-CSFNPs for killing the residual tumour niche under near infra-red irradiation (NIR) after surgery. The particle size and zeta potentials of ICG-CSFNPs was 120.1 nm and -40.4 mV, respectively. Moreover, ICG-CSFNPs exhibited good stability of particle size in the physiological medium. Meanwhile, the stable photothermal properties of ICG-CSFNPs were not compromised even after several cycles of NIR. Few of the ICG-CSFNPs were phagocytized by RAW264.7 macrophage in vitro, while they were easily internalized by C6 glioma cells, resulting in their significant toxicity on tumour cells after NIR. The pharmacokinetic study showed that ICG-CSFNPs had a longer blood circulation time than ICG-SFNPs, making them more distribution in glioma after intravenous administration in vivo. Meanwhile, the pharmacological study showed the more effective inhibition of tumour growth was exhibited by ICG-CSFNPs in C6 glioma-bearing mice after NIR. Overall, the cross-linked nanoparticles of silk fibroin may be a promising vehicle of ICG for photothermal therapy of glioma after surgical resection.

Tumor-Microenvironment-Activatable Nanoreactor Based on a Polyprodrug for Multimodal-Imaging-Medicated Enhanced Cancer Chemo/Phototherapy.

Anticancer nanomedicine-based multimodal imaging and synergistic therapy hold great promise in cancer diagnosis and therapy owing to their abilities to improve therapeutic efficiency and reduce unnecessary side effects, producing promising clinical prospects. Herein, we integrated chemotherapeutic drug camptothecin (CPT) and near-infrared-absorbing new indocyanine green (IR820) into a single system by charge interaction and obtained a tumor-microenvironment-activatable PCPTSS/IR820 nanoreactor to perform thermal/fluorescence/photoacoustic-imaging-guided chemotherapy and photothermal therapy simultaneously. Specifically, the generated PCPTSS/IR820 showed an excellent therapeutic agent loading content and size stability, and the trials in vitro and in vivo suggested that the smart PCPTSS/IR820 could deeply permeate into tumor tissues due to its suitable micellar size. Upon near-infrared laser irradiation, the nanoreactor further produced a terrific synergism of chemo-photo treatment for cancer therapy. Therefore, the PCPTSS/IR820 polyprodrug-based nanoreactor holds outstanding promise for multimodal imaging and combined dual therapy.

Water-Responsive Hybrid Nanoparticles Codelivering ICG and DOX Effectively Treat Breast Cancer via Hyperthermia-aided DOX Functionality and Drug Penetration.

Tumor growth and metastasis are the major causes of high mortality in breast cancer. In this study, a water-responsive phospholipid-calcium-carbonate hybrid nanoparticle (PL/ACC-DOX&ICG) surface modified with a phospholipid shell is designed and covered with a shielding polymer polyethylene glycol; this development is loaded with the photosensitizer indocyanine green (ICG) and the chemotherapeutic drug doxorubicin (DOX) for near-infrared (NIR) imaging and chemophotothermal combination therapy against breast cancer. PL/ACC-DOX&ICG exhibits satisfactory stability against various aqueous environments with minimal drug leakage and can readily decompose to facilitate quick drug release into cancer cells. In vivo biodistribution studies, PL/ACC-DOX&ICG demonstrated strong tumor-homing properties. Interestingly, the in vitro cellular uptake and intratumoral penetration depth of PL/ACC-DOX&ICG are significantly enhanced under NIR laser irradiation, owing to ICG-induced hyperthermia, which not only enhances cell permeability and fluidity but also disrupts the dense tumor extracellular matrix. Compared to chemotherapy or photothermal therapy alone, chemophotothermal combination therapy synergistically induces apoptosis and death in 4T1 cells. Moreover, compared with the phosphate buffer saline group, the combined treatment suppress primary tumor growth at a rate of approximately 94.88% and decrease the number of metastatic nodules by about 93.6%. Therefore, PL/ACC-DOX&ICG may be a promising nanoplatform for breast cancer treatment.

Phototheranostics: Active Targeting of Orthotopic Glioma Using Biomimetic Proteolipid Nanoparticles.

Advances in phototheranostics revolutionized glioma intraoperative fluorescence imaging and phototherapy. However, the lack of desired active targeting agents for crossing the blood-brain barrier (BBB) significantly compromises the theranostic efficacy. In this study, biomimetic proteolipid nanoparticles (NPs) with U.S. Food and Drug Administration (FDA)-approved indocyanine green (ICG) were constructed to allow fluorescence imaging, tumor margin detection, and phototherapy of orthotopic glioma in mice. By embedding glioma cell membrane proteins into NPs, the obtained biomimetic ICG-loaded liposome (BLIPO-ICG) NPs could cross BBB and actively reach glioma at the early stage thanks to their specific binding to glioma cells due to their excellent homotypic targeting and immune escaping characteristics. High accumulation in the brain tumor with a signal to background ratio of 8.4 was obtained at 12 h post-injection. At this time point, the glioma and its margin were clearly visualized by near-infrared fluorescence imaging. Under the imaging guidance, the glioma tissue could be completely removed as a proof of concept. In addition, after NIR laser irradiation (1 W/cm2, 5 min), the photothermal effect exerted by BLIPO-ICG NPs efficiently suppressed glioma cell proliferation with a 94.2% tumor growth inhibition. No photothermal damages of normal brain tissue and treatment-induced side effects were observed. These results suggest that the biomimetic proteolipid NP is a promising phototheranostic nanoplatform for brain-tumor-specific imaging and therapy.

Chemodrug-Gated Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Multimodal Imaging-Guided Low-Temperature Photothermal Therapy/Chemotherapy of Cancer.

Noninvasive physical treatment with relatively low intensity stimulation and the development of highly efficient anticancer medical strategy are still desirable for cancer therapy. Herein a versatile, biodegradable, hollow mesoporous organosilica nanocapsule (HMONs) nanoplatform that is capped by the gemcitabine (Gem) molecule through a pH-sensitive acetal covalent bond is designed. The fabricated nanocapsule exhibits desirable small molecule release at the tumor tissues/cell sites and shows a reduced risk for drug accumulation. After loading indocyanine green (ICG), the heat-shock protein 90 (Hsp 90) inhibitor, and 17AAG and modification with polyethylene glycol (NH2-PEG), the resulting ICG-17AAG@HMONs-Gem-PEG exhibited a precisely controlled release of ICG and 17AAG and low-temperature photothermal therapy (PTT) (∼41 °C) with excellent tumor destruction efficacy. In addition, ICG loading conferred the nanoplatform with near-infrared fluorescence imaging (FL) and photoaccoustic (PA) imaging capability. In short, this work not only presents a smart drug self-controlled nanoplatform with pH-responsive payload release and theranostic performance but also provides an outstanding low-temperature PTT strategy, which is highly valid in the inhibition of cancer cells with minimal damage to the organism. Therefore, this research provides a paradigm that has a chemodrug-gated HMONs-based theranostic nanoplatform with intrinsic biodegradability, multimodal imaging capacity, high low-temperature PTT/chemotherapy efficacy, and reduced systemic toxicity.

On-Demand Versatile Prodrug Nanomicelle for Tumor-Specific Bioimaging and Photothermal-Chemo Synergistic Cancer Therapy.

Photothermal therapy is a promising approach for antitumor application although regrettably restricted by available photothermal agents. Physical entrapment of organic near-infrared dyes into nanosystems was extensively studied to reverse the dilemma. However, problems still remained, such as drug bursting and leakage. We developed here an amphiphilic prodrug conjugate by chemically modifying indocyanine green derivative (ICG-COOH) and paclitaxel (PTX) to hyaluronic acid (HA) backbone for integration of photothermal-chemotherapy and specific tumor imaging. The prepared ICG-HA-PTX conjugates could self-assemble into nanomicelles to improve the stability and reduce systemic toxicity of the therapeutic agents. The high local concentration of ICG-COOH in nanomicelles resulted in fluorescence self-quenching, leading to no fluorescence signal being detected in circulation. When the nanomicelles reached the tumor site via electron paramagnetic resonance effect and HA-mediated active targeting, the overexpressed esterase in tumor cells ruptured the ester linkage between drugs and HA, achieving tumor-targeted therapy and specific imaging. A series of in vitro and in vivo experiments demonstrated that the easily prepared ICG- HA-PTX nanomicelles with high stability, smart release behavio r, and excellent tumor targeting ability showed formidable synergy in tumor inhibition, which provided new thoughts in developing an organic near-infrared-dye-based multifunctional delivery system for tumor theranostics.

Calcium-carbonate packaging magnetic polydopamine nanoparticles loaded with indocyanine green for near-infrared induced photothermal/photodynamic therapy.

Indocyanine green (ICG) is an efficient photosensitizer that can facilitate producing cytotoxic reactive oxygen species (ROS). At the same time, ICG also has characteristic absorption of near-infrared light and thus can induce a strong photothermal effect. Both of these important features of ICG may be applied for noninvasive light-induced tumor ablation. On the other hand, ICG is lack of stability in blood circulation and susceptible to aggregation or premature clearance from the body. These issues need to be effectively addressed before antitumor application of ICG becomes possible. Herein, a nanocomposite consisting of calcium carbonate modified magnetic polydopamine (PDA) nanoparticles and loaded with ICG, namely Fe3O4@PDA@CaCO3/ICG (FPCI) NPs, was developed to integrate the photothermal capability of PDA with the photodynamic capability of ICG. Particularly, calcium carbonate not only entrapped ICG in the form of stable aggregate to evade blood clearance, but also facilitated controlled release of ICG in response to acidic tumor microenvironment via self-decomposition. With the aid of magnetic guidance, this multifunctional therapeutic agent makes it possible to achieve the combination of photothermal (PTT) and photodynamic therapies (PDT) against tumors, which was demonstrated by this proof-of-concept study based on in vitro and in vivo tumor models. STATEMENT OF SIGNIFICANCE: Currently, there is an ongoing trend of realizing precise and targeted tumor therapy using functional nanocomplexes. Magnetic particles, which can be manipulated by a magnetic field, have attracted increasing attention for tumor therapy. This submitted work demonstrated that calcium carbonate nanoshell was precipitated onto magnetic nanocores mediated by polydopamine. Moreover, indocyanine green (ICG), as a potent photosensitizer, was embedded in this nanocomplex and protected by the calcium carbonate nanoshell, resulting in high drug loading efficiency and enhanced drug stability on the carrier. This new nanocomposite was demonstrated to achieve controlled and pH-responsive release of ICG in tumor environment. This work explored the relationship between the physiochemical properties of the nanocomplex and their potential biomedical applications, aiming to inspire the development of analogous nanoplatforms featured with calcium carbonate blocks.

[Preclinical application of MR and fluorescent dual-modality imaging combined with photothermal therapy in HER-2 positive breast cancer].

Objective: To construct superparamagnetic iron oxide nanoparticles (SPIONs) coated on trastuzumab and indocyanine green (ICG) and then investigate whether the coated nanoparticles (NPs) targeted to human epidermal growth factor receptor-2 (HER-2) receptors on breast cancer cells in vitro and in vivo. Methods: The Fe(3)O(4)-trastuzumab-ICG NPs were constructed. And a series of characteristics of the NPs were evaluated. The uptake ability of SK-BR-3, a HER-2 positive breast cancer cell, was observed by transmission electron microscopy. Then the NPs were injected in the tail veins of SK-BR-3 xenograft tumor-bearing mice to observe the aggregation of NPs in the tumor sites by MRI and fluorescent imaging. Furthermore, when the NPs was gathered at the tumor sites, the near infrared thermal imaging system was used to monitor the tumor temperature after the near infrared radiation. Results: The successfully constructed Fe(3)O(4)-trastuzumab-ICG NPs had the size of (25.93±4.25) nm. The absorption peak was 828 nm, which was as same as the emission wavelength of ICG. The NPs had a high relaxation rate of approximately 107.65 mM(-1)·s(-1). The maximum temperature of NPs solution could reach to 57.8℃ after continuous near infrared laser irradiation. The transmission electron microscopy imaging revealed that the NPs could target and enter into the endoplasmic reticulum of SK-BR-3 cells. MRI analysis showed the lowest T(2) relaxation time in the tumor sites 24 h after tail vein injection of the NPs. The △T(2) of the tumor sites in the Fe(3)O(4)-trastuzumab-ICG group (30.7±4.8) ms was higher compared with that of control group (3.1±1.1) ms, Fe(3)O(4)-IgG-ICG group (4.4±0.9) ms and trastuzumab + Fe(3)O(4)-trastuzumab-ICG group (11.3±3.8) ms., respectively, all showing statistically significant differences (P<0.05). The fluorescence imaging revealed that the NPs was concentrated transiently in the intraperitoneal organs and tumor sites, then excreted into the bladder. After 24 h, there was an obvious aggregation in the tumor sites. The near infrared thermal imaging experiments showed that the temperature of tumor sites in Fe(3)O(4)-trastuzumab-ICG group could go up to 49.4℃ after continuous near infrared light irradiation. Conclusion: The newly constructed Fe(3)O(4)-trastuzumab-ICG NPs have the potential to act as a multifunctional imaging agent and a powerful tool for photothermal therapy for HER-2 positive breast cancer.

Homing of ICG-loaded liposome inlaid with tumor cellular membrane to the homologous xenografts glioma eradicates the primary focus and prevents lung metastases through phototherapy.

Currently, phototherapy initiated by local irradiation with a near-infrared (NIR) laser has emerged as a promising strategy for cancer treatment owing to its low toxicity. However, a key problem for effective phototherapy is how to specifically deliver a sufficient dose of photosensitizers to a tumor focus. Herein, indocyanine green (ICG), a United States Food and Drug Administration (US FDA)-approved photosensitizer, was first encapsulated in an inner aqueous compartment of liposome (ICG-LIP) to improve its stability. Thereafter, tumor cell membranes were isolated from native glioma cells and subsequently inlaid in the bilayer lipid membrane of ICG-LIP to construct cell-like liposomes (ICG-MCLs). ICG was easily encapsulated into the ICG-MCLs with a very high encapsulation efficiency, reaching 78.01 ± 0.72% and its concentration in the final formulation reached 200 µg mL-1. The ICG-MCLs displayed a spherical morphology with a hydrodynamic diameter (Dh) of 115.0 ± 0.5 nm, a PDI of 0.14, and a zeta potential of -11.2 ± 0.9 mV. Moreover, ICG-MCLs exhibited a good stability in terms of particle size and significantly improved the chemical stability of ICG in pH 7.4 PBS at 37 °C. In addition, the temperature of the ICG-MCLs rapidly increased to 63 °C after 10 min irradiation and this was maintained for a longer time. Owing to the cancer cell membrane associated protein, the ICG-MCLs were specifically internalized by homogenous glioma C6 cells in vitro, which resulted in the strong red fluorescence of ICG in cytoplasm. Moreover, in vivo imaging showed that the ICG-MCLs were effectively homed to the tumor site of C6 glioma-bearing Xenograft nude mice through vein injection, which resulted in the temperature of the tumor site rapidly rising, allowing the killing of tumor cells after local NIR irradiation. After treatment with the ICG-MCLs, the primary tumor focus was completely eradicated and lung metastases were effectively inhibited. In conclusion, liposomes inlaid with tumor cellular membranes may serve as an excellent nanoplatform for homologous-targeting phototherapy using ICG.

Multifunctional nanoparticles for trimodal photodynamic therapy-mediated photothermal and chemotherapeutic effects.

Herein, we posit a biocompatible and pH-switchable integrated nano-delivery of CBP/ICG to the in vitro and in vivo experiments demonstrate that nanoparticles (NPs) have insignificant toxicity and good biocompatibility, and possess excellent tumor targeting efficiency as evidenced by highly efficient tumor ablation under near -infrared (NIR) illumination. In addition, we have conjugated folic acid as a targeting ligand for folate receptor-targeted delivery. Particularly, targeted delivery of dual CBP/ICG loaded NPs provide targeted detection and transporting potential to specific receptor-expressing tumors, and then CBP interfering with DNA damage and ICG generates singlet oxygen as well as photothermal heat when irradiated with NIR for simultaneous trimodal PDT/PTT/Chemotherapy. Using an animal model, a dramatic reduction in tumor growth without any evidence of significant long-term toxicity to organs after administration of NPs for trimodal therapy subjecting to NIR illumination. Thus, the in vivo satisfactory antitumor trimodal combined efficacy concurrent with complete tumor eradication and promising potential for advanced clinical phototherapy.

Dual pH/reduction-responsive hybrid polymeric micelles for targeted chemo-photothermal combination therapy.

The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed new pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs exhibited nano-sized structure (∼100 nm) with good monodispersity, high encapsulation efficiency of both ICG and DOX, triggered DOX release in response to acid pH and reduction environment, and excellent temperature conversion with laser irradiation. In vitro cellular uptake study indicated FA Co-PMs achieved significant targeting to BEL-7404 cells via folate receptor-mediated endocytosis, and laser-induced hyperthermia further enhanced drug accumulation into cancer cells. In vivo biodistribution study indicated that FA Co-PMs prolonged drug circulation and enhanced drug accumulation into the tumor via EPR effect and FA targeting. Furthermore, the ICG-based photo-triggered hyperthermia combined with DOX-based chemotherapy synergistically induced the BEL-7404 cell death and apoptosis, and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs were promising theranostic nanocarriers for versatile antitumor drug delivery and imaging-guided cancer chemo-photothermal combination therapy. STATEMENT OF SIGNIFICANCE: The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed novel pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs triggered DOX release in response to acid pH and reduction environment and exhibited excellent temperature conversion with laser irradiation. The results indicated FA Co-PMs achieved significant targeting to BEL-7404 cells in vitro and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs displayed great potential in imaging-guided cancer chemo-photothermal combination therapy as theranostic nanocarriers.

Folic acid modified cell membrane capsules encapsulating doxorubicin and indocyanine green for highly effective combinational therapy in vivo.

A combination of chemotherapy and phototherapy has emerged as a promising strategy for cancer treatment. To achieve effective combinational therapy of cancer with reduced toxicity, it is highly desirable to improve the targeting of chemotherapeutic and near-infrared photosensitizers to enhance their accumulation in tumor. Here we report a novel tumor targeting cell membrane capsule (CMC), originate from living cells, to load doxorubicin hydrochloride (DOX) and indocyanine green (ICG), for combinational photo-chemotherapy against cancer. As a result, folic acid modified CMC (CMC-FA, with a diameter about 200 nm and a FA density of 0.4 molecule/nm2) showed 3-4 fold higher cell uptake by cancer cells in vitro and 2.3 times higher accumulation in mouse cancer xenografts in vivo than pristine CMC. DOX and ICG with therapeutically significant concentrations can be sequentially encapsulated into CMC-FA by temporary permeating the plasma membranes with high efficiency. The systematic administration of cancer targeting CMC-FA loaded with DOX and ICG could significantly inhibit tumor growth in mouse xenografts in the presence of a near-infrared light at 808 nm, without noticeable toxicity. These findings suggest that cancer targeting CMC may have considerable benefits in drug delivery and combinational cancer therapy. STATEMENT OF SIGNIFICANCE: A combination of chemotherapy and photothermal/photodynamic therapy has emerged as a promising strategy for cancer therapy. In current study, a novel cancer targeting cell membrane capsule (CMC-FA), originate from living cells and surface modified with folic acid, was developed to load doxorubicin hydrochloride (DOX) and indocyanine green (ICG), for combinational photo-chemotherapy against cancer. The systematic administration of drug loaded CMC-FA can significantly inhibit tumor growth in mouse xenografts in the presence of a near-infrared light at 808 nm, without noticeable toxicity. This study provides a simple and robust strategy to develop biocompatible therapeutic cell membrane capsules, holds strong translational potential in precise cancer treatment.

Bubble-generating polymersomes loaded with both indocyanine green and doxorubicin for effective chemotherapy combined with photothermal therapy.

The combination of chemotherapy and photothermaltherapy (PTT) via stimuli-responsive nanovesicles has great potential in tumor treatment. In the present study, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug and photosensitizing agent for the synergistic chemo-photothermal tumor therapy. Photosensitizer indocyanine green (ICG) was encapsulated into the bilayer of polymersomes formed by amphiphilic triblock copolymer PCL8000-PEG8000-PCL8000 through thin film re-hydration method, while chemotherapeutic doxorubicin (DOX) was loaded into the hydrophilic lumen using a transmembrane ammonium bicarbonate gradient loading procedure. Under acidic condition or laser irradiation, the ammonium bicarbonate (NH4HCO3) encapsulated in the bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would decompose to produce CO2 bubbles, resulting in destruction of vesicle structure and rapid drug release. In vitro drug release study confirmed that acidic environment and NIR laser irradiation could accelerate DOX release from the BG-DIPS. Cellular uptake study indicated that laser-induced hyperthermia highly enhanced endocytosis of BG-DIPS into 4T1-Luc cancer cells. In vitro cytotoxicity study demonstrated that BG-DIPS exhibited much higher cytotoxicity than free drugs under laser irradiation. In vivo biodistribution study indicated that BG-DIPS could accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. Furthermore, in vivo antitumor study showed that BG-DIPS with laser irradiation efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy. STATEMENT OF SIGNIFICANCE: The combination of chemotherapy and photothermaltherapy via stimuli-responsive nanovesicles has great potential in tumor treatment. Herein, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug (DOX) and photosensitizing agent (ICG) for the synergistic chemo-photothermal tumor therapy. The results in vitro and in vivo demonstrated that bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would accelerate DOX release from the BG-DIPS and accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. BG-DIPS with laser irradiation could efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.