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16 pages, 4329 KiB

Open AccessArticle

Thiophene Derivatives as Anticancer Agents and Their Delivery to Tumor Cells Using Albumin Nanoparticles

by Guangsheng Cai, Simiao Wang, Lang Zhao, Yating Sun, Dongsheng Yang, Robert J. Lee, Menghui Zhao, Huan Zhang and Yulin Zhou

Molecules 2019, 24(1), 192; https://doi.org/10.3390/molecules24010192 - 6 Jan 2019

Cited by 20 | Viewed by 5366

Abstract

A series of thiophene derivatives (TPs) were synthesized and evaluated for cytotoxicity in HepG2 and SMMC-7721 cell lines by MTT assay. TP 5 was identified as a potential anticancer agent based on its ability to inhibit tumor cell growth. Drawbacks of TPs, including [...] Read more.

A series of thiophene derivatives (TPs) were synthesized and evaluated for cytotoxicity in HepG2 and SMMC-7721 cell lines by MTT assay. TP 5 was identified as a potential anticancer agent based on its ability to inhibit tumor cell growth. Drawbacks of TPs, including poor solubility and high toxicity, were overcome through delivery using self-assembling HSA nanoparticles (NPs). The optimum conditions for TP 5-NPs synthesis obtained by adjusting the temperature and concentration of TP 5. The NPs had an encapsulation efficiency of 99.59% and drug-loading capacity of 3.70%. TP 5 was slowly released from TP 5-NPs in vitro over 120 h. HepG2 and SMMC-7721 cell lines were employed to study cytotoxicity of TP 5-NPs, which exhibited high potency. ROS levels were elevated and mitochondrial membrane potentials reversed when the two cell lines were treated with TP 5-NPs for 12 h. Cellular uptake of fluorescence-labeled TP 5-NPs in vitro was analyzed by flow cytometry and laser confocal scanning microscopy. Fluorescence intensity increased over time, suggesting that TP 5-NPs were efficiently taken up by tumor cells. In conclusion, TP 5-NPs showed great promise as an anticancer therapeutic agent. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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16 pages, 3093 KiB

Open AccessArticle

Impact of Gelatin Supplemented with Gum Arabic, Tween 20, and β-Cyclodextrin on the Microencapsulation of Turkish Oregano Extract

by Juste Baranauskaite, Dalia M. Kopustinskiene and Jurga Bernatoniene

Molecules 2019, 24(1), 176; https://doi.org/10.3390/molecules24010176 - 4 Jan 2019

Cited by 20 | Viewed by 5678

Abstract

Microencapsulation protects core materials from deteriorating due to environmental conditions, such as moisture or oxidation, and improves the bioavailability of active compounds, allowing one to make solid formulations from oils and increase their solubility. Wall and core material properties determine the microencapsulation efficiency [...] Read more.

Microencapsulation protects core materials from deteriorating due to environmental conditions, such as moisture or oxidation, and improves the bioavailability of active compounds, allowing one to make solid formulations from oils and increase their solubility. Wall and core material properties determine the microencapsulation efficiency and the best results are achieved when a wall material mixture is used to prepare the microcapsules. In this work, we optimized the wall material composition (gelatin supplemented with gum Arabic, Tween 20, and β-cyclodextrin) of Turkish oregano microcapsules prepared by spray-drying technology to increase the product yield, the encapsulation efficiency, and to achieve narrower particle size distribution. When the wall material solution contained 10 g of gelatin, 7.5 g of gum Arabic, 1.99 g of Tween 20, 1.98 g of β-cyclodextrin, and 20 g of ethanolic oregano extract, the encapsulation efficiency of oregano’s active compounds, rosmarinic acid and carvacrol, were 96.7% and 99.8%, respectively, and the product yield was 85.63%. The physicochemical properties, microscopic morphology, and in vitro release of the prepared microcapsules were characterized in the study. The use of gelatin as the main coating material, in supplementation with gum Arabic, Tween 20, and β-cyclodextrin, not only improved the encapsulation efficiency, but also increased the in vitro release of both main active compounds of Turkish oregano extract—rosmarinic acid and carvacrol. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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16 pages, 4318 KiB

Open AccessArticle

Hyaluronic Acid Coated Acid-Sensitive Nanoparticles for Targeted Therapy of Adjuvant-Induced Arthritis in Rats

by Changhui Yu, Xiangyu Li, Yufei Hou, Xiangxue Meng, Deli Wang, Jiaxin Liu, Fengying Sun and Youxin Li

Molecules 2019, 24(1), 146; https://doi.org/10.3390/molecules24010146 - 2 Jan 2019

Cited by 44 | Viewed by 4918

Abstract

Activated macrophages play a vital role in rheumatoid arthritis (RA) pathophysiology. CD44 is an overexpressed receptor on activated macrophages that is a potential target site for RA treatment. In this study, we prepared hyaluronic acid (HA) coated acid-sensitive polymeric nanoparticles (HAPNPs) composed of [...] Read more.

Activated macrophages play a vital role in rheumatoid arthritis (RA) pathophysiology. CD44 is an overexpressed receptor on activated macrophages that is a potential target site for RA treatment. In this study, we prepared hyaluronic acid (HA) coated acid-sensitive polymeric nanoparticles (HAPNPs) composed of egg phosphatidylcholine, polyethylenimine, and poly (cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK) loaded with dexamethasone (Dex) for the treatment of RA. PCADK was used to form polymeric cores because of its acid-sensitivity. The HAPNPs were about 150 nm in size and had a zeta potential of −2.84 mV. The release rate of Dex from HAPNPs/Dex in vitro increased markedly when the pH decreased from 7.4 to 4.5, indicating that the HAPNPs were pH-sensitive. In a cellular uptake study, stronger fluorescence signals were observed in activated macrophages treated with HAPNPs, suggesting that HAPNPs could be effective nanodevices target to activated macrophages. In rats with adjuvant-induced arthritis, HAPNPs could inhibited the progression of RA. Taken together, these results suggest that the HAPNPs could be useful in RA therapy. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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12 pages, 1776 KiB

Open AccessArticle

Optimization of Extended-Release ZL-004 Nanosuspensions for In Vivo Pharmacokinetic Study to Enhance Low Solubility and Compliance

by Chengyue Guo, Yanna Chen, Junzhe Zhu, Jiaxin Wang, Ying Xu, Hansen Luan and Hao Wang

Molecules 2019, 24(1), 7; https://doi.org/10.3390/molecules24010007 - 20 Dec 2018

Cited by 14 | Viewed by 3189

Abstract

ZL-004, a promising small molecule that increases white blood cell counts, was developed for extended-release nanosuspensions to improve low solubility and compliance of patients. In vivo pharmacokinetic studies of nanosuspensions with different particle sizes and administration volumes were conducted. Unexpectedly, C_max of [...] Read more.

ZL-004, a promising small molecule that increases white blood cell counts, was developed for extended-release nanosuspensions to improve low solubility and compliance of patients. In vivo pharmacokinetic studies of nanosuspensions with different particle sizes and administration volumes were conducted. Unexpectedly, C_max of NS-PC-L (1156 nm) was 1.3 fold higher than NS-PB-L (836 nm), and area under plasma concentration-time curve (AUC) was similar. It suggested that in vivo behavior of nanosuspensions was influenced significantly by the original dissolved drug, which did not only rely on the particle size but also the amount of the free stabilizers. In addition, smaller administration volume (0.1 mL) achieved significantly lower C_max and AUC than the higher volume (0.5 mL), due to the reduced amount of dissolved drug. DSC and XPRD demonstrated that the crystal forms of nanosuspensions prepared by the precipitation method and high-pressure homogenization were similar; therefore, in vivo behaviors did not show significant differences. An additional 0.15% PEG 4000 enhanced the redispersity and maintained the particle size for 3 months. Finally, a nanosuspensions with the desired initial release was achieved, which lasted approximately 32 days steadily after a single dose. AUC and t_1/2 were 161.2 fold and 22.9 fold higher than oral administration. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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14 pages, 5321 KiB

Open AccessArticle

An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors

by Xin Xue, Gang Bao, Hai-Qing Zhang, Ning-Yi Zhao, Yuan Sun, Yue Zhang and Xiao-Long Wang

Molecules 2018, 23(12), 3174; https://doi.org/10.3390/molecules23123174 - 1 Dec 2018

Cited by 3 | Viewed by 3335

Abstract

The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first [...] Read more.

The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs. activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs. Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of K_i from 10² to 10³ nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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10 pages, 3387 KiB

Open AccessArticle

Study of Osteocyte Behavior by High-Resolution Intravital Imaging Following Photo-Induced Ischemia

by Hengfeng Yuan, Wen Jiang, Yuanxin Chen and Betty Y. S. Kim

Molecules 2018, 23(11), 2874; https://doi.org/10.3390/molecules23112874 - 4 Nov 2018

Cited by 4 | Viewed by 3341

Abstract

Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, [...] Read more.

Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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11 pages, 2889 KiB

Open AccessArticle

Optimization of Fermentation Condition for Echinacoside Yield Improvement with Penicillium sp. H1, an Endophytic Fungus Isolated from Ligustrum lucidum Ait Using Response Surface Methodology

by Fangxue Xu, Hui Cao, Xiaowei Cui, Hong Guo and Chunchao Han

Molecules 2018, 23(10), 2586; https://doi.org/10.3390/molecules23102586 - 10 Oct 2018

Cited by 12 | Viewed by 3451

Abstract

(1) Background: Application of echinacoside has become increasingly important for its significant biological activities. However, there are many disadvantages in existing synthesis methods such as contaminating the environment, harsh reaction conditions and so on. Therefore, it is urgent to invent a novel alternative [...] Read more.

(1) Background: Application of echinacoside has become increasingly important for its significant biological activities. However, there are many disadvantages in existing synthesis methods such as contaminating the environment, harsh reaction conditions and so on. Therefore, it is urgent to invent a novel alternative method that can increase the yield of echinacoside. (2) Methods: In this study, we isolated and purified an endophyte from the leaves of Ligustrum lucidum Ait. Then, we improved the yield of echinacoside by optimizing the fermentation condition with an endophytic fungus. Penicillium sp. H1 was isolated from Ligustrum lucidum Ait. In addition, response surface methodology was used to optimize the fermentation condition. (3) Results: The results indicate that the maximal yield of echinacoside (37.16 mg/L) was obtained when inoculation rate, temperature and days were 13.98%, 27.85 °C and 26.06 days, respectively. The yield of echinacoside was 150.47 times higher under the optimal conditions than under the control conditions. The results indicate that the yield of echinacoside could be improved with endophytic fermentation by optimizing the fermentation condition. We provide an alternative method for echinacoside production by endophytic fermentation in this paper. It may have a profound effect on the application of echinacoside. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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16 pages, 6638 KiB

Open AccessArticle

Study on the Quality Evaluation of Compound Danshen Preparations Based on the xCELLigence Real-Time Cell-Based Assay and Pharmacodynamic Authentication

by Guojun Yan, Zhitao Zhu, Liliang Jin, Jun Chen, Hui Xie, Jackelyn Miozzi, Feifei Lei, Xuchao Wei and Jinhuo Pan

Molecules 2018, 23(9), 2090; https://doi.org/10.3390/molecules23092090 - 21 Aug 2018

Cited by 12 | Viewed by 3697

Abstract

Objective: To perform a preliminary study on the quality evaluation of compound Danshen preparations based on the xCELLigence Real-Time Cell-based Assay (RTCA) system and make a pharmacodynamics verification. Methods: The compound Danshen was discussed as a methodological example, and the bioactivity [...] Read more.

Objective: To perform a preliminary study on the quality evaluation of compound Danshen preparations based on the xCELLigence Real-Time Cell-based Assay (RTCA) system and make a pharmacodynamics verification. Methods: The compound Danshen was discussed as a methodological example, and the bioactivity of the compound Danshen preparations were evaluated by real-time cell electronic analysis technology. Meanwhile, an in vivo experiment on an acute blood stasis rat model was performed in order to verify this novel evaluation through the curative effect of dissipating blood stasis. Results: We determined the cell index (CI) and IC50 of the compound Danshen preparations and produced time/dose-dependent cell response profiles (TCRPs). The quality of the three kinds of compound Danshen preparations was evaluated through the RTCA data. The trend of CI and TCRPs reflected the effect of drugs on the cell (promoting or inhibiting), and it was verified that the results correlated with the biological activity of the drugs using a pharmacodynamics experiment. Conclusion: The RTCA system can be used to evaluate the quality of compound Danshen Preparations, and it can provide a new idea and new method for quantitatively characterizing the biological activity of traditional Chinese medicines (TCMs). Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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20 pages, 4742 KiB

Open AccessReview

MicroRNAs as a Novel Tool in the Diagnosis of Liver Lipid Dysregulation and Fatty Liver Disease

by Jingwei Yu, Jun Peng, Zhilin Luan, Feng Zheng and Wen Su

Molecules 2019, 24(2), 230; https://doi.org/10.3390/molecules24020230 - 9 Jan 2019

Cited by 24 | Viewed by 5345

Abstract

In recent years, metabolic disorder, especially fatty liver disease, has been considered a major challenge to global health. The attention of researchers focused on expanding knowledge of the regulation mechanism behind these diseases and towards the new diagnostics tools and treatments. The pathophysiology [...] Read more.

In recent years, metabolic disorder, especially fatty liver disease, has been considered a major challenge to global health. The attention of researchers focused on expanding knowledge of the regulation mechanism behind these diseases and towards the new diagnostics tools and treatments. The pathophysiology of the fatty liver disease is undoubtedly complex. Abnormal hepatic lipid accumulation is a major symptom of most metabolic diseases. Therefore, the identification of novel regulation factors of lipid metabolism is important and meaningful. As a new diagnostic tool, the function of microRNAs during fatty liver disease has recently come into notice in biological research. Accumulating evidence supports the influence of miRNAs in lipid metabolism. In this review, we discuss the potential role of miRNAs in liver lipid metabolism and the pathogenesis of fatty liver disease. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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11 pages, 1635 KiB

Open AccessReview

Application of Real-Time Cell Electronic Analysis System in Modern Pharmaceutical Evaluation and Analysis

by Guojun Yan, Qian Du, Xuchao Wei, Jackelyn Miozzi, Chen Kang, Jinnv Wang, Xinxin Han, Jinhuo Pan, Hui Xie, Jun Chen and Weihua Zhang

Molecules 2018, 23(12), 3280; https://doi.org/10.3390/molecules23123280 - 11 Dec 2018

Cited by 44 | Viewed by 4783

Abstract

Objective: We summarized the progress of the xCELLigence real-time cell analysis (RTCA) technology application in recent years for the sake of enriching and developing the application of RTCA in the field of Chinese medicine. Background: The RTCA system is an established electronic cellular [...] Read more.

Objective: We summarized the progress of the xCELLigence real-time cell analysis (RTCA) technology application in recent years for the sake of enriching and developing the application of RTCA in the field of Chinese medicine. Background: The RTCA system is an established electronic cellular biosensor. This system uses micro-electronic biosensor technology that is confirmed for real-time, label-free, dynamic and non-offensive monitoring of cell viability, migration, growth, spreading, and proliferation. Methods: We summarized the relevant experiments and literature of RTCA technology from the principles, characteristics, applications, especially from the latest application progress. Results and conclusion: RTCA is attracting more and more attention. Now it plays an important role in drug screening, toxicology, Chinese herbal medicine and so on. It has wide application prospects in the area of modern pharmaceutical evaluation and analysis. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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19 pages, 4080 KiB

Open AccessReview

A Review on Electroporation-Based Intracellular Delivery

by Junfeng Shi, Yifan Ma, Jing Zhu, Yuanxin Chen, Yating Sun, Yicheng Yao, Zhaogang Yang and Jing Xie

Molecules 2018, 23(11), 3044; https://doi.org/10.3390/molecules23113044 - 21 Nov 2018

Cited by 187 | Viewed by 18431

Abstract

Intracellular delivery is a critical step in biological discoveries and has been widely utilized in biomedical research. A variety of molecular tools have been developed for cell-based gene therapies, including FDA approved CAR-T immunotherapy, iPSC, cell reprogramming and gene editing. Despite the inspiring [...] Read more.

Intracellular delivery is a critical step in biological discoveries and has been widely utilized in biomedical research. A variety of molecular tools have been developed for cell-based gene therapies, including FDA approved CAR-T immunotherapy, iPSC, cell reprogramming and gene editing. Despite the inspiring results of these applications, intracellular delivery of foreign molecules including nucleic acids and proteins remains challenging. Efficient yet non-invasive delivery of biomolecules in a high-throughput manner has thus long fascinates the scientific community. As one of the most popular non-viral technologies for cell transfection, electroporation has gone through enormous development with the assist of nanotechnology and microfabrication. Emergence of miniatured electroporation system brought up many merits over the weakness of traditional electroporation system, including precise dose control and high cell viability. These new generation of electroporation systems are of considerable importance to expand the biological applications of intracellular delivery, bypassing the potential safety issue of viral vectors. In this review, we will go over the recent progresses in the electroporation-based intracellular delivery and several potential applications of cutting-edge research on the miniatured electroporation, including gene therapy, cellular reprogramming and intracellular probe. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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23 pages, 3102 KiB

Open AccessReview

Microfluidic-Based Single-Cell Study: Current Status and Future Perspective

by Haiwa Wu, Jing Zhu, Yao Huang, Daming Wu and Jingyao Sun

Molecules 2018, 23(9), 2347; https://doi.org/10.3390/molecules23092347 - 13 Sep 2018

Cited by 29 | Viewed by 5871

Abstract

Investigation of cell behavior under different environments and manual operations can give information in specific cellular processes. Among all cell-based analysis, single-cell study occupies a peculiar position, while it can avoid the interaction effect within cell groups and provide more precise information. Microfluidic [...] Read more.

Investigation of cell behavior under different environments and manual operations can give information in specific cellular processes. Among all cell-based analysis, single-cell study occupies a peculiar position, while it can avoid the interaction effect within cell groups and provide more precise information. Microfluidic devices have played an increasingly important role in the field of single-cell study owing to their advantages: high efficiency, easy operation, and low cost. In this review, the applications of polymer-based microfluidics on cell manipulation, cell treatment, and cell analysis at single-cell level are detailed summarized. Moreover, three mainly types of manufacturing methods, i.e., replication, photodefining, and soft lithography methods for polymer-based microfluidics are also discussed. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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23 pages, 1992 KiB

Open AccessReview

Recent Progress in Metal-Based Nanoparticles Mediated Photodynamic Therapy

by Jingyao Sun, Semen Kormakov, Ying Liu, Yao Huang, Daming Wu and Zhaogang Yang

Molecules 2018, 23(7), 1704; https://doi.org/10.3390/molecules23071704 - 12 Jul 2018

Cited by 91 | Viewed by 7222

Abstract

Photodynamic therapy (PDT) is able to non-invasively treat and diagnose various cancers and nonmalignant diseases by combining light, oxygen, and photosensitizers (PSs). However, the application of PDT is hindered by poor water solubility and limited light-penetration depth of the currently available photosensitizers (PSs). [...] Read more.

Photodynamic therapy (PDT) is able to non-invasively treat and diagnose various cancers and nonmalignant diseases by combining light, oxygen, and photosensitizers (PSs). However, the application of PDT is hindered by poor water solubility and limited light-penetration depth of the currently available photosensitizers (PSs). Water solubility of PSs is crucial for designing pharmaceutical formulation and administration routes. Wavelength of light source at visible range normally has therapeutic depth less than 1 mm. In this review, focus is on the recent research progress of metal-based nanoparticles being applied in PDT. The potential toxicity of these nanoscales and future directions are further discussed. Full article

(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)

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