2020

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16 pages, 4126 KiB

Open AccessArticle

Silver Nanoparticles Stimulates Spermatogenesis Impairments and Hematological Alterations in Testis and Epididymis of Male Rats

by Janet Olayemi Olugbodi, Oladipupo David, Ene Naomi Oketa, Bashir Lawal, Bamidele Joseph Okoli and Fanyana Mtunzi

Molecules 2020, 25(5), 1063; https://doi.org/10.3390/molecules25051063 - 27 Feb 2020

Cited by 47 | Viewed by 4905

Abstract

The potential pharmaceutical application of nanoparticles has led to the toxicity within the male reproductive system. In the present study, the effects of silver nanoparticles (Ag-NPs) on hematological parameters, free radical generation, antioxidant system, sperm parameters, and organ histo-morphometry in male rats were [...] Read more.

The potential pharmaceutical application of nanoparticles has led to the toxicity within the male reproductive system. In the present study, the effects of silver nanoparticles (Ag-NPs) on hematological parameters, free radical generation, antioxidant system, sperm parameters, and organ histo-morphometry in male rats were investigated. Ag-NPs were produced by the reduction of silver ions, while the formation of which was monitored by UV–visible spectrophotometry. Zeta potential, transmission, and scanning electron microscopies were applied for the characterization of AgNPs. A total of 30 rats were divided into 6 groups and were sub-dermally exposed to Ag-NPs at the dosage of 0 (control), 10, and 50 mg/kg bodyweight (bw) doses for either 7 or 28 days. Ag-NP administration altered hematological indices and caused dose-dependent decreases in sperm motility, velocity, kinematic parameters, concentrations of luteinizing hormone, follicle-stimulating hormone, and testosterone. In the epididymis and testis, the concentrations of malondialdehyde and peroxide increases while superoxide dismutase, catalase, reduced glutathione, and total thiol group decreases. These findings suggest that Ag-NP triggered hormonal imbalance and induce oxidative stress in testis and epididymis; which negatively affect sperm parameters of male rats. Full article

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2019

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17 pages, 1758 KiB

Open AccessArticle

The Preparation, Determination of a Flexible Complex Liposome Co-Loaded with Cabazitaxel and β-Elemene, and Animal Pharmacodynamics on Paclitaxel-Resistant Lung Adenocarcinoma

by Yi-Ying Zeng, Yi-Jun Zeng, Na-Na Zhang, Chen-Xi Li, Tian Xie and Zhao-Wu Zeng

Molecules 2019, 24(9), 1697; https://doi.org/10.3390/molecules24091697 - 30 Apr 2019

Cited by 31 | Viewed by 4047

Abstract

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung [...] Read more.

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and β-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, β-elemene liposome and cabazitaxel-β-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and β-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and β-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and β-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and β-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that β-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity. Full article

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2018

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16 pages, 3674 KiB

Open AccessArticle

Liposomes Loaded with Cisplatin and Magnetic Nanoparticles: Physicochemical Characterization, Pharmacokinetics, and In-Vitro Efficacy

by Alfonso Toro-Cordova, Mario Flores-Cruz, Jaime Santoyo-Salazar, Ernesto Carrillo-Nava, Rafael Jurado, Pavel A. Figueroa-Rodriguez, Pedro Lopez-Sanchez, Luis A. Medina and Patricia Garcia-Lopez

Molecules 2018, 23(9), 2272; https://doi.org/10.3390/molecules23092272 - 06 Sep 2018

Cited by 48 | Viewed by 6270

Abstract

With the aim improving drug delivery, liposomes have been employed as carriers for chemotherapeutics achieving promising results; their co-encapsulation with magnetic nanoparticles is evaluated in this work. The objective of this study was to examine the physicochemical characteristics, the pharmacokinetic behaviour, and the [...] Read more.

With the aim improving drug delivery, liposomes have been employed as carriers for chemotherapeutics achieving promising results; their co-encapsulation with magnetic nanoparticles is evaluated in this work. The objective of this study was to examine the physicochemical characteristics, the pharmacokinetic behaviour, and the efficacy of pegylated liposomes loaded with cisplatin and magnetic nanoparticles (magnetite) (Cis-MLs). Cis-MLs were prepared by a modified reverse-phase evaporation method. To characterize their physicochemical properties, an evaluation was made of particle size, ζ-potential, phospholipid and cholesterol concentration, phase transition temperature (T_m), the encapsulation efficiency of cisplatin and magnetite, and drug release profiles. Additionally, pharmacokinetic studies were conducted on normal Wistar rats, while apoptosis and the cytotoxic effect were assessed with HeLa cells. We present a method for simultaneously encapsulating cisplatin at the core and also embedding magnetite nanoparticles on the membrane of liposomes with a mean vesicular size of 104.4 ± 11.5 nm and a ζ-potential of −40.5 ± 0.8 mV, affording a stable formulation with a safe pharmacokinetic profile. These liposomes elicited a significant effect on cell viability and triggered apoptosis in HeLa cells. Full article

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17 pages, 6321 KiB

Open AccessArticle

A Gelatin Hydrogel-Containing Nano-Organic PEI–Ppy with a Photothermal Responsive Effect for Tissue Engineering Applications

by Mantosh Kumar Satapathy, Batzaya Nyambat, Chih-Wei Chiang, Chih-Hwa Chen, Pei-Chun Wong, Po-Hsien Ho, Pei-Ru Jheng, Thierry Burnouf, Ching-Li Tseng and Er-Yuan Chuang

Molecules 2018, 23(6), 1256; https://doi.org/10.3390/molecules23061256 - 24 May 2018

Cited by 53 | Viewed by 9014

Abstract

The introduction and designing of functional thermoresponsive hydrogels have been recommended as recent potential therapeutic approaches for biomedical applications. The development of bioactive materials such as thermosensitive gelatin-incorporated nano-organic materials with a porous structure and photothermally triggerable and cell adhesion properties may potentially [...] Read more.

The introduction and designing of functional thermoresponsive hydrogels have been recommended as recent potential therapeutic approaches for biomedical applications. The development of bioactive materials such as thermosensitive gelatin-incorporated nano-organic materials with a porous structure and photothermally triggerable and cell adhesion properties may potentially achieve this goal. This novel class of photothermal hydrogels can provide an advantage of hyperthermia together with a reversibly transformable hydrogel for tissue engineering. Polypyrrole (Ppy) is a bioorganic conducting polymeric substance and has long been used in biomedical applications owing to its brilliant stability, electrically conductive features, and excellent absorbance around the near-infrared (NIR) region. In this study, a cationic photothermal triggerable/guidable gelatin hydrogel containing a polyethylenimine (PEI)–Ppy nanocomplex with a porous microstructure was established, and its physicochemical characteristics were studied through dynamic light scattering, scanning electronic microscopy, transmission electron microscopy, an FTIR; and cellular interaction behaviors towards fibroblasts incubated with a test sample were examined via MTT assay and fluorescence microscopy. Photothermal performance was evaluated. Furthermore, the in vivo study was performed on male Wistar rat full thickness excisions model for checking the safety and efficacy of the designed gelatin–PEI–Ppy nanohydrogel system in wound healing and for other biomedical uses in future. This photothermally sensitive hydrogel system has an NIR-triggerable property that provides local hyperthermic temperature by PEI–Ppy nanoparticles for tissue engineering applications. Features of the designed hydrogel may fill other niches, such as being an antibacterial agent, generation of free radicals to further improve wound healing, and remodeling of the promising photothermal therapy for future tissue engineering applications. Full article

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14 pages, 1667 KiB

Open AccessArticle

Encapsulation of Gold Nanostructures and Oil-in-Water Nanocarriers in Microgels with Biomedical Potential

by Mariela Inostroza-Riquelme, Andrea Vivanco, Pablo Lara, Simón Guerrero, Edison Salas-Huenuleo, Alejandro Chamorro, Lisette Leyton, Karen Bolaños, Eyleen Araya, Andrew F. G. Quest, Marcelo J. Kogan and Felipe Oyarzun-Ampuero

Molecules 2018, 23(5), 1208; https://doi.org/10.3390/molecules23051208 - 18 May 2018

Cited by 16 | Viewed by 5002

Abstract

Here we report the incorporation of gold nanostructures (nanospheres or nanorods, functionalized with carboxylate-end PEG) and curcumin oil-in-water (O/W) nanoemulsions (CurNem) into alginate microgels using the dripping technique. While gold nanostructures are promising nanomaterials for photothermal therapy applications, CurNem possess important pharmacological activities [...] Read more.

Here we report the incorporation of gold nanostructures (nanospheres or nanorods, functionalized with carboxylate-end PEG) and curcumin oil-in-water (O/W) nanoemulsions (CurNem) into alginate microgels using the dripping technique. While gold nanostructures are promising nanomaterials for photothermal therapy applications, CurNem possess important pharmacological activities as reported here. In this sense, we evaluated the effect of CurNem on cell viability of both cancerous and non-cancerous cell lines (AGS and HEK293T, respectively), demonstrating preferential toxicity in cancer cells and safety for the non-cancerous cells. After incorporating gold nanostructures and CurNem together into the microgels, microstructures with diameters of 220 and 540 µm were obtained. When stimulating microgels with a laser, the plasmon effect promoted a significant rise in the temperature of the medium; the temperature increase was higher for those containing gold nanorods (11–12 °C) than nanospheres (1–2 °C). Interestingly, the incorporation of both nanosystems in the microgels maintains the photothermal properties of the gold nanostructures unmodified and retains with high efficiency the curcumin nanocarriers. We conclude that these results will be of interest to design hydrogel formulations with therapeutic applications. Full article

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29 pages, 35021 KiB

Open AccessReview

Nanotechnology for Cancer Therapy Based on Chemotherapy

by Chen-Yang Zhao, Rui Cheng, Zhe Yang and Zhong-Min Tian

Molecules 2018, 23(4), 826; https://doi.org/10.3390/molecules23040826 - 04 Apr 2018

Cited by 236 | Viewed by 16834

Abstract

Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been [...] Read more.

Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics. Full article

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2017

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265 KiB

Open AccessReview

The Use of Liposomes and Nanoparticles as Drug Delivery Systems to Improve Cancer Treatment in Dogs and Cats

by Katarzyna Zabielska-Koczywąs and Roman Lechowski

Molecules 2017, 22(12), 2167; https://doi.org/10.3390/molecules22122167 - 07 Dec 2017

Cited by 40 | Viewed by 9326

Abstract

Background: Cancer remains a leading cause of death in companion animals. In human medicine, liposomes and nanoparticles have been extensively investigated as drug delivery systems (DDS) for anticancer agents due to their ability to target cancerous cells and reduce the negative side effects [...] Read more.

Background: Cancer remains a leading cause of death in companion animals. In human medicine, liposomes and nanoparticles have been extensively investigated as drug delivery systems (DDS) for anticancer agents due to their ability to target cancerous cells and reduce the negative side effects of free cytostatic drugs. In this review, the authors discuss the results of clinical trials using liposomes and polymer-based nanoparticles as DDS to improve cancer treatment in dogs and cats, indicating which ones seem worth further evaluation. The authors then overview ongoing animal cancer clinical trials, evaluating nano-DDS registered on the American Veterinary Medical Association Animal Health Studies Database. Finally, the authors indicate the nano-drugs that require further in vivo evaluation based on the encouraging results obtained from in vitro studies. Conclusions: Liposomes have been the most investigated nano-DDS in veterinary medicine. The lack of cardiotoxicity of the commercially available liposomal doxorubicin (Doxil/Caelyx) suggests it should be used in dogs with cardiac disorders, rather than using free doxorubicin. Cisplatin-incorporated hyaluronic acid nanoparticles, nanocrystals of cisplatin, and paclitaxel are the most promising nano-drugs for potent applications in treating various canine cancers (e.g. oral melanoma, oral sarcoma, and anal gland adenocarcinoma) and their translation into the treatment of human diseases. Full article

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Open AccessArticle

Novel Anti-Tuberculosis Nanodelivery Formulation of Ethambutol with Graphene Oxide

by Bullo Saifullah, Alina Chrzastek, Arundhati Maitra, Bullo Naeemullah, Sharida Fakurazi, Sanjib Bhakta and Mohd Zobir Hussein

Molecules 2017, 22(10), 1560; https://doi.org/10.3390/molecules22101560 - 12 Oct 2017

Cited by 24 | Viewed by 6981

Abstract

Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients’ noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century [...] Read more.

Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients’ noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century old standard chemotherapy have been made based on a nanoformulation strategy to improve pharmacokinetic efficacy. In this study, we have designed a new nanodelivery formulation, using graphene oxide as the nanocarrier, loaded with the anti-TB antibiotic, ethambutol. The designed formulation was characterized using a number of molecular analytical techniques. It was found that sustained release of the drug resulted in better bioavailability. In addition, the designed formulation demonstrated high biocompatibility with mouse fibroblast cells. The anti-TB activity of the nanodelivery formulation was determined using whole-cell resazurin microtiter plate assay, modified-spot culture growth inhibition assay, and biofilm inhibition assay. The nanodelivery formulation showed good anti-mycobacterial activity. The anti-mycobacterial activity of Ethambutol was unaffected by the drug loading and release process. The results of this study demonstrated the potential of this new nanodelivery formulation strategy to be considered for modifying existing chemotherapy to yield more efficacious antibiotic treatment against TB. Full article

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2294 KiB

Open AccessArticle

Rapid Complexation of Aptamers by Their Specific Antidotes

by Heidi Stoll, Heidrun Steinle, Nadja Wilhelm, Ludmilla Hann, Silju-John Kunnakattu, Miwako Narita, Christian Schlensak, Hans P. Wendel and Meltem Avci-Adali

Molecules 2017, 22(6), 954; https://doi.org/10.3390/molecules22060954 - 08 Jun 2017

Cited by 10 | Viewed by 5171

Abstract

Nucleic acid ligands, aptamers, harbor the unique characteristics of small molecules and antibodies. The specificity and high affinity of aptamers enable their binding to different targets, such as small molecules, proteins, or cells. Chemical modifications of aptamers allow increased bioavailability. A further great [...] Read more.

Nucleic acid ligands, aptamers, harbor the unique characteristics of small molecules and antibodies. The specificity and high affinity of aptamers enable their binding to different targets, such as small molecules, proteins, or cells. Chemical modifications of aptamers allow increased bioavailability. A further great benefit of aptamers is the antidote (AD)-mediated controllability of their effect. In this study, the AD-mediated complexation and neutralization of the thrombin binding aptamer NU172 and Toll-like receptor 9 (TLR9) binding R10-60 aptamer were determined. Thereby, the required time for the generation of aptamer/AD-complexes was analyzed at 37 °C in human serum using gel electrophoresis. Afterwards, the blocking of aptamers’ effects was analyzed by determining the activated clotting time (ACT) in the case of the NU172 aptamer, or the expression of immune activation related genes IFN-1β, IL-6, CXCL-10, and IL-1β in the case of the R10-60 aptamer. Gel electrophoresis analyses demonstrated the rapid complexation of the NU172 and R10-60 aptamers by complementary AD binding after just 2 min of incubation in human serum. A rapid neutralization of anticoagulant activity of NU172 was also demonstrated in fresh human whole blood 5 min after addition of AD. Furthermore, the TLR9-mediated activation of PMDC05 cells was interrupted after the addition of the R10-60 AD. Using these two different aptamers, the rapid antagonizability of the aptamers was demonstrated in different environments; whole blood containing numerous proteins, cells, and different small molecules, serum, or cell culture media. Thus, nucleic acid ADs are promising molecules, which offer several possibilities for different in vivo applications, such as antagonizing aptamer-based drugs, immobilization, or delivery of oligonucleotides to defined locations. Full article

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2016

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6036 KiB

Open AccessReview

Time-Resolved Fluorescence Spectroscopy and Fluorescence Lifetime Imaging Microscopy for Characterization of Dendritic Polymer Nanoparticles and Applications in Nanomedicine

by Alexander Boreham, Robert Brodwolf, Karolina Walker, Rainer Haag and Ulrike Alexiev

Molecules 2017, 22(1), 17; https://doi.org/10.3390/molecules22010017 - 24 Dec 2016

Cited by 32 | Viewed by 10196

Abstract

The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the [...] Read more.

The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the nanoparticles a proper characterization is not trivial. This review highlights the application of time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy (FLIM) for the analysis of nanoparticles, covering aspects ranging from molecular properties to particle detection in tissue samples. The latter technique is particularly important as FLIM allows for distinguishing of target molecules from the autofluorescent background and, due to the environmental sensitivity of the fluorescence lifetime, also offers insights into the local environment of the nanoparticle or its interactions with other biomolecules. Thus, these techniques offer highly suitable tools in the fields of particle development, such as organic chemistry, and in the fields of particle application, such as in experimental dermatology or pharmaceutical research. Full article

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Open AccessArticle

New Oral Formulation and in Vitro Evaluation of Docetaxel-Loaded Nanomicelles

by Atefeh Hekmat, Hossein Attar, Ali Akbar Seyf Kordi, Maryam Iman and Mahmoud Reza Jaafari

Molecules 2016, 21(9), 1265; https://doi.org/10.3390/molecules21091265 - 21 Sep 2016

Cited by 14 | Viewed by 6688

Abstract

Intravenous administration of Taxotere^® (a commercial form of docetaxel, DTX) leads to many problems such as hypersensitivity, hemolysis, cutaneous allergy, and patient refusal due to its prolonged injection. The oral absorption of DTX is very low due to its hydrophobic nature. The [...] Read more.

Intravenous administration of Taxotere^® (a commercial form of docetaxel, DTX) leads to many problems such as hypersensitivity, hemolysis, cutaneous allergy, and patient refusal due to its prolonged injection. The oral absorption of DTX is very low due to its hydrophobic nature. The purpose of this study was to prepare and carry out an in vitro evaluation of DTX-loaded nanomicelles for oral administration in order to increase the oral delivery of DTX. Studied formulations were prepared with the two surfactants Tween 20 and Tween 80 and were characterized for their particle size, zeta potential, stability, encapsulation efficiency, stability studies in gastric fluid and intestinal fluid, toxicity studies in C26 colon carcinoma cell line, and cellular uptake. The prepared nanomicelles with particle size of around 14 nm and encapsulation efficiency of 99% were stable in gastric fluid and intestinal fluid for at least 6 h and IC50 decreased significantly after 72 h exposure compared to that of Taxotere^®. Nanomicelles increased the water solubility of DTX more than 1500 times (10 mg/mL in nanomicelles compared to 6 µg/mL in water). Results of this study reveal that the new formulation of DTX could be used for the oral delivery of DTX and merits further investigation. Full article

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Open AccessArticle

Layered Double Hydroxide as a Vehicle to Increase Toxicity of Gallate Ions against Adenocarcinoma Cells

by Jenny Arratia-Quijada, Selma Rivas-Fuentes, Karina J. Parra Saavedra, Adriana M. Macías Lamas and Gregorio Guadalupe Carbajal Arízaga

Molecules 2016, 21(7), 928; https://doi.org/10.3390/molecules21070928 - 16 Jul 2016

Cited by 9 | Viewed by 5456

Abstract

The antineoplasic activity of gallic acid has been reported. This compound induces apoptosis and inhibits the growth of several neoplasic cells. However, this molecule is easily oxidized and degraded in the body. The aim of this work was to intercalate gallate ions into [...] Read more.

The antineoplasic activity of gallic acid has been reported. This compound induces apoptosis and inhibits the growth of several neoplasic cells. However, this molecule is easily oxidized and degraded in the body. The aim of this work was to intercalate gallate ions into layered double hydroxide (LDH) nanoparticles under controlled conditions to reduce oxidation of gallate and to evaluate its toxicity against the A549 adenocarcinoma cell line. An isopropanol medium under nitrogen atmosphere was adequate to intercalate gallate ions with a lesser oxidation degree as detected by electron spin resonance spectroscopy. Concentrations of the hybrid LDH-gallate nanoparticles between 0.39 and 25 µg/mL reduced the cell viability to 67%, while the value reached with the pure gallic acid and LDH was 90% and 78%, respectively, thus proving that the combination of gallate ions with the inorganic nanoparticles increases the toxicity potential within this dose range. Full article

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1358 KiB

Open AccessReview

Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes

by Gudepalya Renukaiah Rudramurthy, Mallappa Kumara Swamy, Uma Rani Sinniah and Ali Ghasemzadeh

Molecules 2016, 21(7), 836; https://doi.org/10.3390/molecules21070836 - 27 Jun 2016

Cited by 386 | Viewed by 16079

Abstract

Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals). Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, [...] Read more.

Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals). Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs) depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future. Full article

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Open AccessArticle

Optimization of Preparation Conditions for Lysozyme Nanoliposomes Using Response Surface Methodology and Evaluation of Their Stability

by Zhipan Wu, Rongfa Guan, Fei Lyu, Mingqi Liu, Jianguo Gao and Guozou Cao

Molecules 2016, 21(6), 741; https://doi.org/10.3390/molecules21060741 - 08 Jun 2016

Cited by 13 | Viewed by 5326

Abstract

The main purpose of this study was to optimize the preparation of lysozyme nanoliposomes using response surface methodology and measure their stability. The stabilities of lysozyme nanoliposomes in simulated gastrointestinal fluid (SGF), simulated intestinal fluid (SIF), as well as pH, temperature and sonication [...] Read more.

The main purpose of this study was to optimize the preparation of lysozyme nanoliposomes using response surface methodology and measure their stability. The stabilities of lysozyme nanoliposomes in simulated gastrointestinal fluid (SGF), simulated intestinal fluid (SIF), as well as pH, temperature and sonication treatment time were evaluated. Reverse-phase evaporation method is an easy, speedy, and beneficial approach for nanoliposomes’ preparation and optimization. The optimal preparative conditions were as follows: phosphatidylcholine-to-cholesterol ratio of 3.86, lysozyme concentration of 1.96 mg/mL, magnetic stirring time of 40.61 min, and ultrasound time of 14.15 min. At the optimal point, encapsulation efficiency and particle size were found to be 75.36% ± 3.20% and 245.6 nm ± 5.2 nm, respectively. The lysozyme nanoliposomes demonstrated certain stability in SGF and SIF at a temperature of 37 °C for 4 h, and short sonication handling times were required to attain nano-scaled liposomes. Under conditions of high temperature, acidity and alkalinity, lysozyme nanoliposomes are unstable. Full article

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Open AccessArticle

Poly (l-γ-glutamylglutamine) Polymer Enhances Doxorubicin Accumulation in Multidrug Resistant Breast Cancer Cells

by Ting Peng, Kai Liu, Liefang Gao, Lipeng Gao, Jing Chen, Jing Wang, Yu Liu, Yiting Wang, Zhiqiang Yan and Lei Yu

Molecules 2016, 21(6), 720; https://doi.org/10.3390/molecules21060720 - 02 Jun 2016

Cited by 10 | Viewed by 6213

Abstract

Background: Drug resistance is one of the bottlenecks of cancer chemotherapy in the clinic. Polymeric nanomedicine is one of the most promising strategies for overcoming poor chemotherapy responses due to the multidrug resistance (MDR). Methods: In this study, a new polymer-based [...] Read more.

Background: Drug resistance is one of the bottlenecks of cancer chemotherapy in the clinic. Polymeric nanomedicine is one of the most promising strategies for overcoming poor chemotherapy responses due to the multidrug resistance (MDR). Methods: In this study, a new polymer-based drug delivery system, poly (l-γ-glutamylglutamine)-doxorubicin (PGG-Dox) conjugate, was studied in both drug-induced resistant human breast cancer MDA-MB-231/MDR cells and their parent human breast cancer MDA-MB-231 cells. The effect of PGG on facilitating the growth inhibition of Dox against multidrug resistant cells were investigated by evaluating the cytotoxicity of PGG-Dox conjugate, PGG/Dox unconjugated complex and free Dox on both cells. The underlying mechanisms in resistant cells were further studied via the intracellular traffic studies. Results: Both conjugated and unconjugated PGG significantly increased Dox uptake, prolonged Dox retention and reduced Dox efflux in the MDA-MB-231/MDR cells. The PGG-Dox conjugate is taken up by tumor cells mainly by pinocytosis pathway, in which PGG-Dox conjugate-containing vesicles are formed and enter the cells. Conclusions: This study indicated that both polymer-drug conjugate and unconjugated complex are promising strategies of overcoming resistance of anti-tumor drugs. Full article

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Open AccessArticle

An Electrostatically Self-Assembled Ternary Nanocomplex as a Non-Viral Vector for the Delivery of Plasmid DNA into Human Adipose-Derived Stem Cells

by Sun-Hee Cho, Young-Woock Noh, Mi Young Cho and Yong Taik Lim

Molecules 2016, 21(5), 572; https://doi.org/10.3390/molecules21050572 - 29 Apr 2016

Cited by 6 | Viewed by 6991

Abstract

In this study, we developed electrostatically self-assembled ternary nanocomplexes as a safe and effective non-viral vector for the delivery of plasmid DNA (pDNA) into human adipose-derived stem cells (hASCs). Although polyethylenimine (PEI) polymers initially showed excellent performance as gene delivery carriers, their broad [...] Read more.

In this study, we developed electrostatically self-assembled ternary nanocomplexes as a safe and effective non-viral vector for the delivery of plasmid DNA (pDNA) into human adipose-derived stem cells (hASCs). Although polyethylenimine (PEI) polymers initially showed excellent performance as gene delivery carriers, their broad use has been limited by cytotoxicity resulting from their strong positive charge. To reduce the cytotoxicity, we utilized anionic hyaluronic acid (HA) as a corona layer material for pDNA/PEI binary nanocomplexes. HA was also introduced to increase the targeting efficiency of pDNA/PEI nanocomplexes because HA has can bind CD44 that is highly expressed on the surface of hASCs. We confirmed that the addition of HA changed the surface charge of pDNA/PEI nanocomplexes from positive to negative. The pDNA/PEI/HA ternary nanocomplexes showed high transfection efficiency and low cytotoxicity compared with commercially available products. When hASCs were pretreated with HA to passivate CD44, the transfection efficiency of pDNA/PEI/HA nanocomplexes was significantly reduced. These results suggest that HA that can act as a targeting ligand to CD44 contributed to the improved transfection of pDNA into hASCs. Our novel pDNA/PEI/HA nanocomplexes may be used as an effective non-viral pDNA delivery system for hASCs. Full article

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Open AccessArticle

Evaluation of the Nano-TiO₂ as a Novel Deswelling Material

by Ming Chu, Yue-Long Hou, Lan Xu, Zheng-Yun Chu, Ming-Bo Zhang and Yue-Dan Wang

Molecules 2016, 21(1), 57; https://doi.org/10.3390/molecules21010057 - 04 Jan 2016

Cited by 5 | Viewed by 5455

Abstract

Nano-TiO₂ is widely applied in the automobile exhaust hose reels as a catalyst to reduce oxynitride emissions, including nitric oxide (NO). In the biomedicine field, NO plays an important role in vasodilation and edema formation in human bodies. However, the deswelling activity [...] Read more.

Nano-TiO₂ is widely applied in the automobile exhaust hose reels as a catalyst to reduce oxynitride emissions, including nitric oxide (NO). In the biomedicine field, NO plays an important role in vasodilation and edema formation in human bodies. However, the deswelling activity of nano-TiO₂ has not been reported. Here, we demonstrated that nano-TiO₂ can significantly degrade the production of NO in LPS-induced RAW264.7 mouse macrophages. Further study indicated that nano-TiO₂ exhibited an effect on vascular permeability inhibition, and prevented carrageenan-induced footpad edema. Therefore, we prepared a nano-TiO₂ ointment and observed similar deswelling effects. In conclusion, nano-TiO₂ might act as a novel deswelling agent related with its degradation of NO, which will aid in our ability to design effective interventions for edema involved diseases. Full article

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2015

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1896 KiB

Open AccessArticle

Detecting and Quantifying Biomolecular Interactions of a Dendritic Polyglycerol Sulfate Nanoparticle Using Fluorescence Lifetime Measurements

by Alexander Boreham, Jens Pikkemaat, Pierre Volz, Robert Brodwolf, Christian Kuehne, Kai Licha, Rainer Haag, Jens Dernedde and Ulrike Alexiev

Molecules 2016, 21(1), 22; https://doi.org/10.3390/molecules21010022 - 24 Dec 2015

Cited by 25 | Viewed by 7586

Abstract

Interactions of nanoparticles with biomaterials determine the biological activity that is key for the physiological response. Dendritic polyglycerol sulfates (dPGS) were found recently to act as an inhibitor of inflammation by blocking selectins. Systemic application of dPGS would present this nanoparticle to various [...] Read more.

Interactions of nanoparticles with biomaterials determine the biological activity that is key for the physiological response. Dendritic polyglycerol sulfates (dPGS) were found recently to act as an inhibitor of inflammation by blocking selectins. Systemic application of dPGS would present this nanoparticle to various biological molecules that rapidly adsorb to the nanoparticle surface or lead to adsorption of the nanoparticle to cellular structures such as lipid membranes. In the past, fluorescence lifetime measurements of fluorescently tagged nanoparticles at a molecular and cellular/tissue level have been proven to reveal valuable information on the local nanoparticle environment via characteristic fluorescent lifetime signatures of the nanoparticle bound dye. Here, we established fluorescence lifetime measurements as a tool to determine the binding affinity to fluorescently tagged dPGS (dPGS-ICC; ICC: indocarbocyanine). The binding to a cell adhesion molecule (L-selectin) and a human complement protein (C1q) to dPGS-ICC was evaluated by the concentration dependent change in the unique fluorescence lifetime signature of dPGS-ICC. The apparent binding affinity was found to be in the nanomolar range for both proteins (L-selectin: 87 ± 4 nM and C1q: 42 ± 12 nM). Furthermore, the effect of human serum on the unique fluorescence lifetime signature of dPGS-ICC was measured and found to be different from the interactions with the two proteins and lipid membranes. A comparison between the unique lifetime signatures of dPGS-ICC in different biological environments shows that fluorescence lifetime measurements of unique dPGS-ICC fluorescence lifetime signatures are a versatile tool to probe the microenvironment of dPGS in cells and tissue. Full article

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222 KiB

Open AccessEditorial

Introduction to Nanomedicine

by Didier Astruc

Molecules 2016, 21(1), 4; https://doi.org/10.3390/molecules21010004 - 22 Dec 2015

Cited by 25 | Viewed by 6844

Abstract

Although mentions of nanoparticles in relation to biomedicine appeared in the late 1970s and are now the subject of over 10,000 publications per year, the term “Nanomedicine” only appeared at the turn of this century, and less than 30 papers including this term [...] Read more.

Although mentions of nanoparticles in relation to biomedicine appeared in the late 1970s and are now the subject of over 10,000 publications per year, the term “Nanomedicine” only appeared at the turn of this century, and less than 30 papers including this term were published up to 2005. [...] Full article

1806 KiB

Open AccessArticle

Anti-Lymphoma Efficacy Comparison of Anti-Cd20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug Conjugates

by Ondřej Lidický, Olga Janoušková, Jiří Strohalm, Mahmudul Alam, Pavel Klener and Tomáš Etrych

Molecules 2015, 20(11), 19849-19864; https://doi.org/10.3390/molecules201119664 - 04 Nov 2015

Cited by 18 | Viewed by 7882

Abstract

Here we describe the synthesis and biological properties of two types of star-shaped polymer-doxorubicin conjugates: non-targeted conjugate prepared as long-circulating high-molecular-weight (HMW) polymer prodrugs with a dendrimer core and a targeted conjugate with the anti-CD20 monoclonal antibody (mAb) rituximab (RTX). The copolymers were [...] Read more.

Here we describe the synthesis and biological properties of two types of star-shaped polymer-doxorubicin conjugates: non-targeted conjugate prepared as long-circulating high-molecular-weight (HMW) polymer prodrugs with a dendrimer core and a targeted conjugate with the anti-CD20 monoclonal antibody (mAb) rituximab (RTX). The copolymers were linked to the dendrimer core or to the reduced mAb via one-point attachment forming a star-shaped structure with a central antibody or dendrimer surrounded by hydrophilic polymer chains. The anticancer drug doxorubicin (DOX) was attached to the N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer chain in star polymer systems via a pH-labile hydrazone linkage. Such polymer-DOX conjugates were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly acidic environments at pH 5–5.5 by hydrolysis of the hydrazone bonds. The cytotoxicity of the polymer conjugates was tested on several CD20-positive or negative human cell lines. Similar levels of in vitro cytotoxicity were observed for all tested polymer conjugates regardless of type or structure. In vivo experiments using primary cell-based murine xenograft models of human diffuse large B-cell lymphoma confirmed the superior anti-lymphoma efficacy of the polymer-bound DOX conjugate when compared with the original drug. Targeting with RTX did not further enhance the anti-lymphoma efficacy relative to the non-targeted star polymer conjugate. Two mechanisms could play roles in these findings: changes in the binding ability to the CD-20 receptor and a significant loss of the immunological properties of RTX in the polymer conjugates. Full article

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2664 KiB

Open AccessReview

The Phe-Phe Motif for Peptide Self-Assembly in Nanomedicine

by Silvia Marchesan, Attilio V. Vargiu and Katie E. Styan

Molecules 2015, 20(11), 19775-19788; https://doi.org/10.3390/molecules201119658 - 03 Nov 2015

Cited by 128 | Viewed by 15673

Abstract

Since its discovery, the Phe-Phe motif has gained in popularity as a minimalist building block to drive the self-assembly of short peptides and their analogues into nanostructures and hydrogels. Molecules based on the Phe-Phe motif have found a range of applications in nanomedicine, [...] Read more.

Since its discovery, the Phe-Phe motif has gained in popularity as a minimalist building block to drive the self-assembly of short peptides and their analogues into nanostructures and hydrogels. Molecules based on the Phe-Phe motif have found a range of applications in nanomedicine, from drug delivery and biomaterials to new therapeutic paradigms. Here we discuss the various production methods for this class of compounds, and the characterization, nanomorphologies, and application of their self-assembled nanostructures. We include the most recent findings on their remarkable properties, which hold substantial promise for the creation of the next generation nanomedicines. Full article

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2155 KiB

Open AccessArticle

Tetracycline-Containing MCM-41 Mesoporous Silica Nanoparticles for the Treatment of Escherichia coli

by Bhuvaneswari Koneru, Yi Shi, Yu-Chieh Wang, Sai H. Chavala, Michael L. Miller, Brittany Holbert, Maricar Conson, Aiguo Ni and Anthony J. Di Pasqua

Molecules 2015, 20(11), 19690-19698; https://doi.org/10.3390/molecules201119650 - 30 Oct 2015

Cited by 45 | Viewed by 8682

Abstract

Tetracycline (TC) is a well-known broad spectrum antibiotic, which is effective against many Gram positive and Gram negative bacteria. Controlled release nanoparticle formulations of TC have been reported, and could be beneficial for application in the treatment of periodontitis and dental bone infections. [...] Read more.

Tetracycline (TC) is a well-known broad spectrum antibiotic, which is effective against many Gram positive and Gram negative bacteria. Controlled release nanoparticle formulations of TC have been reported, and could be beneficial for application in the treatment of periodontitis and dental bone infections. Furthermore, TC-controlled transcriptional regulation systems (Tet-on and Tet-off) are useful for controlling transgene expression in vitro and in vivo for biomedical research purposes; controlled TC release systems could be useful here, as well. Mesoporous silica nanomaterials (MSNs) are widely studied for drug delivery applications; Mobile crystalline material 41 (MCM-41), a type of MSN, has a mesoporous structure with pores forming channels in a hexagonal fashion. We prepared 41 ± 4 and 406 ± 55 nm MCM-41 mesoporous silica nanoparticles and loaded TC for controlled dug release; TC content in the TC-MCM-41 nanoparticles was 18.7% and 17.7% w/w, respectively. Release of TC from TC-MCM-41 nanoparticles was then measured in phosphate-buffered saline (PBS), pH 7.2, at 37 °C over a period of 5 h. Most antibiotic was released from both over this observation period; however, the majority of TC was released over the first hour. Efficacy of the TC-MCM-41 nanoparticles was then shown to be superior to free TC against Escherichia coli (E. coli) in culture over a 24 h period, while blank nanoparticles had no effect. Full article

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1275 KiB

Open AccessArticle

Poly(Propylene Imine) Dendrimers and Amoxicillin as Dual-Action Antibacterial Agents

by Natalia Wrońska, Aleksandra Felczak, Katarzyna Zawadzka, Martyna Poszepczyńska, Sylwia Różalska, Maria Bryszewska, Dietmar Appelhans and Katarzyna Lisowska

Molecules 2015, 20(10), 19330-19342; https://doi.org/10.3390/molecules201019330 - 23 Oct 2015

Cited by 21 | Viewed by 9979

Abstract

Besides acting as antimicrobial compounds, dendrimers can be considered as agents that improve the therapeutic effectiveness of existing antibiotics. In this work we present a new approach to using amoxicillin (AMX) against reference strains of common Gram-negative pathogens, alone and in combination with [...] Read more.

Besides acting as antimicrobial compounds, dendrimers can be considered as agents that improve the therapeutic effectiveness of existing antibiotics. In this work we present a new approach to using amoxicillin (AMX) against reference strains of common Gram-negative pathogens, alone and in combination with poly(propylene imine) (PPI) dendrimers, or derivatives thereof, in which 100% of the available hydrogen atoms are substituted with maltose (PPI 100%malG3). The concentrations of dendrimers used remained in the range non-toxic to eukaryotic cells. The results indicate that PPI dendrimers significantly enhance the antibacterial effect of amoxicillin alone, allowing antibiotic doses to be reduced. It is important to reduce doses of amoxicillin because its widespread use in medicine could lead to the development of bacterial resistance and environmental pollution. This is the first report on the combined antibacterial activity of PPI surface-modified maltose dendrimers and amoxicillin. Full article

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3358 KiB

Open AccessArticle

Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids

by Annkathrin Hornung, Marina Poettler, Ralf P. Friedrich, Jan Zaloga, Harald Unterweger, Stefan Lyer, Johannes Nowak, Stefan Odenbach, Christoph Alexiou and Christina Janko

Molecules 2015, 20(10), 18016-18030; https://doi.org/10.3390/molecules201018016 - 30 Sep 2015

Cited by 29 | Viewed by 7500

Abstract

Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide nanoparticles (SPION) loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in [...] Read more.

Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide nanoparticles (SPION) loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO) with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPION^MTO) are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPION^MTO has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo. Full article

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2031 KiB

Open AccessReview

Designing Dendrimer and Miktoarm Polymer Based Multi-Tasking Nanocarriers for Efficient Medical Therapy

by Anjali Sharma and Ashok Kakkar

Molecules 2015, 20(9), 16987-17015; https://doi.org/10.3390/molecules200916987 - 17 Sep 2015

Cited by 51 | Viewed by 12357

Abstract

To address current complex health problems, there has been an increasing demand for smart nanocarriers that could perform multiple complimentary biological tasks with high efficacy. This has provoked the design of tailor made nanocarriers, and the scientific community has made tremendous effort in [...] Read more.

To address current complex health problems, there has been an increasing demand for smart nanocarriers that could perform multiple complimentary biological tasks with high efficacy. This has provoked the design of tailor made nanocarriers, and the scientific community has made tremendous effort in meeting daunting challenges associated with synthetically articulating multiple functions into a single scaffold. Branched and hyper-branched macromolecular architectures have offered opportunities in enabling carriers with capabilities including location, delivery, imaging etc. Development of simple and versatile synthetic methodologies for these nanomaterials has been the key in diversifying macromolecule based medical therapy and treatment. This review highlights the advancement from conventional “only one function” to multifunctional nanomedicine. It is achieved by synthetic elaboration of multivalent platforms in miktoarm polymers and dendrimers by physical encapsulation, covalent linking and combinations thereof. Full article

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1334 KiB

Open AccessArticle

Inorganic Phosphate Prevents Erk1/2 and Stat3 Activation and Improves Sensitivity to Doxorubicin of MDA-MB-231 Breast Cancer Cells

by Luigi Sapio, Luca Sorvillo, Michela Illiano, Emilio Chiosi, Annamaria Spina and Silvio Naviglio

Molecules 2015, 20(9), 15910-15928; https://doi.org/10.3390/molecules200915910 - 01 Sep 2015

Cited by 25 | Viewed by 7232

Abstract

Due to its expression profile, triple-negative breast cancer (TNBC) is refractory to the most effective targeted therapies available for breast cancer treatment. Thus, cytotoxic chemotherapy represents the mainstay of treatment for early and metastatic TNBC. Therefore, it would be greatly beneficial to develop [...] Read more.

Due to its expression profile, triple-negative breast cancer (TNBC) is refractory to the most effective targeted therapies available for breast cancer treatment. Thus, cytotoxic chemotherapy represents the mainstay of treatment for early and metastatic TNBC. Therefore, it would be greatly beneficial to develop therapeutic approaches that cause TNBC cells to increase their sensitivity to cytotoxic drugs. Inorganic phosphate (Pi) is emerging as an important signaling molecule in many cell types. Interestingly, it has been shown that Pi greatly enhances the sensitivity of human osteosarcoma cell line (U2OS) to doxorubicin. We investigated the effects of Pi on the sensitivity of TNBC cells to doxorubicin and the underlying molecular mechanisms, carrying out flow cytometry-based assays of cell-cycle progression and cell death, MTT assays, direct cell number counting and immunoblotting experiments. We report that Pi inhibits the proliferation of triple-negative MDA-MB-231 breast cancer cells mainly by slowing down cell cycle progression. Interestingly, we found that Pi strongly increases doxorubicin-induced cytotoxicity in MDA-MB-231 cells by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was dynamically accompanied by profound changes in Erk1/2 and Stat3 protein and phosphorylation levels. Altogether, our data enforce the evidence of Pi acting as a signaling molecule in MDA-MB-231 cells, capable of inhibiting Erk and Stat3 pathways and inducing sensitization to doxorubicin of TNBC cells, and suggest that targeting Pi levels at local sites might represent the rationale for developing effective and inexpensive strategies for improving triple-negative breast cancer therapy. Full article

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Open AccessArticle

Anti-Tumor Effects of Bak-Proteoliposomes against Glioblastoma

by Lavinia Liguori, Fabio Pastorino, Xavier Rousset, Silvia Alfano, Sandra Cortes, Laura Emionite, Antonio Daga, Mirco Ponzoni and Jean-Luc Lenormand

Molecules 2015, 20(9), 15893-15909; https://doi.org/10.3390/molecules200915893 - 01 Sep 2015

Cited by 6 | Viewed by 6204

Abstract

Despite palliative treatments, glioblastoma (GBM) remains a devastating malignancy with a mean survival of about 15 months after diagnosis. Programmed cell-death is de-regulated in almost all GBM and the re-activation of the mitochondrial apoptotic pathway through exogenous bioactive proteins may represent a powerful [...] Read more.

Despite palliative treatments, glioblastoma (GBM) remains a devastating malignancy with a mean survival of about 15 months after diagnosis. Programmed cell-death is de-regulated in almost all GBM and the re-activation of the mitochondrial apoptotic pathway through exogenous bioactive proteins may represent a powerful therapeutic tool to treat multidrug resistant GBM. We have reported that human Bak protein integrated in Liposomes (LB) was able, in vitro, to activate the mitochondrial apoptotic pathway in colon cancer cells. To evaluate the anti-tumor effects of LB on GBM, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and Western blot analysis were performed on GL26 murine cell line. LB treatment shows a dose-dependent inhibition of cell viability, followed by an up-regulation of Bax and a down-modulation of JNK1 proteins. In GL26-bearing mice, two different routes of administration were tested: intra-tumor and intravenous. Biodistribution, tumor growth and animal survival rates were followed. LB show long-lasting tumor accumulation. Moreover, the intra-tumor administration of LB induces tumor growth delay and total tumor regression in about 40% of treated mice, while the intravenous injection leads to a significant increased life span of mice paralleled by an increased tumor cells apoptosis. Our findings are functional to the design of LB with potentiated therapeutic efficacy for GBM. Full article

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3898 KiB

Open AccessArticle

A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4

by Suresh Panneerselvam, Dhanusha Yesudhas, Prasannavenkatesh Durai, Muhammad Ayaz Anwar, Vijayakumar Gosu and Sangdun Choi

Molecules 2015, 20(8), 14915-14935; https://doi.org/10.3390/molecules200814915 - 14 Aug 2015

Cited by 24 | Viewed by 8833

Abstract

Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the [...] Read more.

Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs. Full article

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Open AccessArticle

Solid Lipid Nanoparticles: A Potential Multifunctional Approach towards Rheumatoid Arthritis Theranostics

by João Albuquerque, Catarina Costa Moura, Bruno Sarmento and Salette Reis

Molecules 2015, 20(6), 11103-11118; https://doi.org/10.3390/molecules200611103 - 16 Jun 2015

Cited by 68 | Viewed by 8135

Abstract

Rheumatoid arthritis (RA) is the most common joint-related autoimmune disease and one of the most severe. Despite intensive investigation, the RA inflammatory process remains largely unknown and finding effective and long lasting therapies that specifically target RA is a challenging task. This study [...] Read more.

Rheumatoid arthritis (RA) is the most common joint-related autoimmune disease and one of the most severe. Despite intensive investigation, the RA inflammatory process remains largely unknown and finding effective and long lasting therapies that specifically target RA is a challenging task. This study proposes a different approach for RA therapy, taking advantage of the new emerging field of nanomedicine to develop a targeted theranostic system for intravenous administration, using solid lipid nanoparticles (SLN), a biocompatible and biodegradable colloidal delivery system, surface-functionalized with an anti-CD64 antibody that specifically targets macrophages in RA. Methotrexate (MTX) and superparamagnetic iron oxide nanoparticles (SPIONs) were co-encapsulated inside the SLNs to be used as therapeutic and imaging agents, respectively. All the formulations presented sizes under 250 nm and zeta potential values lower than −16 mV, suitable characteristics for intravenous administration. Transmission electron microscopy (TEM) photographs indicated that the SPIONs were encapsulated inside the SLN matrix and MTX association efficiency values were higher than 98%. In vitro studies, using THP-1 cells, demonstrated that all formulations presented low cytotoxicity at concentrations lower than 500 μg/mL. It was proven that the proposed NPs were not cytotoxic, that both a therapeutic and imaging agent could be co-encapsulated and that the SLN could be functionalized for a potential future application such as anti-body specific targeting. The proposed formulations are, therefore, promising candidates for future theranostic applications. Full article

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Open AccessReview

Multifunctional Iron Bound Lactoferrin and Nanomedicinal Approaches to Enhance Its Bioactive Functions

by Jagat R. Kanwar, Kislay Roy, Yogesh Patel, Shu-Feng Zhou, Manju Rawat Singh, Deependra Singh, Muhammad Nasir, Rakesh Sehgal, Alka Sehgal, Ram Sarup Singh, Sanjay Garg and Rupinder K. Kanwar

Molecules 2015, 20(6), 9703-9731; https://doi.org/10.3390/molecules20069703 - 26 May 2015

Cited by 96 | Viewed by 19768

Abstract

Lactoferrin (Lf), an iron-binding protein from the transferrin family has been reported to have numerous functions. Even though Lf was first isolated from milk, it is also found in most exocrine secretions and in the secondary granules of neutrophils. Antimicrobial and anti-inflammatory activity [...] Read more.

Lactoferrin (Lf), an iron-binding protein from the transferrin family has been reported to have numerous functions. Even though Lf was first isolated from milk, it is also found in most exocrine secretions and in the secondary granules of neutrophils. Antimicrobial and anti-inflammatory activity reports on lactoferrin identified its significance in host defense against infection and extreme inflammation. Anticarcinogenic reports on lactoferrin make this protein even more valuable. This review is focused on the structural configuration of iron-containing and iron-free forms of lactoferrin obtained from different sources such as goat, camel and bovine. Apart for emphasizing on the specific beneficial properties of lactoferrin from each of these sources, the general antimicrobial, immunomodulatory and anticancer activities of lactoferrin are discussed here. Implementation of nanomedicinial strategies that enhance the bioactive function of lactoferrin are also discussed, along with information on lactoferrin in clinical trials. Full article

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Open AccessArticle

Self-Assembled Polyelectrolyte Nanoparticles as Fluorophore-Free Contrast Agents for Multicolor Optical Imaging

by Da Hye Shin, Min Beom Heo and Yong Taik Lim

Molecules 2015, 20(3), 4369-4382; https://doi.org/10.3390/molecules20034369 - 09 Mar 2015

Cited by 13 | Viewed by 7686

Abstract

In this work, we describe the fabrication of self-assembled polyelectrolyte nanoparticles that provide a multicolor optical imaging modality. Poly(γ-glutamic acid)(γ-PGA) formed self-assembled nanoparticles through electrostatic interactions with two different cationic polymers: poly(L-lysine)(PLL) and chitosan. The self-assembled γ-PGA/PLL and γ-PGA/chitosan nanoparticles were crosslinked by [...] Read more.

In this work, we describe the fabrication of self-assembled polyelectrolyte nanoparticles that provide a multicolor optical imaging modality. Poly(γ-glutamic acid)(γ-PGA) formed self-assembled nanoparticles through electrostatic interactions with two different cationic polymers: poly(L-lysine)(PLL) and chitosan. The self-assembled γ-PGA/PLL and γ-PGA/chitosan nanoparticles were crosslinked by glutaraldehyde. Crosslinking of the ionic self-assembled nanoparticles with glutaraldehyde not only stabilized the nanoparticles but also generated a strong autofluorescence signal. Fluorescent Schiff base bonds (C=N) and double bonds (C=C) were generated simultaneously by crosslinking of the amine moiety of the cationic polyelectrolytes with monomeric glutaraldehyde or with polymeric glutaraldehyde. The unique optical properties of the nanoparticles that resulted from the crosslinking by glutaraldehyde were analyzed using UV/Vis and fluorescence spectroscopy. We observed that the fluorescence intensity of the nanoparticles could be regulated by adjusting the crosslinker concentration and the reaction time. The nanoparticles also exhibited high performance in the labeling and monitoring of therapeutic immune cells (macrophages and dendritic cells). These self-assembled nanoparticles are expected to be a promising multicolor optical imaging contrast agent for the labeling, detection, and monitoring of cells. Full article

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