Determination of anti-tuberculosis activity of biosynthesized gold nanocompounds against M. tuberculosis H37RV.

BACKGROUND: The biosynthesis of gold nanoparticles using medicinal plants as reducing and stabilizing agent for synthesis is an emerging area of research due to their cost effectiveness and further diversified applications in various fields. People with HIV are prone to these opportunistic infections like TB due to the immunocompromised condition. In the present study, the nanoparticles and nanoconjugates were screened for effective anti-mycobacterial efficiency against opportunistic infections. METHODS: Incidentally, the nanoparticles were biosynthesized using single plant extract. The biosynthesized nanoparticles were initially screened for effective anti-tuberculosis activity against Mycobacterium tuberculosis. Based on the effective antimicrobial activity, a nanoconjugate was biosynthesized combining three plant extracts for a cumulative activity. RESULTS: The biosynthesized gold nanoparticles and nanoconjugates showed MIC demonstrating for 99% inhibition and MIC99 was found to be 6.42 µg/ml. Among all the 15 nanoparticles tested, seven NPs showed exceptional anti-TB activities NP1, NP2, NP6, NP7, NP10, NP12 and NP15 and the other nanoparticles exhibited varying degrees of inhibition - anti-TB activities. In the 12 nanoconjugate tested, seven nanoconjugate demonstrated exceptional anti-TB activities such as NCC1, NCC2, NCC5, NCC6, NCV1, NCV6 and NCV4. CONCLUSION: The objective of the study was to identify the nanoparticles and nanoconjugates which demonstrated potential activity against M. tuberculosis so that a single nanoparticle or nanoconjugate can be targeted to treat patients with TB. Minimum Inhibitory Concentration (MIC) of the biosynthesized gold nanoparticles and nanoconjugates were determined against M. tuberculosis H37Rv.

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment.

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal-curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of ß-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.

Enhanced antimycotic activity of nanoconjugates from fungal chitosan and Saussurea costus extract against resistant pathogenic Candida strains.

Targeting the control of pathogenic Candida spp., especially the fungicides resistant strains from C. albicans and C. glabrata, nanoconjugates from the biopolymer (chitosan) and costus root extract (Saussurea costus) was synthesized and characterized. Chitosan was extracted from the grown mycelia of Aspergillus niger and characterized with high deacetylation degree of 91.2% and moderate molecular weight of 106.8 kDa. Synthesis of nanoconjugates from fungal chitosan/costus extract (NCt/CE) was conducted using ionic gelation technique; the resulted NCt/CE particles were characterized with mean diameter of 48 nm, positive zeta potentiality (+3.28 mV) and high stability. The infra-red spectra of synthesized nanoconjugates indicated their strong biochemical cross-linkage. The antimycotic activities, of the synthesized NCt, CE and their nanocomposite, were evaluated against standard and antibiotic-resistant strains from C. albicans and C. glabrata and revealed that the entire agents had notable antimycotic potentiality against all examined strains; the NCt/CE nanoconjugates had significantly stronger antimicrobial action. The scanning microscope imaging, of exposed resistant strains to NCt/CE, indicated their vigorous structural and morphological alterations and confirmed the antimycotic activity of the nanocomposite. NCt/CE nanoconjugates' synthesis could be exceedingly recommended as a natural, biodegradable and effectual antimycotic agent to control resistant pathogenic yeast strains.

Black Phosphorus-Based Multimodal Nanoagent: Showing Targeted Combinatory Therapeutics against Cancer Metastasis.

In breast cancer chemophotothermal therapy, it is a great challenge for the development of multifunctional nanoagents for precision targeting and the effective treatment of tumors, especially for metastasis. Herein, we successfully design and synthesize a multifunctional black phosphorus (BP)-based nanoagent, BP/DTX@PLGA, to address this challenge. In this composite nanoagent, BP quantum dots (BPQDs) are loaded into poly(lactic-co-glycolic acid) (PLGA) with additional conjugation of a chemotherapeutic agent, docetaxel (DTX). The in vivo distribution results demonstrate that BP/DTX@PLGA shows striking tropism for targeting both primary tumors and lung metastatic tumors. Moreover, BP/DTX@PLGA exhibits outstanding controllable chemophotothermal combinatory therapeutics, which dramatically improves the efficacy of photothermal tumor ablation when combined with near-light irradiation. Mechanistically, accelerated DTX release from the nanocomplex upon heating and thermal treatment per se synergistically incurs apoptosis-dependent cell death, resulting in the elimination of lung metastasis. Meanwhile, in vitro and in vivo results further confirm that BP/DTX@PLGA possesses good biocompatibility. This study provides a promising BP-based multimodal nanoagent to constrain cancer metastasis.

Angelica sinensis polysaccharide nanoparticles as a targeted drug delivery system for enhanced therapy of liver cancer.

In recent years, the utilization of polysaccharides as targeted drug carriers has attracted considerable attention. Herein, Angelica sinensis polysaccharide (ASP), a plant polysaccharide with good biocompatibility, excellent aqueous solubility and intrinsic liver-targeted capability, was modified with hydrophobic group (deoxycholic acid) to fabricate amphiphilic conjugate (ASP-DOCA). Self-assembled nanoparticles were successfully developed for hepatoma-targeted delivery of therapeutic drug doxorubicin (DOX). The DOX loaded nanoparticles (DOX/ASP-DOCA NPs) were spherical in shape with a particle size of 228 nm and negatively charged around -17 mV. DOX was released from nanoparticles in a sustainable and pH-dependent manner. In vitro cellular uptake revealed that DOX/ASP-DOCA NPs were internalized into HepG2 cells through asialoglycoprotein receptor (ASGPR)-mediated endocytosis, resulting in a higher anti-proliferation effect than DOX-loaded dextran derivative DOX/DEX-DOCA NPs. Additionally, DOX/ASP-DOCA NPs showed higher inhibition on the growth of HepG2 multicellular spheroids (MCs) than DOX/DEX-DOCA NPs. In vivo imaging demonstrated that ASP-DOCA NPs specifically targeted HepG2 tumors via ASGPR, improving the accumulation of DOX/ASP-DOCA NPs in tumors and generating superior antitumor activity compared with free DOX and DOX/DEX-DOCA NPs. Taken together, ASP-DOCA NPs possess potential applications in drug delivery systems targeting liver cancer.

[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.

Folic acid conjugated PEG coated gold-iron oxide core-shell nanocomplex as a potential agent for targeted photothermal therapy of cancer.

This study reports the synthesis and characterization of poly(ethylene glycol) coated gold@iron oxide core-shell nanoparticles conjugated with folic acid (FA-PEG-Au@IONP). Also, targeted therapeutic properties of such a nanocomplex were studied on human nasopharyngeal carcinoma cell line KB and human breast adenocarcinoma cell line MCF-7 in vitro. The synthesized nanocomplex was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), UV-Vis spectroscopy, vibrating sample magnetometry (VSM), and Fourier transform infrared (FTIR) spectroscopy. The photothermal effects of nanocomplex on both KB and MCF-7 cell lines were studied. Cell death and apoptosis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry using an annexin V-fluorescein isothiocyanate/propidiumiodide apoptosis detection kit. It was found that nanocomplex is spherical in shape and its size is approximately 60 nm. UV-vis spectrum showed that nanocomplex has appropriate absorption near infrared region. FTIR spectra obtained from nanocomplex before and after conjugation with FA confirmed the formation of folate conjugated nanocomplex. Significant cell lethality was observed for KB (∼62%) and MCF-7 (∼33%) cells following photothermal therapy. Also, it was found that majority of the cell deaths were related to apoptosis process. It can be concluded that, the synthesized nanocomplex is an effective and promising multifunctional nanoplatform for targeted photothermal therapy of cancer.

Science to Practice: Enhancing Photothermal Ablation of Colorectal Liver Metastases with Targeted Hybrid Nanoparticles.

Image-guided percutaneous thermal ablation has been one of the principal tools in management of unresectable liver malignancies, including colorectal liver metastases (CRLM) ( 1 ). Currently, however, this technique is suitable mainly for tumors less than 4-5 cm in diameter and also results in incomplete ablation at tumor margins ( 2 ). To solve these problems, efforts have been made to combine thermal ablation with other treatment options, such as systemic and intra-arterial administration of therapeutics ( 3 - 5 ). In this issue of Radiology, White et al ( 6 ) introduced their work on development of an alternative approach by using biofunctionalized hybrid magnetic gold nanoparticles (HNPs) as catalysts for photothermal ablation of CRLM. They found that (a) the targeted (anti-MG1) HNPs are noncytotoxic and have greater than 20% intratumoral accumulation and (b) systemic administration of anti-MG1 HNPs can enlarge a tumor's necrotic zone with photothermal ablation. The results of this study establish the proof of the concept that targeted HNPs can enhance the therapeutic effect of photothermal ablation, which presents an exciting strategy for complete removal of CRLM by integrating two rapidly advancing scientific fields-interventional radiology and nanotechnology.

Biofunctionalized Hybrid Magnetic Gold Nanoparticles as Catalysts for Photothermal Ablation of Colorectal Liver Metastases.

Purpose To demonstrate that anti-MG1 conjugated hybrid magnetic gold nanoparticles (HNPs) act as a catalyst during photothermal ablation (PTA) of colorectal liver metastases, and thus increase ablation zones. Materials and Methods All experiments were performed with approval of the institutional animal care and use committee. Therapeutic and diagnostic multifunctional HNPs conjugated with anti-MG1 monoclonal antibodies were synthesized, and the coupling efficiency was determined. Livers of 19 Wistar rats were implanted with 5 × 106 rat colorectal liver metastasis cell line cells. The rats were divided into three groups according to injection: anti-MG1-coupled HNPs (n = 6), HNPs only (n = 6), and cells only (control group, n = 7). Voxel-wise R2 and R2* magnetic resonance (MR) imaging measurements were obtained before, immediately after, and 24 hours after injection. PTA was then performed with a fiber-coupled near-infrared (808 nm) diode laser with laser power of 0.56 W/cm2 for 3 minutes, while temperature changes were measured. Tumors were assessed for necrosis with hematoxylin-eosin staining. Organs were analyzed with inductively coupled plasma mass spectrometry to assess biodistribution. Therapeutic efficacy and tumor necrosis area were compared by using a one-way analysis of variance with post hoc analysis for statistically significant differences. Results The coupling efficiency was 22 µg/mg (55%). Significant differences were found between preinfusion and 24-hour postinfusion measurements of both T2 (repeated measures analysis of variance, P = .025) and T2* (P < .001). Significant differences also existed for T2* measurements between the anti-MG1 HNP and HNP-only groups (P = .034). Mean temperature ± standard deviation with PTA in the anti-MG1-coated HNP, HNP, and control groups was 50.2°C ± 7.8, 51°C ± 4.4, and 39.5°C ± 2.0, respectively. Inductively coupled plasma mass spectrometry revealed significant tumor targeting and splenic sequestration. Mean percentages of tumor necrosis in the anti-MG1-coated HNP, HNP, and control groups were 38% ± 29, 14% ± 17, and 7% ± 8, respectively (P = .043). Conclusion Targeted monoclonal antibody-conjugated HNPs can serve as a catalyst for photothermal ablation of colorectal liver metastases by increasing ablation zones. © RSNA, 2017.

Selective ex vivo photothermal nano-therapy of solid liver tumors mediated by albumin conjugated gold nanoparticles.

We have used albumin (BSA) bound to gold nanoparticles (GNPs) as active vectors to target liver cells. Our incentive to develop an original model of living liver cancer sprang from the ethical drawbacks that hindered the assessment of the selective character and the therapeutic capacity of these nano-biosystems in cancer patients. Ex vivo-perfused liver specimens were obtained from hepatocellular carcinoma patients similarly to the surgical technique of transplantation. Albumin bound to GNPs was inoculated intra-arterially onto the resulting specimen and determined the specific delivery of the nano-bioconjugate into the malignant tissue by means of the capillary bed. The extent of necrosis was considerable following laser therapy and at the same time surrounding parenchyma was not seriously affected. The selective photothermal ablation of the malignant liver tissue was obtained after the selective accumulation of BSA bound to GNPs into tumor cells following ex-vivo intra-vascular perfusion.

Photo-thermal therapy of bladder cancer with Anti-EGFR antibody conjugated gold nanoparticles.

The aim of this study was to enhance the effectiveness of photo thermal therapy (PTT) in the targeting of superficial bladder cancers using a green light laser in conjunction with gold nanoparticles (GNPs) conjugated to antibody fragments (anti-EGFR). GNPs conjugated with anti-EGFR-antibody fragments were used as probes in the targeting of tumor cells and then exposed to a green laser (532nm), resulting in the production of sufficient thermal energy to kill urothelial carcinomas both in vitro and in vivo. Nanoparticles conjugated with antibody fragments are capable of damaging cancer cells even at relatively very low energy levels, while non-conjugated nanoparticles would require an energy level of 3 times under the same conditions. The lower energy required by the nanoparticles allows this method to destroy cancerous cells while preserving normal cells when applied in vivo. Nanoparticles conjugated with antibody fragments (anti-EGFR) require less than half the energy of non-conjugated nanoparticles to kill cancer cells. In an orthotopic bladder cancer model, the group treated using PTT presented significant differences in tumor development.

An imaging-guided platform for synergistic photodynamic/photothermal/chemo-therapy with pH/temperature-responsive drug release.

To integrate biological imaging and multimodal therapies into one platform for enhanced anti-cancer efficacy, we have designed a novel core/shell structured nano-theranostic by conjugating photosensitive Au25(SR)18 - (SR refers to thiolate) clusters, pH/temperature-responsive polymer P(NIPAm-MAA), and anti-cancer drug (doxorubicin, DOX) onto the surface of mesoporous silica coated core-shell up-conversion nanoparticles (UCNPs). It is found that the photodynamic therapy (PDT) derived from the generated reactive oxygen species and the photothermal therapy (PTT) arising from the photothermal effect can be simultaneously triggered by a single 980 nm near infrared (NIR) light. Furthermore, the thermal effect can also stimulate the pH/temperature sensitive polymer in the cancer sites, thus realizing the targeted and controllable DOX release. The combined PDT, PTT and pH/temperature responsive chemo-therapy can markedly improve the therapeutic efficacy, which has been confirmed by both in intro and in vivo assays. Moreover, the doped rare earths endow the platform with dual-modal up-conversion luminescent (UCL) and computer tomography (CT) imaging properties, thus achieving the target of imaging-guided synergistic therapy under by a single NIR light.

Heparin-anthranoid conjugates associated with nanomagnetite particles and their cytotoxic effect on cancer cells.

The paper describes a methodology for preparing monodisperse, water-soluble magnetite nanoparticles, coated with heparin and loaded with 4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid (Rhein), able to be used as a drug delivery system for cancer chemotherapy. Upon preparation, nanoparticles structure and morphology were investigated. The surface charge and the equivalent dimensions of the nanoparticles dispersed in water were measured, as a function of the suspension pH. The concentration of the drug into the nanoparticles shell, and the drug release profile was determined. The functionality of Rhein-loaded heparin-coated magnetic nanoparticles was assessed by monitoring their cytotoxic effect on cultured human tumor hepatocyte cell line, HepG2, using MTT assay. We found that upon exposure of HepG2 cells to Rhein-loaded heparin-coated nanoparticles, the cell viability was drastically reduced (to approximately 10%) as compared to that of the cells exposed to the free drug, indicating the potential of these magnetite nanoparticles to be used in cancer therapy.

Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (P<0.05). In animal experiments, targeted gold nanoconjugates halted the growth of subcutaneous Hep3B xenografts in combination with RF exposure (P<0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ~275-fold lower than the current clinically-delivered systemic dose of gemcitabine. FROM THE CLINICAL EDITOR: In a model of hepatocellular carcinoma, the authors demonstrate that non-invasive RF-induced hyperthermia applied with cetuximab targeted delivery of Au NP-gemcitabine conjugate is more effective and safe at dosages ~ 275-fold lower than the current clinically-used systemic dose of gemcitabine.

[Application and advancement of magnetic iron-oxide nanoparticles in tumor-targeted therapy].

Recently, nanometer-sized magnetic particles have been intensively concerned and investigated due to their particularly large surface-to-volume ratio, quantum-size effect, magnetic character as well as their potential application in the area of bioscience and medicine. The most promising nanoparticles are magnetic iron oxide nanoparticles with appropriate surface modification, which have been widely used experimentally for numerous in vivo applications such as magnetic resonance imaging contrast enhancement, tissue repair, immunoassay, detoxification of biological fluids, drug delivery, hyperthermia and cell separation. To focus on one of the most important and fascinating subjects in nanobiotechnology, this review describes the current situation and development of magnetic iron oxide nanoparticles and their applications in drug delivery and hyperthermia in tumor-targeted therapy. The possible perspectives and some challenges to further development of these nanoparticles are also analyzed and discussed.