Publications by authors named "Guangxi Zhai"

126 Publications

A sonosensitiser-based polymeric nanoplatform for chemo-sonodynamic combination therapy of lung cancer.

J Nanobiotechnology 2021 Feb 25;19(1):57. Epub 2021 Feb 25.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, People's Republic of China.

Background: Lung cancer is the most common type of tumour worldwide. Its relative lethality is considerably high. However, since the tumour tissues are located deep within the human body, traditional technologies, such as photodynamic therapy, do not have the desired effect. Sonosensitisers can penetrate deeply into tissues, and sonodynamic therapy (SDT) effectively inhibits tumours by generating reactive oxygen species. Ultrasound can also penetrate deeply, with a favourable tumour inhibition effect.

Results: A redox/ultrasound-responsive Rhein-chondroitin sulphate-based nano-preparation encapsulating docetaxel was fabricated. The nanoparticles displayed increased cellular uptake with quick drug release, good stability, and a monodispersed form in the physiological environment. Rhein induced apoptosis and altered mitochondrial membrane potential, which enhanced the expression of apoptosis-related proteins. SDT inhibited the metastasis and angiogenesis of cancer cells and activated anti-tumour capacity by reducing the expression of M2 macrophages.

Conclusions: The potential of Rhein for SDT was demonstrated. Production of reaction oxygen species was markedly enhanced after ultrasound treatment. The nanoplatform enhanced the synergistic anti-tumour effects of SDT and chemotherapeutic efficacy. The approach was biocompatibility. The findings could inform investigations of chemo-SDT for different cancers.
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http://dx.doi.org/10.1186/s12951-021-00804-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905889PMC
February 2021

Research progress in tumor targeted immunotherapy.

Expert Opin Drug Deliv 2021 Apr 14:1-23. Epub 2021 Apr 14.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.

Introduction: Compared with traditional cancer treatment methods, tumor-targeted immunotherapy can combine targeted therapy and immunotherapy with long-lasting responses to achieve synergistic therapy, which brings hope to the complete cure of cancer.

Areas Covered: This review summarizes the newest and most up-to-date advances in tumor-targeted immunotherapy, including tumor-associated macrophages (TAMs) targeted immunotherapy, regulatory T (Treg) cells targeted immunotherapy, tumor-associated fibroblasts (TAFs) targeted immunotherapy and immune checkpoints targeted immunotherapy.

Expert Opinion: Immunotherapy can restore anti-tumor immunity in the tumor microenvironment and produce a lasting immune surveillance effect. Smart multifunctional nano delivery system can effectively combine targeted therapy with immunotherapy, which has attracted extensive attention. With the deepening of research, more and more tumor-targeted immunotherapy enter into the clinical trial phases, especially antibodies and inhibitors. Tumor-targeted immunotherapy is a promising approach for conquering cancer and bringing hope for human health.
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http://dx.doi.org/10.1080/17425247.2021.1882992DOI Listing
April 2021

Galactosamine-modified PEG-PLA/TPGS micelles for the oral delivery of curcumin.

Int J Pharm 2021 Feb 21;595:120227. Epub 2021 Jan 21.

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address:

In this study, galactosamine-modified poly(ethylene glycol)-poly(lactide) (Gal-PEG-PLA) polymers were synthesized and Gal-PEG-PLA/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles named as GPP micelles were designed to promote the oral absorption of a hydrophobic drug, curcumin (CUR). CUR-loaded Gal-PEG-PLA/TPGS micelles (CUR@GPP micelles) were fabricated using the thin-film dispersion method. CUR@GPP micelles had a size of about 100 nm, a near-neutral zeta potential, drug loading (DL) of 14.6%, and sustained release properties. GPP micelles with high Gal density (GPP3 micelles) were superior in facilitating uptake in epithelial cells and improving intestinal permeation. In situ intestinal absorption studies suggested that the jejunum and ileum were the best absorption segments in the intestinal tract. Additionally, biodistribution results revealed that GPP3 micelles could be remarkably taken up by the jejunum and ileum. Pharmacokinetics revealed that the maximum plasma concentration (C) and the area under the plasma concentration-time curve from 0 to 24 h (AUC) for CUR@GPP3 micelles were both significantly increased, and that the relative bioavailability of CUR@GPP3 micelles to CUR-loaded mPEG-PLA/TPGS micelles (CUR@PP micelles) was 258.8%. Furthermore, CUR-loaded micelles could reduce damage to the liver and intestinal tissues. This study highlights the importance of Gal content in the design of targeting nanocarrier Gal-modified micelles, which have broad prospects for oral delivery of hydrophobic drugs. Therefore, they could serve as a promising candidate for targeted delivery to the liver.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120227DOI Listing
February 2021

A review of nanocarrier-mediated drug delivery systems for posterior segment eye disease: challenges analysis and recent advances.

J Drug Target 2021 Feb 1:1-35. Epub 2021 Feb 1.

School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology, Ministry of Education, Shandong University, Jinan, China.

Posterior segment eye disease is a leading cause of irreversible vision impairment and blindness. As the unique organ for vision, eyes are protected by various protective barriers. The existence of physiological barriers and elimination mechanisms makes it challenging to treat the posterior segment eye diseases. To achieve efficient drug delivery to the posterior segment of eyes, different drug delivery systems have been proposed. Due to their abilities to enhance ocular tissue permeability, make controlled drug release and target retina, nanocarriers, such as lipid nanoparticles, liposomes and polymeric nanomicelles, have been widely studied for posterior segment drug delivery. However, clinical applications of nanocarrier mediated drug delivery systems as non-invasive ocular drops is still not ready. The delivery of nanocarrier-mediated drug for posterior segment disease still faces the choice of being more effective or more invasive for long-term treatment. Therefore, it is necessary to have a clear understanding of the barriers and the routes of ocular drug delivery while developing the delivery systems. In this review, types of ocular barriers and drug administration routes are categorised in a more intuitive way. Recent advances in nanocarrier mediated drug delivery systems with focus on posterior segment are reviewed with illustrative examples.
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http://dx.doi.org/10.1080/1061186X.2021.1878366DOI Listing
February 2021

Redox-responsive nanoparticles based on Chondroitin Sulfate and Docetaxel prodrug for tumor targeted delivery of Docetaxel.

Carbohydr Polym 2021 Mar 10;255:117393. Epub 2020 Nov 10.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong Province, 250012, China. Electronic address:

In this paper, a novel redox-responsive nanoparticles has been designed for targeted delivery of docetaxel (DTX). Chondroitin sulfate (CS) was used to construct the nanoparticles due to the ability of tumor targeting through binding with CD44 receptor that overexpresses on the surfaces of various tumor cells. A redox-responsive small-molecular DTX prodrug was prepared through modifying with cystamine containing disulfide bonds (Cys-DTX). Then the DTX prodrug was grafted to the CS to construct the amphiphilic polymer (CS-ss-DTX). Further, Cys-DTX/CS-ss-DTX nanoparticles were formed by self-assembly of amphiphilic polymer and incorporation of free Cys-DTX prodrug. This category of nanosized DTX delivery system was expected for not only exhibiting high permeability and cytotoxicity of Cys-DTX prodrug, but also targeting transportation of encapsulated redox-responsive Cys-DTX prodrug. According to results of related researches on physicochemical properties and biological evaluation, the novel redox-responsive Cys-DTX/CS-ss-DTX nanoparticles increased amount of DTX released from the nanoparticles in reductive environment, improved permeability in tumor tissues, enhanced cytotoxicity and decreased side effects compared with free DTX. All of these results showed that this kind of Cys-DTX/CS-ss-DTX nanoparticles were worthy of being expectation in tumor chemotherapy in future.
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http://dx.doi.org/10.1016/j.carbpol.2020.117393DOI Listing
March 2021

Chondroitin sulfate-based nanoparticles for enhanced chemo-photodynamic therapy overcoming multidrug resistance and lung metastasis of breast cancer.

Carbohydr Polym 2021 Feb 1;254:117459. Epub 2020 Dec 1.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China. Electronic address:

As a major therapeutic approach for cancer treatment, the effectiveness of chemotherapy is challenged by multidrug resistance (MDR). Herein, we fabricated novel redox-responsive, chondroitin sulfate-based nanoparticles that could simultaneously deliver quercetin (chemosensitizer), chlorin e6 (photosensitizer) and paclitaxel (chemotherapeutic agent) to exert enhanced chemo-photodynamic therapy for overcoming MDR and lung metastasis of breast cancer. In vitro cell study showed that nanoparticles down-regulated the expression of P-glycolprotein (P-gp) on MCF-7/ADR cells and thereby improved the anticancer efficacy of PTX against MCF-7/ADR cells. Moreover, NIR laser irradiation could induce nanoparticles to generate cellular reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and meanwhile facilitating lysosomal escape of drugs. Importantly, the novel nanoplatform exhibited effective in vivo MDR inhibition and anti-metastasis efficacy through enhanced chemo-photodynamic therapy. Thus, the study suggested that the multifunctional nanoplatform had good application prospect for effective breast cancer therapy.
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http://dx.doi.org/10.1016/j.carbpol.2020.117459DOI Listing
February 2021

Quantitative prediction of the bitterness of atomoxetine hydrochloride and taste-masked using hydroxypropyl-β-cyclodextrin: A biosensor evaluation and interaction study.

Asian J Pharm Sci 2020 Jul 26;15(4):492-505. Epub 2019 Nov 26.

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan, 250012, China.

The bitterness of a drug is a major challenge for patient acceptability and compliance, especially for children. Due to the toxicity of medication, a human taste panel test has certain limitations. Atomoxetine hydrochloride (HCl), which is used for the treatment of attention deficit/hyperactivity disorder (ADHD), has an extremely bitter taste. The aim of this work is to quantitatively predict the bitterness of atomoxetine HCl by a biosensor system. Based on the mechanism of detection of the electronic tongue (E-tongue), the bitterness of atomoxetine HCl was evaluated, and it was found that its bitterness was similar to that of quinine HCl. The bitterness threshold of atomoxetine HCl was 8.61 µg/ml based on the Change of membrane Potential caused by Adsorption (CPA) value of the BT0 sensor. In this study, the taste-masking efficiency of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) was assessed by Euclidean distances on a principle component analysis (PCA) map with the SA402B Taste Sensing System, and the host-guest interactions were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy (SEM). Biosensor evaluation and characterization of the inclusion complex indicated that atomoxetine HCl could actively react with 2-hydroxypropyl-β-cyclodextrin.
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http://dx.doi.org/10.1016/j.ajps.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486553PMC
July 2020

Paclitaxel and quercetin co-loaded functional mesoporous silica nanoparticles overcoming multidrug resistance in breast cancer.

Colloids Surf B Biointerfaces 2020 Dec 29;196:111284. Epub 2020 Jul 29.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address:

Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) (MSNs-ChS@PQ) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo. Taken together, our research provides a viable approach to overcome MDR in breast cancer.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111284DOI Listing
December 2020

A novel progress of drug delivery system for organelle targeting in tumour cells.

J Drug Target 2021 Jan 23;29(1):12-28. Epub 2020 Jul 23.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.

At present, malignant tumours have become one of the most serious diseases that endanger human health. According to a survey on causes of death in Chinese population in early 1990s, the malignant tumours were the second leading cause of death. In the treatment of tumours, the ideal situation is that drugs should target and accumulate at tumour sites and destroy tumour cells specifically, without affecting normal cells and stem cells with regenerative capacity. This requires drugs to be specifically transported to the target organs, tissues, cells, and even specific organelles, like mitochondria, nuclei, lysosomes, endoplasmic reticulum (ER), and Golgi apparatus (GA). The nano drug delivery system can not only protect drugs from degradation but also facilitate functional modification and targeted drug delivery to the tumour site. This article mainly reviews the targeting of nano drug delivery systems to tumour cytoplasmic matrix, nucleus, mitochondria, ER, and lysosomes. Organelle-specific drug delivery system will be a major mean of targeting drug delivery with lower toxicity, less dosage and higher drug concentration in tumour cells.
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http://dx.doi.org/10.1080/1061186X.2020.1797051DOI Listing
January 2021

Research Progress in Bioinspired Drug Delivery Systems.

Expert Opin Drug Deliv 2020 09 25;17(9):1269-1288. Epub 2020 Jun 25.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , Jinan, PR China.

Introduction: To tackle challenges associated with traditional drug carriers, investigators have explored cells, cellular membrane, and macromolecular components including proteins and exosomes for the fabrication of delivery vehicles, owing to their excellent biocompatibility, lower toxicity, lower immunogenicity and similarities with the host. Biomacromolecule- and biomimetic nanoparticle (NP)-based drug/gene carriers are drawing immense attention, and biomimetic drug delivery systems (BDDSs) have been conceived and constructed.

Areas Covered: This review focuses on BDDS based on mammalian cells, including blood cells, cancer cells, adult stem cells, endogenous proteins, pathogens and extracellular vesicles (EVs).

Expert Opinion: Compared with traditional drug delivery systems (DDSs), BDDSs are based on biological nanocarriers, exhibiting superior biocompatibility, fewer side effects, natural targeting, and diverse modifications. In addition to directly employing natural biomaterials such as cells, proteins, pathogens and EVs as carriers, BDDSs offer these advantages by mimicking the structure of natural nanocarriers through bioengineering technologies. Furthermore, BDDSs demonstrate fewer limitations and irregularities than natural materials and can overcome several shortcomings associated with natural carriers. Although research remains ongoing to resolve these limitations, it is anticipated that BDDSs possess the potential to overcome challenges associated with traditional DDS, with a promising future in the treatment of human diseases.
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http://dx.doi.org/10.1080/17425247.2020.1783235DOI Listing
September 2020

Erratum: Multifunctional Polyethylene Glycol (PEG)-Poly (Lactic-Co-Glycolic Acid) (PLGA)-Based Nanoparticles Loading Doxorubicin and Tetrahydrocurcumin for Combined Chemoradiotherapy of Glioma.

Med Sci Monit 2020 06 12;26:e926333. Epub 2020 Jun 12.

Department of Pharmacy, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland).

The authors informed the journal that an error occurred in their manuscript. Figure 2D was mistakenly overlooked by the authors during the galley proof stage. Reference: 1. Zhang X, Zhao L, Zhai G, Ji J, Liu A. Multifunctional Polyethylene Glycol (PEG)-Poly (Lactic-Co-Glycolic Acid) (PLGA)-Based Nanoparticles Loading Doxorubicin and Tetrahydrocurcumin for Combined Chemoradiotherapy of Glioma. Med Sci Monit, 2019; 25: 9737-9751. doi: 10.12659/MSM.918899.
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http://dx.doi.org/10.12659/MSM.926333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307716PMC
June 2020

Development of stimuli-responsive intelligent polymer micelles for the delivery of doxorubicin.

J Drug Target 2020 12 19;28(10):993-1011. Epub 2020 May 19.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.

Doxorubicin is still used as a first-line drug in current therapeutics for numerous types of malignant tumours (including lymphoma, transplantable leukaemia and solid tumour). Nevertheless, to overcome the serious side effects like cardiotoxicity and myelosuppression caused by effective doses of doxorubicin remains as a world-class puzzle. In recent years, the usage of biocompatible polymeric nanomaterials to form an intelligently sensitive carrier for the targeted release in tumour microenvironment has attracted wide attention. These different intelligent polymeric micelles (PMs) could change the pharmacokinetics process of drugs or respond in the special microenvironment of tumour site to maximise the efficacy and reduce the toxicity of doxorubicin in other tissues and organs. Several intelligent PMs have already been in the clinical research stage and planned for market. Therefore, related research remains active, and the latest nanotechnology approaches for doxorubicin delivery are always in the spotlight. Centring on the model drugs doxorubicin, this review summarised the mechanisms of PMs, classified the polymers used in the application of doxorubicin delivery and discussed some interesting and imaginative smart PMs in recent years.
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http://dx.doi.org/10.1080/1061186X.2020.1766474DOI Listing
December 2020

Photo-triggered self-destructive ROS-responsive nanoparticles of high paclitaxel/chlorin e6 co-loading capacity for synergetic chemo-photodynamic therapy.

J Control Release 2020 07 20;323:333-349. Epub 2020 Apr 20.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address:

To improve the anti-cancer therapeutic effect of nanosystems for chemo-photodynamic therapy, there remain several hurdles to be addressed, e.g., limited co-loading efficiency, insufficient stimulus-responsiveness and lack of synergetic effect. This work reported novel reactive‑oxygen-species (ROS)-responsive chlorin e6 (Ce6) and paclitaxel (PTX) co-encapsulated chondroitin sulfate-g-poly (propylene sulfide) nanoparticles (CP/ChS-g-PPS NPs), wherein the drug loading efficiencies of Ce6 and PTX were as high as 14.93% and 24.31%, respectively. To enlarge the ROS signal at tumor sites thus enhancing the ROS-responsiveness of ChS-g-PPS NPs, near-infrared (NIR) light was utilized to induce Ce6 to produce more ROS to destruct the NPs. Our data showed that the photo-triggered self-destructive property of NPs helped drugs to spread deeper in tumors upon laser irradiation, making the NPs promising to thoroughly remove tumor cells. CP/ChS-g-PPS NPs exhibited a synergetic chemo-photodynamic therapy effect in vitro, which was suggested by the combination indexes of PTX and Ce6 lower than 1 when 20-80% inhibition rates of MCF-7 cells were achieved. As for the in vivo antitumor activity, the tumor inhibition rates of CP/ChS-g-PPS NPs (with laser irradiation) were as high as 92.76% and 88.57% in 4T1 bearing BALB/c mice and MCF-7 bearing BALB/c nude mice, respectively, which were significantly higher than those of other treatment groups. This work provided a simple yet effective strategy to develop photo-triggered ROS-responsive NPs for synergetic chemo-photodynamic therapy with quick ROS-responsive self-destruction, spatiotemporally controllability, reduced off-target toxicity, and desirable therapeutic effect.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.027DOI Listing
July 2020

Chondroitin sulfate derived theranostic and therapeutic nanocarriers for tumor-targeted drug delivery.

Carbohydr Polym 2020 Apr 11;233:115837. Epub 2020 Jan 11.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China. Electronic address:

The standard chemotherapy is facing the challenges of lack of cancer selectivity and development of drug resistance. Currently, with the application of nanotechnology, the rationally designed nanocarriers of chondroitin sulfate (CS) have been fabricated and their unique features of low toxicity, biocompatibility, and active and passive targeting made them drug delivery vehicles of the choice for cancer therapy. The hydrophilic and anionic CS could be incorporated as a building block into- or decorated on the surface of nanoformulations. Micellar nanoparticles (NPs) self-assembled from amphiphilic CS-drug conjugates and CS-polymer conjugates, polyelectrolyte complexes (PECs) and nanogels of CS have been widely implicated in cancer directed therapy. The surface modulation of organic, inorganic, lipid and metallic NPs with CS promotes the receptor-mediated internalization of NPs to the tumor cells. The potential contribution of CS and CS-proteoglycans (CSPGs) in the pathogenesis of various cancer types, and CS nanocarriers in immunotherapy, radiotherapy, sonodynamic therapy (SDT) and photodynamic therapy (PDT) of cancer are summarized in this review paper.
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http://dx.doi.org/10.1016/j.carbpol.2020.115837DOI Listing
April 2020

Multifunctional Polyethylene Glycol (PEG)-Poly (Lactic-Co-Glycolic Acid) (PLGA)-Based Nanoparticles Loading Doxorubicin and Tetrahydrocurcumin for Combined Chemoradiotherapy of Glioma.

Med Sci Monit 2019 Dec 19;25:9737-9751. Epub 2019 Dec 19.

Department of Pharmacy, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland).

BACKGROUND This study aimed to prepare doxorubicin- and tetrahydrocurcumin-loaded and transferrin-modified PEG-PLGA nanoparticles (Tf-NPs-DOX-THC) for enhanced and synergistic chemoradiotherapy. MATERIAL AND METHODS Tf-NPs-DOX-THC were prepared via the double-emulsion method. The morphologies and particle sizes of the prepared nanoparticles were examined by TEM and DLS, respectively. The in vitro MTT, apoptosis, and clone formation assays were performed to detect the proliferation and radiosensitivity of cells with various treatments. Cellular uptake assay was also conducted. The tissue distribution of Tf-NPs was investigated by ex vivo DOX fluorescence imaging. The in vivo tumor growth inhibition efficiency of various treatments was evaluated in orthotopic C6 mouse models and C6 subcutaneously grafted mouse models. RESULTS Tf-NPs-DOX-THC exhibited high drug-loading efficiency (6.56±0.32%) and desirable particle size (under 250 nm). MTT, apoptosis, and clone formation assays revealed the enhanced anti-cancer activity and favorable radiosensitizing effect of Tf-NPs-DOX-THC. Strong fluorescence was observed in the brains of mice treated with Tf-NPs-DOX. The in vitro release of drug from nanoparticles was in a pH-sensitive manner. Tf-NPs-DOX-THC in combination with radiation also achieved favorable anti-tumor efficacy in vivo. CONCLUSIONS All results suggest that a combination of Tf-NPs-DOX-THC and radiation is a promising strategy for synergistic and sensitizing chemoradiotherapy of glioma.
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http://dx.doi.org/10.12659/MSM.918899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934137PMC
December 2019

Enzyme responsiveness enhances the specificity and effectiveness of nanoparticles for the treatment of B16F10 melanoma.

J Control Release 2019 12 2;316:208-222. Epub 2019 Nov 2.

School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, China. Electronic address:

The clinical treatment of melanoma continues to present many challenges including poor prognosis because neither monotherapy nor combination therapies have shown maximal treatment efficacy. In this study, an enzyme-responsive nanoparticle was designed for tumor subtypes with the high expression of heparanase-1, since highly metastatic tumors such as melanoma generally express significant levels of heparanase-1. PTX-DOTAP@alloferon-1-heparin/protamine, an enzyme-responsive nanoparticle, has a particle size of 106.1 ± 1.113 nm and a ζ-potential of -45.1 ± 0.455 mV, which enables enrichment in the tumor site by passive targeting. Subsequently, heparanase-1, which is highly expressed in the extracellular matrix, rapidly recognizes and degrades heparin in the outer layer of the nanoparticle and releases encapsulated alloferon-1 by ion diffusion to activate inhibited NK cells in the tumor microenvironment. The size of the smart nanoparticle will eventually decrease to 59.30 ± 0.783 nm and the ζ-potential will reverse to 25.4 ± 0.257 mV, which is beneficial for deep penetration and tumor cell uptake (due to the high negative charge on the tumor cell surface) of PTX-DOTAP cores. Paclitaxel is released in the cytoplasm, and the tumor cells are arrested in the G2/M phase. The nanoparticle characterization experiment demonstrated that in vivo drug delivery could be completed. In subsequent cell and animal experiments, the experimental data demonstrated the efficient therapeutic effects of the nanoparticle. This study provides an excellent template nanoparticle for the treatment of highly metastatic tumors to enhance future prognosis.
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http://dx.doi.org/10.1016/j.jconrel.2019.10.052DOI Listing
December 2019

Cell-penetrating peptide: a means of breaking through the physiological barriers of different tissues and organs.

J Control Release 2019 09 16;309:106-124. Epub 2019 Jul 16.

School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology, Ministry of Education, Shandong University, Jinan 250012, China. Electronic address:

The selective infiltration of cell membranes and tissue barriers often blocks the entry of most active molecules. This natural defense mechanism prevents the invasion of exogenous substances and limits the therapeutic value of most available molecules. Therefore, it is particularly important to find appropriate ways of membrane translocation and therapeutic agent delivery to its target site. Cell penetrating peptides (CPPs) are a group of short peptides harnessed in this condition, possessing a significant capacity for membrane transduction and could be exploited to transfer various biologically active cargoes into the cells. Since their discovery, CPPs have been employed for delivery of a wide variety of therapeutic molecules to treat various disorders including cranial nerve involvement, ocular inflammation, myocardial ischemia, dermatosis and cancer. The promising results of CPPs-derived therapeutics in various tumor models demonstrated a potential and worthwhile scope of CPPs in chemotherapy. This review describes the detailed description of CPPs and CPPs-assisted molecular delivery against various tissues and organs disorders. An emphasis is focused on summarizing the novel insights and achievements of CPPs in surmounting the natural membrane barriers during the last 5 years.
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http://dx.doi.org/10.1016/j.jconrel.2019.07.020DOI Listing
September 2019

Pluronic F127-functionalized molybdenum oxide nanosheets with pH-dependent degradability for chemo-photothermal cancer therapy.

J Colloid Interface Sci 2019 Oct 20;553:567-580. Epub 2019 Jun 20.

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address:

Traditional cancer therapies carry a risk of serious side effects and toxicity. Developing an alternative treatment modality that is highly effective, has low toxicity and is noninvasive is urgently required. Here, we exploited molybdenum oxide (MoOx) nanosheets as a drug carrier and degradable photothermal agent to provide a chemo-photothermal combination cancer therapy. The MoOx nanosheets were synthesized by a one-pot hydrothermal method and then modified with pluronic F127 to improve physiological stability and biocompatibility. The F127-modified nanosheets (MoOX@F127) showed ultrahigh drug loading efficiency (DLE) of doxorubicin (DOX) (DLE%; 65%, W/[W + W]), strong near-infrared (NIR) absorption and desirable pH-dependent degradability. After intravenous injection, MoOx@F127 nanosheets were degraded at physiological pH and were rapidly excreted from normal organs, while they were effectively accumulated and retained long-term in the more acidic tumor tissue. This simultaneously ensured effective tumor ablation after NIR irradiation and avoided long-term retention and toxicity in vivo. Compared to chemotherapy or photothermal therapy alone, in vitro and in vivo tumor ablation studies have shown a notably improved synergistic effect of the combination therapy. Our study presents a multifunctional nanosystem with a desirable degradability for chemo-photothermal combination cancer therapy that has great potential in biomedical applications.
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http://dx.doi.org/10.1016/j.jcis.2019.06.066DOI Listing
October 2019

The progresses in curcuminoids-based metal complexes: especially in cancer therapy.

Future Med Chem 2019 05 29;11(9):1035-1056. Epub 2019 May 29.

College of Pharmacy, Department of Pharmaceutics, Shandong University, Jinan 250012, PR China.

Curcuminoids (CURs), a series of derivatives in turmeric (), are commonly discovered to control the deterioration of cancers. However, the physiochemical properties and the original side effects of many CURs complexes put barriers in their medical applications. To address them, the investigation of metal-based complexes with CURs is in progress. The complexes were summarized according to articles in recent years. The results showed that the complexes improved the physicochemical properties or therapeutic performances compared with pure CURs. Further, it is possible for the novel complexes to be applied in chemical detecting, paramagnetic-luminescent and bio-imaging fields. Therefore, the formation of the metal-based CURs complexes (MBCCs) is beneficial for the development of CURs especially in medical fields.
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http://dx.doi.org/10.4155/fmc-2018-0190DOI Listing
May 2019

Characterization and bioactivity of self-assembled anti-angiogenic chondroitin sulfate-ES2-AF nanoparticle conjugate.

Int J Nanomedicine 2019 10;14:2573-2589. Epub 2019 Apr 10.

National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,

Background: In the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life.

Materials And Methods: The CS-ES2-AF nanoparticle conjugate was synthesized and characterized using H-nuclear magnetic resonance spectroscopy, transmission electron microscopy, and particle size and zeta potential analyzer. The anti-angiogenic ability was studied using MTT, migration, tube formation, and chick chorioallantoic membrane assays. The targeting ability of CS-ES2-AF was studied by ELISA, surface plasmon resonance, and bioimaging. The pharmacokinetics was also studied.

Results: The CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life.

Conclusion: CS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy.
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http://dx.doi.org/10.2147/IJN.S195934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462165PMC
May 2019

Inhibition of the adenosinergic pathway: the indispensable part of oncological therapy in the future.

Purinergic Signal 2019 03 26;15(1):53-67. Epub 2019 Feb 26.

School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, People's Republic of China.

In recent years, immunotherapy has produced many unexpected breakthroughs in oncological therapy; however, it still has many deficiencies. For example, the number of patients who are unresponsive to anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-like antigen-4 (CTLA4), and anti-programmed death-1 (PD1) therapies cannot be ignored, and the search for an undiscovered immunosuppressive pathway is imminent. Five decades ago, researchers found that activation of the adenosinergic pathway was negatively correlated with prognosis in many cancers. This review describes the entire process of the adenosinergic pathway in the tumor microenvironment and the mechanism of immunosuppression, which promotes tumor metastasis and drug resistance. Additionally, the review explores factors that regulate this pathway, including signaling factors secreted by the tumor microenvironment and certain anti-tumor drugs. Additionally, the combination of adenosinergic pathway inhibitors with chemotherapy, checkpoint blockade therapy, and immune cell-based therapy is summarized. Finally, certain issues regarding treatment via inhibition of this pathway and the use of targeted nanoparticles to reduce adverse reactions in patients are put forward in this review. Graphical Abstract The inhibitors of adenosinergic pathway loaded nanoparticles enter tumor tissue through EPR effect, and inhibit adenosinergic pathway to enhance or restore the effect of immune checkpoint blockade therapy, chemotherapies and immune cell-based therapy. Note: EPR means enhanced penetration and retention, × means blockade.
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http://dx.doi.org/10.1007/s11302-018-9641-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439062PMC
March 2019

Advances in curcumin-loaded nanopreparations: improving bioavailability and overcoming inherent drawbacks.

J Drug Target 2019 11 6;27(9):917-931. Epub 2019 Feb 6.

a College of Pharmacy, Shandong University , Jinan , China.

Curcumin (CUR), one of the major extracts of turmeric, has gained extensive attention owing to its extraordinary benefits as anti-cancer, anti-bacterial, anti-ulcerative, anti-depressant, anti-inflammatory and wound healing agent. However, a major barrier in its application lies in its inherent nature of low water solubility, instability, and short half-life. Different strategies have been adopted to overcome these barriers like preparing nano-sized formulations and exploiting stable and hydrophilic derivatives, and collaborative drug delivery. Nanopreparations could maintain the pharmacological effect of drugs, even the holistic effects of drug extracts. In addition, nanopreparations based on novel materials make it a reality to regulate the drug release rate according to the various environmental conditions. The therapeutic applications and novel investigated nanopreparations of CUR for prevention and treatment of various diseases, especially, cancer and inflammatory disorders are discussed in this review.
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http://dx.doi.org/10.1080/1061186X.2019.1572158DOI Listing
November 2019

Heparin-reduced graphene oxide nanocomposites for curcumin delivery: in vitro, in vivo and molecular dynamics simulation study.

Biomater Sci 2019 Feb;7(3):1011-1027

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.

Graphene-based nanomaterials (GBNMs) have great potential in drug delivery and photothermal therapy owing to their unique physicochemical properties. However, inferior water solubility and biocompatibility related issues greatly restricted their further applications. Herein, to rectify the obstructive problems, we prepared uniform and smaller sized graphene oxide (GO) nanosheets (∼85 nm) via a modified Hummers' method, which exhibited significantly improved hemocompatibility compared to random large sized GO nanosheets prepared by a common method. Then, we grafted unfractionated heparin (UFH) onto reduced graphene oxide (rGO) covalently using adipic acid dihydrazide (ADH) as a linker to fabricate biocompatible nanocomposites for the cellular delivery of curcumin (Cur). The novel nanocomposites showed quite a small size of 42 nm in average lateral dimension and exhibited a significantly stronger photothermal effect than GO nanosheets. Besides, in vitro cell experiments verified that the potential anticancer efficacy of Cur-loaded vehicles and cytotoxicity of rGO-UFH/Cur against MCF-7 and A549 cells could be further enhanced under 808 nm irradiation, suggesting the possibility of combinational chemotherapy and photothermal therapy. Moreover, consistent with the in vitro sustained drug release performance, an in vivo pharmacokinetics study also indicated that the retention time of Cur could be significantly prolonged when loaded on rGO-UFH nanocomposites than in free Cur solution. Notably, we firstly discussed the interaction between rGO and Cur, and demonstrated the meliorative biocompatibility of uniform rGO compared to GRO via a molecular dynamics simulation (MD) study. Thus, the in vitro, in vivo and computational study demonstrated that the small sized rGO-UFH nanocomposites had wide application prospects as drug delivery vehicles.
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http://dx.doi.org/10.1039/c8bm00907dDOI Listing
February 2019

Crosslinked self-assembled nanoparticles for chemo-sonodynamic combination therapy favoring antitumor, antimetastasis management and immune responses.

J Control Release 2018 11 9;290:150-164. Epub 2018 Oct 9.

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address:

Sonodynamic therapy (SDT) has been proposed as a new modality for cancer management through low-intensity ultrasound induced activation of sonosensitizers. Here, we designed a novel redox/enzyme/ultrasound responsive chondroitin sulfate-chlorin e6-lipoic acid nanoplatform loading docetaxel, combining SDT and chemotherapy, for antiproliferation and antimetastasis of melanoma. The reversibly crosslinked and self-assembled nanoparticles possessed monodispersive size distribution, stability in physical conditions, while showing increased uptake with rapid drug release in simulated tumor microenvironment (reductive potentials and degradative hyaluronidase-1). With synthesized ultrasound sensitive polymer backbones, SDT induced the generation of cellular reactive oxygen species and mitochondrial damage, exerting the apoptotic effect through the release of cytochrome C, the expression of cleaved caspase-9 followed by the functional cleaved caspase-3. Chemo-sonodynamic therapy not only inhibited tumor growth and metastasis with reduced metastatic protein expression, but also caused immune response via the release of tumor-associated antigens. It was initially demonstrated that SDT could induce the tumor cell death, therefore having potentials to recruit cytotoxic lymphocytes into tumor sites. Notably, the nanoplatforms exhibited good in vivo stability and blood compatibility, indicating the safety and efficiency in drug delivery. Our work thus presents a convenient approach to fabricate intelligent multifunctional nanoparticles and paves a path for effective cancer therapies.
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http://dx.doi.org/10.1016/j.jconrel.2018.10.007DOI Listing
November 2018

Recent progress of drug nanoformulations targeting to brain.

J Control Release 2018 12 9;291:37-64. Epub 2018 Oct 9.

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address:

Most of the potential therapeutic agents capable to modulate the pathophysiology or treat the neurological disorders and brain tumors are useless in the current modern and advanced era of neuroscience due to the impeding action of biological barriers. Among various therapeutic strategies applied for translocation of drug delivery across the blood-brain barrier (BBB), nanoformulations set an excellent platform for brain targeting by overcoming the biological and chemical barriers and protecting drug from efflux to promote the optimum therapeutic drug concentration in brain parenchyma tissues. Nanocarriers are the most widely studied delivery vehicles for BBB translocation with the efficiency of selectively targeting or exploiting inherent biological molecules, receptors, carriers or mechanisms of the brain. Nearly all of the available drug delivery nanocarriers explored in recent years for brain therapeutics and theranostics are based on lipid or polymeric materials. Polymeric nanoparticles (NPs) and lipid based nanocarriers including liposomes, solid lipid NPs (SLNs) and micelles, etc. are under the direct focus of neuroscientists due to the promising attributes and vast applications in neurological disorders. Surface modification of nanovehicles with proper targeting moiety or coating with surfactants promotes the interaction with endothelial cells and passage of nanocarriers to the brain. This review comprehensively depicts challenges to the brain targeted drug delivery, mechanisms of drug transportation across the BBB, and potential contributions of endogenous cells as NPs delivery cells and novel targeting ligands decorated nanoformulations in imaging, treating and controlling neurological disorders.
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http://dx.doi.org/10.1016/j.jconrel.2018.10.004DOI Listing
December 2018

Lipid nanoparticles loading triptolide for transdermal delivery: mechanisms of penetration enhancement and transport properties.

J Nanobiotechnology 2018 Sep 15;16(1):68. Epub 2018 Sep 15.

Department of Pharmacy, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.

Background: In recent years, nanoparticles (NPs) including nanostructured lipid carries (NLC) and solid lipid nanoparticles (SLN) captured an increasing amount of attention in the field of transdermal drug delivery system. However, the mechanisms of penetration enhancement and transdermal transport properties of NPs are not fully understood. Therefore, this work applied different platforms to evaluate the interactions between skin and NPs loading triptolide (TPL, TPL-NLC and TPL-SLN). Besides, NPs labeled with fluorescence probe were tracked after administration to investigate the dynamic penetration process in skin and skin cells. In addition, ELISA assay was applied to verify the in vitro anti-inflammatory effect of TPL-NPs.

Results: Compared with the control group, TPL-NPs could disorder skin structure, increase keratin enthalpy and reduce the SC infrared absorption peak area. Besides, the work found that NPs labeled with fluorescence probe accumulated in hair follicles and distributed throughout the skin after 1 h of administration and were taken into HaCaT cells cytoplasm by transcytosis. Additionally, TPL-NLC could effectively inhibit the expression of IL-4, IL-6, IL-8, IFN-γ, and MCP-1 in HaCaT cells, while TPL-SLN and TPL solution can only inhibit the expression of IL-6.

Conclusions: TPL-NLC and TPL-SLN could penetrate into skin in a time-dependent manner and the penetration is done by changing the structure, thermodynamic properties and components of the SC. Furthermore, the significant anti-inflammatory effect of TPL-NPs indicated that nanoparticles containing NLC and SLN could serve as safe prospective agents for transdermal drug delivery system.
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http://dx.doi.org/10.1186/s12951-018-0389-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138933PMC
September 2018

CuS@MOF-Based Well-Designed Quercetin Delivery System for Chemo-Photothermal Therapy.

ACS Appl Mater Interfaces 2018 Oct 26;10(40):34513-34523. Epub 2018 Sep 26.

School of Pharmacy and Medical Sciences , University of South Australia , Adelaide , South Australia 5000 , Australia.

Quercetin (QT) is one promising candidate for the treatment of various cancers with virtually no toxic side effects. However, its anticancer effect is severely restricted by its poor bioavailability, low water solubility, and chemical instability in the neutral and alkaline medium. Herein, zeolitic imidazolate framework-8 (ZIF-8) is first reported as the multifunctional nanoplatform to the codelivery of quercetin as an anticancer agent and CuS nanoparticles as a photothermal therapy (PTT) agent for synergistic combination of chemotherapy and PTT as well as overcoming the drawbacks of quercetin. Moreover, folic acid-bovine serum albumin (FA-BSA) conjugates are applied to stabilize the CuS@ZIF-8-QT to promote the bioavailability of quercetin and realize active-targeting drug delivery. Near-infrared (NIR) fluorescent imaging demonstrated the highly increased drug accumulations of FA-BSA/CuS@ZIF-8-QT in tumors, resulting from efficient internalization via FA-receptors-mediated endocytosis. The results of in vivo and in vitro anticancer experiments demonstrate that quercetin and PTT agent can work together efficiently under NIR irradiation, thus remarkably improving the anticancer effect. Therefore, our newly designed FA-BSA/CuS@ZIF-8-QT multifunctional drug delivery system might be a promising nanoplatform for cancer treatment.
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http://dx.doi.org/10.1021/acsami.8b13487DOI Listing
October 2018

Biomedical application and controlled drug release of electrospun fibrous materials.

Mater Sci Eng C Mater Biol Appl 2018 Sep 4;90:750-763. Epub 2018 May 4.

Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address:

Electrospinning, as a nanotechnology, is able to produce polymeric fibers materials with nanoscale structure which are also named electrospun fibers material (EFM). These EFMs can be used in many biomedical applications such as wound dressing, tissue engineering, and medical textile materials. Over the last decades, electrospun nanofibers also have been applied to drug delivery such as orodispersible film, solid dispersion and various controlled release dosage forms due to many properties such as high surface to volume ratio, high porous, ease of fabrication and adaptability and so on. This review focuses on the recent advances in biomedical application of EFM, controlled drug release from EFM and devices for producing sophisticated EFM. The processing parameters which influence the physicochemical properties of the resulting EFM are also summarized as well as scaling up techniques for mass production of EFM.
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http://dx.doi.org/10.1016/j.msec.2018.05.007DOI Listing
September 2018

Recent advances in electrospun for drug delivery purpose.

J Drug Target 2019 03 8;27(3):270-282. Epub 2018 Aug 8.

a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China.

Electrospun, an advanced technology, has been successfully employed for fibre production and offers many merits in novel drug delivery systems (DDSs). In recent years, electrospun has gained significant attention and attraction of the scientists in soaring numbers. This technology is superior to other technologies in fabricating the fibres which range from micrometers to manometers scale. The selection of appropriate polymers, electrospun processes and electrospun parameters play important roles in controlling the drug release while, treating serious illness. Besides, electrospraying process has similar characteristics to the electrospun and is presented briefly here. Further, in vivo and in vitro evaluations of the electrospun nanofibers are comprehensively discussed. In addition, the electrospun nanotechnology has been exploited to design drug release systems, investigate drug's pharmacokinetics and further develop DDS. The electrospun nanofibers improve bioactivity of various types of drugs including water-insoluble, soluble, anticancer and antibacterial drugs and genetic materials. In the end, the prospects and challenges in the process of designing drug-loaded electrospun nanofibers are discussed in detail.
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http://dx.doi.org/10.1080/1061186X.2018.1481413DOI Listing
March 2019

Recent progress of functionalised graphene oxide in cancer therapy.

J Drug Target 2019 02 17;27(2):125-144. Epub 2018 Jun 17.

a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China.

In recent years, graphene oxide (GO) nanomaterials have attracted wide attention due to their large surface area, strong light sensitivity and good biocompatibility in cancer treatment. The rich oxygen-containing functional groups on the surface provide it with the opportunity to be modified by many functional molecules to expand biological applications and reduce toxicity. In this review, the properties of GO and the methods of surface modification are presented, and the toxicity of GO is analysed. In addition, the current applications of GO in cancer diagnoses and treatments including biological imaging, drug and gene delivery, phototherapy and imaging-mediated combination therapy are summarised. Finally, the prospects and challenges of GO in cancer treatment are discussed.
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http://dx.doi.org/10.1080/1061186X.2018.1474359DOI Listing
February 2019