Publications by authors named "Robert J Lee"

355 Publications

Study protocol for a multicentre, randomised controlled trial to compare the use of the decellularised dermis allograft in addition to standard care versus standard care alone for the treatment of venous leg ulceration: DAVE trial.

BMJ Open 2021 Apr 2;11(4):e041748. Epub 2021 Apr 2.

Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London, UK

Introduction: Venous leg ulceration (VLU), the most common type of chronic ulcer, can be difficult to heal and is a major cause of morbidity and reduced quality of life. Although compression bandaging is the principal treatment, it is time-consuming and bandage application requires specific training. There is evidence that intervention on superficial venous incompetence can help ulcer healing and recurrence, but this is not accessible to all patients. Hence, new treatments are required to address these chronic wounds. One possible adjuvant treatment for VLU is human decellularised dermis (DCD), a type of skin graft derived from skin from deceased tissue donors. Although DCD has the potential to promote ulcer healing, there is a paucity of data for its use in patients with VLU.

Methods And Analysis: This is a multicentre, parallel group, pragmatic randomised controlled trial. One hundred and ninety-six patients with VLU will be randomly assigned to receive either the DCD allograft in addition to standard care or standard care alone. The primary outcome is the proportion of participants with a healed index ulcer at 12 weeks post-randomisation in each treatment arm. Secondary outcomes include the time to index ulcer healing and the proportion of participants with a healed index ulcer at 12 months. Changes in quality of life scores and cost-effectiveness will also be assessed. All analyses will be carried out on an intention-to-treat (ITT) basis. A mixed-effects, logistic regression on the outcome of the proportion of those with the index ulcer healed at 12 weeks will be performed. Secondary outcomes will be assessed using various statistical models appropriate to the distribution and nature of these outcomes.

Ethics And Dissemination: Ethical approval was granted by the Bloomsbury Research Ethics Committee (19/LO/1271). Findings will be published in a peer-reviewed journal and presented at national and international conferences.

Trial Registration Number: ISRCTN21541209.
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http://dx.doi.org/10.1136/bmjopen-2020-041748DOI Listing
April 2021

Self-Assembled pH-Sensitive Polymeric Nanoparticles for the Inflammation-Targeted Delivery of Cu/Zn-Superoxide Dismutase.

ACS Appl Mater Interfaces 2021 Apr 25;13(15):18152-18164. Epub 2021 Mar 25.

School of Life Sciences, Jilin University, No.2699, Qianjin Street, Changchun, Jilin 130012, China.

The use of superoxide dismutase (SOD) is currently limited by its short half-life, rapid plasma clearance rate, and instability. We synthesized a small library of biofriendly amphiphilic polymers that comprise methoxy poly(ethylene glycol)-poly(cyclohexane-1,4-diyl acetone dimethyleneketal) (mPEG-PCADK) and mPEG-poly((cyclohexane, 1,5-pentanediol)-1,4-diyl acetone dimethylene ketal) (PK3) for the targeted delivery of SOD. The novel polymers could self-assemble into micellar nanoparticles with favorable hydrolysis kinetics, biocompatibility, long circulation time, and inflammation-targeting effects. These materials generated a better pH-response curve and exhibited better hydrolytic kinetic behavior than PCADK and PK3. The polymers showed good biocompatibility with protein drugs and did not induce an acidic microenvironment during degradation in contrast to materials such as PEG--poly(lactic--glycolic acid) (PLGA) and PLGA. The SOD that contained reverse micelles based on mPEG2000-PCADK exhibited good circulation and inflammation-targeting properties. Pharmacodynamic results indicated exceptional antioxidant and anti-inflammatory activities in a rat adjuvant-induced arthritis model and a rat peritonitis model. These results suggest that these copolymers are ideal protein carriers for targeting inflammation treatment.
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http://dx.doi.org/10.1021/acsami.1c03589DOI Listing
April 2021

PAR-2-activated secretion by airway gland serous cells: role for CFTR and inhibition by Pseudomonas aeruginosa.

Am J Physiol Lung Cell Mol Physiol 2021 Mar 3. Epub 2021 Mar 3.

Otorhinolaryngology, University of Pennsylvania, United States.

Airway submucosal gland serous cells are important sites of fluid secretion in conducting airways. Serous cells also express the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that activates secretion from intact airway glands. We tested if and how human nasal serous cells secrete fluid in response to PAR-2 stimulation using Ca imaging and simultaneous differential interference contrast imaging to track isosmotic cell shrinking and swelling reflecting activation of solute efflux and influx pathways, respectively. During stimulation of PAR-2, serous cells exhibited dose-dependent increases in intracellular Ca. At stimulation levels >EC for Ca, serous cells simultaneously shrank ~20% over ~90 sec due to KCl efflux reflecting Ca-activated Cl channel (CaCC, likely TMEM16A)-dependent secretion. At lower levels of PAR-2 stimulation (
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http://dx.doi.org/10.1152/ajplung.00411.2020DOI Listing
March 2021

PLGA/PCADK composite microspheres containing hyaluronic acid-chitosan siRNA nanoparticles: A rational design for rheumatoid arthritis therapy.

Int J Pharm 2021 Mar 23;596:120204. Epub 2021 Jan 23.

School of Life Sciences, Jilin University, Changchun, Jilin, China. Electronic address:

Myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 anti-apoptotic family, is overexpressed in the synovial macrophages of patients with rheumatoid arthritis (RA). Small interfering RNA (siRNA) Mcl-1 can induce macrophage apoptosis in the joints and is a potential therapeutic target of RA. Nevertheless, the application of siRNA is limited owing to its instability and susceptibility to degradation in vivo. To address these shortcomings, we developed composite microspheres (MPs) loaded with hyaluronic acid (HA)-chitosan (CS) nanoparticles (NPs). First, we synthesized HA-CS/siRNA NPs (HCNPs) using ionotropic gelation process. Then, HCNPs, as an internal aqueous phase, were loaded into poly (D, L-lactide-co-glycolide) (PLGA) and poly (cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK) MPs using the double emulsion method. The NPs-in-MPs (NiMPs) composite system provided sustained release of NPs, protected siRNA against nuclease degradation in the serum, and could readily cross the cellular membrane. In addition, we evaluated the advantages of NiMPs in an adjuvant-induced arthritis rat model. Our experimental results demonstrate that NiMPs have greater pharmacodynamic effects than common MPs. Meanwhile, compared with HCNPs, NiMPs reduced the frequency of drug administration. Therefore, NiMPs are a promising and novel siRNA delivery vehicle for RA therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120204DOI Listing
March 2021

Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates injury during mechanical ventilation.

Nat Commun 2021 01 12;12(1):289. Epub 2021 Jan 12.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Columbus, OH, 43210, USA.

Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We use humanized in-vitro systems, mouse models, and biospecimens from patients to elucidate the expression dynamics of miR-146a needed to decrease lung injury during mechanical ventilation. We find that the endogenous increase in miR-146a following injurious ventilation is not sufficient to prevent lung injury. However, when miR-146a is highly overexpressed using a nanoparticle delivery platform it is sufficient to prevent injury. These data indicate that the endogenous increase in microRNA-146a during mechanical ventilation is a compensatory response that partially limits injury and that nanoparticle delivery of miR-146a is an effective strategy for mitigating lung injury during mechanical ventilation.
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http://dx.doi.org/10.1038/s41467-020-20449-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804938PMC
January 2021

Design of a Novel Nucleus-Targeted NLS-KALA-SA Nanocarrier to Delivery Poorly Water-Soluble Anti-Tumor Drug for Lung Cancer Treatment.

J Pharm Sci 2021 Jan 5. Epub 2021 Jan 5.

College of Pharmacy, Guilin Medical University, Guilin 541004, China.

In this study, we designed a novel nucleus-targeted nanocarrier (NLS-KALA-SA, NKSN) consisting of Kala peptide (KALA), nuclear localization signal (NLS) and stearic acid (SA) using Fmoc solid phase synthesis method. We chose Curcumin (CUR), Paclitaxel (PTX), Ginsenoside compound K(CK) as models of poorly water-soluble antitumor drugs, The drugs loaded NLS-KALA-SA nanoparticles (CUR/NKSN, PTX/NKSN, CK/NKSN) were obained by the dialysis method, their physicochemical properties were determined and antitumor activity were evaluated. The NLS-KALA-SA nanoparticles were spherical shaped with an average size of 76.4 ± 7.6 mm and a zeta potential of 43.7 ± 5.8 mV. The drug-loaded NLS-KALA-SA nanoparticles were above 86.1% and 17.1% in entrapment efficiency and drug loading capacity, and had sustained drug release behavior. Biodistribution and cellular uptake study exhibited that PTX/NKSN mainly distributed in tumor site of A549-bearing mice, and coumarin-6(C6) loaded NLS-KALA-SA nanoparticle (C6/NKSN) was predominantly accumulated in the nucleus of A549 cells. Western blot analysis indicated that PTX/NKSN could more remarkably inhibit Bcl-2 expression and enhance the expression of Bax and Caspase-3 as compared to the controls in A549 cells. Cell apoptosis and antitumor activity study showed that PXT/NKSN could more obviously induce apoptosis of A549 cells compared with free PXT, the PTX/NKSN administration was more effective than free PTX for lung cancer treatment and displayed mild toxicity in A549-bearing mice. The results demonstrates that the NLS-KALA-SA nanoparticles system could enhance the antitumor effects of the encapsulated drug and reduce tissue toxicity due to its long circulating properties and tumor targeting, which might provide a promising strategy for lung cancer treatment.
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http://dx.doi.org/10.1016/j.xphs.2020.12.034DOI Listing
January 2021

A solid lipid coated calcium peroxide nanocarrier enables combined cancer chemo/chemodynamic therapy with O/HO self-sufficiency.

Acta Biomater 2021 03 6;122:354-364. Epub 2021 Jan 6.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

The unfavorable factors in tumor microenvironment such as hypoxia and limited HO levels greatly impede the anticancer efficacy of chemotherapy and chemodynamic therapy (CDT). To address these issues and achieve O/HO-sufficient chemo/chemodynamic combination therapy, we synthesized a solid lipid monostearin coated calcium peroxide (CaO) nanocarrier for the co-delivery of a chemotherapeutic drug doxorubicin (DOX) and a biocompatible Fenton catalyst iron-oleate complex. Specifically, the solid lipid shells of nanoparticles could disintegrate in lipase-overexpressed cancer cells to release iron-oleate and expose CaO cores. Afterwards, the uncovered CaO responded to the acidic aqueous environment within cancer cells, leading to the release of DOX molecules and generation of HO. Based on Fenton reactions, Fe liberated from iron-oleate reacted with HO to produce O for hypoxia-relieved chemotherapy, and Fe for the catalytic generation of hydroxyl radical to initiate CDT. Both treatments synergistically contribute to the enhanced antitumor outcomes.
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http://dx.doi.org/10.1016/j.actbio.2020.12.036DOI Listing
March 2021

Perinatal inflammation alters histone 3 and histone 4 methylation patterns: Effects of MiR-29b supplementation.

Redox Biol 2021 01 7;38:101783. Epub 2020 Nov 7.

Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, USA; College of Medicine, The Ohio State University, Columbus, OH, USA. Electronic address:

Preterm birth is still a major health problem and maternal inflammation has been shown to play a role. The combination of maternal inflammation and neonatal hyperoxia contributes to epigenetic changes that influence gene expression and the development of bronchopulmonary dysplasia (BPD). We have previously demonstrated suppression of miR-29b and increases in DNA methylation in infants with severe BPD and in our mouse model of maternal inflammation and neonatal hyperoxia exposure. The present studies further explored epigenetic changes in the murine model to include histone methylation. We identified a global suppression of histone methylation in exposed mice and validated decreases in expression in well-defined histone modifications, specifically H3K4me3, H3K27me3, H3K36me2, H3K79me2, and H4K20me3. We further tested the hypothesis that restoration of miR-29b expression would restore the histone methylation marks. Using lipid nanoparticle delivery of miR-29b, partial to full methylation was reestablished for H3K4me3, H3K27me3, and H4K20me3; all tri-methylation marks. To identify the causes of decreased methylation in exposed mice, we measured commonly identified methylases and demethylases. We found a decreased expression of SUV40H2, a methylase primarily associated with H4K20me3. Further studies are needed to identify the causes for the decreased global histone methylation and potential therapeutic opportunities.
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http://dx.doi.org/10.1016/j.redox.2020.101783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677713PMC
January 2021

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity.

World J Biol Chem 2020 Sep;11(2):30-51

Department of Otorhinolaryngology and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.

The airway innate immune system maintains the first line of defense against respiratory infections. The airway epithelium and associated immune cells protect the respiratory system from inhaled foreign organisms. These cells sense pathogens activation of receptors like toll-like receptors and taste family 2 receptors (T2Rs) and respond by producing antimicrobials, inflammatory cytokines, and chemokines. Coordinated regulation of fluid secretion and ciliary beating facilitates clearance of pathogens mucociliary transport. Airway cells also secrete antimicrobial peptides and radicals to directly kill microorganisms and inactivate viruses. The phosphoinositide-3-kinase/protein kinase B (Akt) kinase pathway regulates multiple cellular targets that modulate cell survival and proliferation. Akt also regulates proteins involved in innate immune pathways. Akt phosphorylates endothelial nitric oxide synthase (eNOS) enzymes expressed in airway epithelial cells. Activation of eNOS can have anti-inflammatory, anti-bacterial, and anti-viral roles. Moreover, Akt can increase the activity of the transcription factor nuclear factor erythroid 2 related factor-2 that protects cells from oxidative stress and may limit inflammation. In this review, we summarize the recent findings of non-cancerous functions of Akt signaling in airway innate host defense mechanisms, including an overview of several known downstream targets of Akt involved in innate immunity.
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http://dx.doi.org/10.4331/wjbc.v11.i2.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520643PMC
September 2020

Exosome-Mediated Crosstalk between Keratinocytes and Macrophages in Cutaneous Wound Healing.

ACS Nano 2020 10 25;14(10):12732-12748. Epub 2020 Sep 25.

Indiana Center for Regenerative Medicine & Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.

Bidirectional cell-cell communication involving exosome-borne cargo such as miRNA has emerged as a critical mechanism for wound healing. Unlike other shedding vesicles, exosomes selectively package miRNA by SUMOylation of heterogeneous nuclear ribonucleoproteinA2B1 (hnRNPA2B1). In this work, we elucidate the significance of exosome in keratinocyte-macrophage crosstalk following injury. Keratinocyte-derived exosomes were genetically labeled with GFP-reporter (Exo) using tissue nanotransfection (TNT), and they were isolated from dorsal murine skin and wound-edge tissue by affinity selection using magnetic beads. Surface N-glycans of Exo were also characterized. Unlike skin exosome, wound-edge Exo demonstrated characteristic N-glycan ions with abundance of low-base-pair RNA and was selectively engulfed by wound macrophages (ωmϕ) in granulation tissue. addition of wound-edge Exo to proinflammatory ωmϕ resulted in conversion to a proresolution phenotype. To selectively inhibit miRNA packaging within Exo, pH-responsive keratinocyte-targeted siRNA-hnRNPA2B1 functionalized lipid nanoparticles (TLNP) were designed with 94.3% encapsulation efficiency. Application of TLNP to the murine dorsal wound-edge significantly inhibited expression of hnRNPA2B1 by 80% in epidermis compared to the TLNP group. Although no significant difference in wound closure or re-epithelialization was observed, the TLNP treated group showed a significant increase in ωmϕ displaying proinflammatory markers in the granulation tissue at day 10 post-wounding compared to the TLNP group. Furthermore, TLNP treated mice showed impaired barrier function with diminished expression of epithelial junctional proteins, lending credence to the notion that unresolved inflammation results in leaky skin. This work provides insight wherein Exo is recognized as a major contributor that regulates macrophage trafficking and epithelial barrier properties postinjury.
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http://dx.doi.org/10.1021/acsnano.0c03064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970718PMC
October 2020

Isoforsythiaside Attenuates Alzheimer's Disease via Regulating Mitochondrial Function Through the PI3K/AKT Pathway.

Int J Mol Sci 2020 Aug 8;21(16). Epub 2020 Aug 8.

School of Life Sciences, Jilin University, Changchun 130012, China.

Improving mitochondrial dysfunction and inhibiting apoptosis has always been regarded as a treatment strategy for Alzheimer's disease (AD). Isoforsythiaside (IFY), a phenylethanoid glycoside isolated from the dried fruit of , displays antioxidant activity. This study examined the neuroprotective effects of IFY and its underlying mechanisms. In the L-glutamate (L-Glu)-induced apoptosis of HT22 cells, IFY increased cell viability, inhibited mitochondrial apoptosis, and reduced the intracellular levels of reactive oxygen species (ROS), caspase-3, -8 and -9 after 3 h of pretreatment and 12-24 h of co-incubation. In the / transgenic (APP/PS1) model, IFY reduced the anxiety of mice, improved their memory and cognitive ability, reduced the deposition of beta amyloid (Aβ) plaques in the brain, restrained the phosphorylation of the tau protein to form neurofibrillary tangles, inhibited the level of 4-hydroxynonenal in the brain, and improved phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway-related mitochondrial apoptosis. In Aβ-induced U251 cells, IFY relieved the mitochondrial swelling, crest ruptures and increased their electron density after 3 h of pretreatment and 18-24 h of co-incubation. The improved cell viability and mitochondrial function after IFY incubation was blocked by the synthetic PI3K inhibitor LY294002. Taken together, these results suggest that IFY exerts a protective effect against AD by enhancing the expression levels of anti-apoptosis proteins and reducing the expression levels of pro-apoptosis proteins of B-cell lymphoma-2 (BCL-2) family members though activating the PI3K/AKT pathway.
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http://dx.doi.org/10.3390/ijms21165687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460834PMC
August 2020

First contact: the role of respiratory cilia in host-pathogen interactions in the airways.

Am J Physiol Lung Cell Mol Physiol 2020 10 12;319(4):L603-L619. Epub 2020 Aug 12.

Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Respiratory cilia are the driving force of the mucociliary escalator, working in conjunction with secreted airway mucus to clear inhaled debris and pathogens from the conducting airways. Respiratory cilia are also one of the first contact points between host and inhaled pathogens. Impaired ciliary function is a common pathological feature in patients with chronic airway diseases, increasing susceptibility to respiratory infections. Common respiratory pathogens, including viruses, bacteria, and fungi, have been shown to target cilia and/or ciliated airway epithelial cells, resulting in a disruption of mucociliary clearance that may facilitate host infection. Despite being an integral component of airway innate immunity, the role of respiratory cilia and their clinical significance during airway infections are still poorly understood. This review examines the expression, structure, and function of respiratory cilia during pathogenic infection of the airways. This review also discusses specific known points of interaction of bacteria, fungi, and viruses with respiratory cilia function. The emerging biological functions of motile cilia relating to intracellular signaling and their potential immunoregulatory roles during infection will also be discussed.
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http://dx.doi.org/10.1152/ajplung.00283.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516383PMC
October 2020

Microfluidic self-assembly of high cabazitaxel loading albumin nanoparticles.

Nanoscale 2020 Aug 10;12(32):16928-16933. Epub 2020 Aug 10.

Jilin University, School of Life Sciences, Changchun, Jilin, China.

Cabazitaxel (CTX) is a promising anticancer drug. In this study, CTX-loaded human serum albumin (HSA) nanoparticles (MF-NPs-CTX) were prepared by a microfluidic (MF) method and were evaluated for tumor inhibition in PC-3 and HeLa cells in vitro and in vivo. The in vitro experiments showed that MF-NPs-CTX had higher drug loading content (DLC) as compared with NPs prepared by the bottom-up (BU) method (BU-NPs-CTX). Besides, MF-NPs-CTX exhibited uniform particle size distribution, high stability, sustained drug release, and high biosafety, in vivo imaging studies demonstrated that MF-NPs-CTX accumulated preferentially at the tumor site, compared to BU-NPs-CTX. The enhanced tumor uptake also increased the therapeutic efficacy of MF-NPs-CTX. Both MF-NPs-CTX and tween-CTX exhibited good tumor inhibition effect in vivo. MF-NPs-CTX had better biosafety and biocompatibility than tween-CTX. These results demonstrated that high CTX loading of MF-NPs-CTX has potential in the clinical treatment of tumors.
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http://dx.doi.org/10.1039/c9nr10941bDOI Listing
August 2020

Platinum complexes of curcumin delivered by dual-responsive polymeric nanoparticles improve chemotherapeutic efficacy based on the enhanced anti-metastasis activity and reduce side effects.

Acta Pharm Sin B 2020 Jun 1;10(6):1106-1121. Epub 2019 Nov 1.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum-curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt-CUR@PSPPN) to facilitate intracellular release and synergistic anti-cancer effects. Pt-CUR@PSPPN was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both and . In addition, Pt-CUR@PSPPN blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt-CUR@PSPPN provided a novel and attractive therapeutic strategy for NSCLC.
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http://dx.doi.org/10.1016/j.apsb.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332658PMC
June 2020

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application.

Front Pharmacol 2020 20;11:697. Epub 2020 May 20.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States.

Cell-penetrating peptides (CPPs) are short peptides (fewer than 30 amino acids) that have been predominantly used in basic and preclinical research during the last 30 years. Since they are not only capable of translocating themselves into cells but also facilitate drug or CPP/cargo complexes to translocate across the plasma membrane, they have potential applications in the disease diagnosis and therapy, including cancer, inflammation, central nervous system disorders, otologic and ocular disorders, and diabetes. However, no CPPs or CPP/cargo complexes have been approved by the US Food and Drug Administration (FDA). Many issues should be addressed before translating CPPs into clinics. In this review, we summarize recent developments and innovations in preclinical studies and clinical trials based on using CPP for improved delivery, which have revealed that CPPs or CPP-based delivery systems present outstanding diagnostic therapeutic delivery potential.
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http://dx.doi.org/10.3389/fphar.2020.00697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251059PMC
May 2020

Dual Hypoxia-Targeting RNAi Nanomedicine for Precision Cancer Therapy.

Nano Lett 2020 07 8;20(7):4857-4863. Epub 2020 Jun 8.

Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.

As a hallmark of solid tumors, hypoxia promotes tumor growth, metastasis, and therapeutic resistance by regulating the expression of hypoxia-related genes. Hypoxia also represents a tumor-specific stimulus that has been exploited for the development of bioreductive prodrugs and advanced drug delivery systems. Cell division cycle 20 (CDC20) functions as an oncogene in tumorigenesis, and we demonstrated the significant upregulation of CDC20 mRNA in the tumor vs paratumor tissues of breast cancer patients and its positive correlation with tumor hypoxia. Herein, a hypoxia-responsive nanoparticle (HRNP) was developed by self-assembly of the 2-nitroimidazole-modified polypeptide and cationic lipid-like compound for delivery of siRNA to specifically target CDC20, a hypoxia-related protumorigenic gene, in breast cancer therapy. The delivery of siCDC20 by HRNPs sufficiently silenced the expression of CDC20 and exhibited potent antitumor efficacy. We expect that this strategy of targeting hypoxia-correlated protumorigenic genes by hypoxia-responsive RNAi nanoparticles may provide a promising approach in cancer therapy.
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http://dx.doi.org/10.1021/acs.nanolett.0c00757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405292PMC
July 2020

Nano Encapsulated Curcumin: And Its Potential for Biomedical Applications.

Int J Nanomedicine 2020 1;15:3099-3120. Epub 2020 May 1.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.

Curcumin, a yellow-colored polyphenol extracted from the rhizome of turmeric root, is commonly used as a spice and nutritional supplement. It exhibits many pharmacological activities such as anti-inflammatory, anti-bacterial, anti-cancer, anti-Alzheimer, and anti-fungal. However, the therapeutic application of curcumin is limited by its extremely low solubility in aqueous buffer, instability in body fluids, and rapid metabolism. Nano delivery system has shown excellent potential to improve the solubility, biocompatibility and therapeutic effect of curcumin. In this review, we focus on the recent development of nano encapsulated curcumin and its potential for biomedical applications.
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http://dx.doi.org/10.2147/IJN.S210320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200256PMC
July 2020

Calcitriol-Loaded Dual-pH-Sensitive Micelle Counteracts Pro-Metastasis Effect of Paclitaxel in Triple-Negative Breast Cancer Therapy.

Adv Healthc Mater 2020 06 17;9(12):e2000392. Epub 2020 May 17.

State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.

The therapy of triple-negative breast cancer (TNBC) relies on chemotherapy basing on cytotoxic agents, including paclitaxel (PTX). Unfortunately, PTX will facilitate the invasion of cancer cells and the formation of metastases. To counteract pro-metastasis of PTX in TNBC therapy, in this work, calcitriol (CTL) is delivered along with PTX by a dual-pH-sensitive micelle. The PTX/CTL-co-loaded dual-pH-sensitive micelle (PCDM) can switch its surface charge from negative to positive at the tumor tissue and release PTX and CTL inside the lysosomes because of the structure change of the polymers composing PCDM under the acidic condition. This property makes PCDM able to escape from mononuclear-phagocyte system clearance and easy to enter tumor cells. PCDM efficiently suppresses the 4T1 primary tumor growth in mice and inhibits lung metastasis, due to downregulation of matrix metalloproteinase-9 and BCL-2 levels, upregulation of E-cadherin level, and counteracting the PTX-induced elevation of C-C motif chemokine ligand 2 (CCL2) and Ly6C monocytes levels by CTL. PCDM shows good biocompatibility without promoting the serum calcium level. Therefore, the combination of PTX and CTL based on this pH-sensitive micelle is promising for the TNBC treatment.
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http://dx.doi.org/10.1002/adhm.202000392DOI Listing
June 2020

Myocardium-targeted transplantation of PHD2 shRNA-modified bone mesenchymal stem cells through ultrasound-targeted microbubble destruction protects the heart from acute myocardial infarction.

Theranostics 2020 6;10(11):4967-4982. Epub 2020 Apr 6.

Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Ultrasound-targeted microbubble destruction (UTMD) is a promising approach to facilitate the precise delivery of bone marrow stem cells (BMSCs) to the ischemic myocardium. However, stem cell therapy for ischemic myocardium is challenging due to the poor survival of transplanted stem cells under severe ischemic conditions. In this study, we investigated whether myocardium-targeted transplantation of prolyl hydroxylase domain protein 2 (PHD2) shRNA-modified BMSCs by UTMD increases the viability of grafted cells, and enhances their cardioprotective effects in acute myocardial infarction. BMSCs were transduced with lentiviral PHD2 shRNA, and a novel microbubble formulation was prepared by a thin-film hydration method. In rats, BMSCs with or without PHD2 shRNA modification were transplanted by UTMD after inducing acute myocardium infarction. Effects of PHD2 shRNA on BMSC survival, myocardial apoptosis, angiogenesis, and cardiac function were evaluated. , anti-apoptotic effects and its mechanisms of PHD2 silencing on BMSC and BMSC-conditioned medium on H9C2 cell were detected. PHD2 shRNA-modified BMSC transplantation by UTMD resulted in increased BMSC survival, reduced myocardial apoptosis, reduced infarct size, increased vascular density, and improved cardiac function compared to the control vector-modified BMSC transplantation by UTMD. PHD2 silencing increased BMSC survival through a HIF-1α-dependent mechanism. The decrease in cardiomyocyte apoptosis by conditioned medium from PHD2 shRNA-treated BMSCs was due to an increase in the expression of insulin-like growth factor (IGF)-1. The delivery of PHD2 shRNA-modified BMSCs by UTMD promoted grafted cell homing and activity, and increased myocardial angiogenesis in the infarcted heart, leading to improved cardiac function. This combination may provide a promising strategy for enhancing the effectiveness of stem cell therapy after acute myocardial infarction.
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http://dx.doi.org/10.7150/thno.43233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163444PMC
April 2020

Anti-inflammation of Erianin in dextran sulphate sodium-induced ulcerative colitis mice model via collaborative regulation of TLR4 and STAT3.

Chem Biol Interact 2020 Jun 6;324:109089. Epub 2020 Apr 6.

School of Life Sciences, Jilin University, Changchun City, 130012, Jilin Province, PR China. Electronic address:

Ulcerative colitis (UC) is a chronic, idiopathic and inflammatory disease of the rectal and colonic mucosa. Studies have shown that Toll-like receptors (TLR) 4 and Signal Transducer and Activator of Transcription 3 (STAT3)-mediated the decline in immune function and inflammatory infiltration are potential pathomechanism of UC occurrence and development. In this study, the anti-inflammation of Erianin, a natural bibenzyl compound with the antioxidant, antitumor, and anti-inflammatory activities, was investigated in a dextran sodium sulphate-induced UC mouse model. Three-week Erianin administration resulted in the increment on the body weight and colon length, and the reduction on the activity index score of UC mice. Liver, spleen, and renal organ indexes and pathological observations confirmed that Erianin was not cytotoxic and had an effect of improving immune organ function. The haematoxylin and eosin staining sections of colon tissue show Erianin's effect of reversing inflammation in the mucosal laye. Proteomic analysis and enzyme-linked immunosorbent assay indicated that Erianin regulated the levels of inflammatory and oxidative stress-related factors and immunochemokines in serum and colon tissues thereby reducing cell peroxidative damage and reducing immune inflammatory responses. Further data obtained by Western Blotting confirmed that Erianin's anti-UC activity was mediated by inhibiting the TLR4 and STAT3 signaling.
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http://dx.doi.org/10.1016/j.cbi.2020.109089DOI Listing
June 2020

Polarization of protease-activated receptor 2 (PAR-2) signaling is altered during airway epithelial remodeling and deciliation.

J Biol Chem 2020 05 2;295(19):6721-6740. Epub 2020 Apr 2.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104

Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI-H520 squamous cells increased intracellular calcium levels and granulocyte macrophage-colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air-liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases.
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http://dx.doi.org/10.1074/jbc.RA120.012710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212650PMC
May 2020

One-pot synthesis of a microporous organosilica-coated cisplatin nanoplatform for HIF-1-targeted combination cancer therapy.

Theranostics 2020 3;10(7):2918-2929. Epub 2020 Feb 3.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Nanoparticle formulations have proven effective for cisplatin delivery. However, the development of a versatile nanoplatform for cisplatin-based combination cancer therapies still remains a great challenge. : In this study, we developed a one-pot synthesis method for a microporous organosilica shell-coated cisplatin nanoplatform using a reverse microemulsion method, and explored its application in co-delivering acriflavine (ACF) for inhibiting hypoxia-inducible factor-1 (HIF-1). : The resulting nanoparticles were tunable, and they could be optimized to a monodisperse population of particles in the desired size range (40-50 nm). In addition, organic mPEG2000-silane and tetrasulfide bond-bridged organosilica were integrated into the surface and silica matrix of nanoparticles for prolonged blood circulation and tumor-selective glutathione-responsive degradation, respectively. After reaching the tumor sites, cisplatin induced cancer cell death and activated HIF-1 pathways, resulting in acquired drug resistance and tumor metastasis. To address this issue, ACF was co-loaded with cisplatin to prevent the formation of HIF-1α/β dimers and suppress HIF-1 function. Hence, the efficacy of cisplatin was improved, and cancer metastasis was inhibited. : Both and results suggested that this core-shell nanostructured cisplatin delivery system represented a highly efficacious and promising nanoplatform for the synergistic delivery of combination therapies involving cisplatin.
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http://dx.doi.org/10.7150/thno.41077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053205PMC
March 2021

Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling.

Cell Mol Life Sci 2021 Jan 14;78(1):271-286. Epub 2020 Mar 14.

Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Ravdin, 5th Floor, Suite A , 3400 Spruce Street, Philadelphia, PA, 19104, USA.

Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (M[Formula: see text]s) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis ~ threefold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance M[Formula: see text] phagocytosis. Together, these data define M[Formula: see text] T2R signal transduction and support an immune recognition role for T2Rs in M[Formula: see text] cell physiology.
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http://dx.doi.org/10.1007/s00018-020-03494-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492447PMC
January 2021

Neuropeptide regulation of secretion and inflammation in human airway gland serous cells.

Eur Respir J 2020 04 16;55(4). Epub 2020 Apr 16.

Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways. To elucidate how neuropeptides regulate serous cells, we tested if human nasal turbinate serous cells secrete bicarbonate (HCO), important for mucus polymerisation and antimicrobial peptide function, during stimulation with cAMP-elevating vasoactive intestinal peptide (VIP) and if this requires CFTR. Serous cells stimulated with VIP exhibited a ∼15-20% cAMP-dependent decrease in cell volume and a ∼0.15 unit decrease in intracellular pH (pH), reflecting activation of Cl and HCO secretion, respectively. HCO secretion was directly dependent on CFTR and was absent in cells from CF patients. In contrast, neuropeptide Y (NPY) reduced VIP-evoked cAMP increases, CFTR activation, and Cl/HCO secretion. Culture of primary serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO secretion. Moreover, VIP enhanced antimicrobial peptide secretion and antimicrobial efficacy of secretions while NPY reduced antimicrobial efficacy. In contrast, NPY enhanced cytokine release while VIP reduced cytokine release through a mechanism requiring CFTR. As levels of VIP and NPY are up-regulated in diseases like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control mucus rheology and inflammatory responses in serous cells. Furthermore, the loss of CFTR conductance in serous cells may contribute to CF pathophysiology by increasing serous cells inflammatory responses in addition to directly impairing Cl and HCO secretion.
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http://dx.doi.org/10.1183/13993003.01386-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166175PMC
April 2020

A Liposomal Formulation for Improving Solubility and Oral Bioavailability of Nifedipine.

Molecules 2020 Jan 14;25(2). Epub 2020 Jan 14.

Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China.

Proliposomes were used to improve the solubility and oral bioavailability of nifedipine. Nifedipine proliposomes were prepared by methanol injection-spray drying method. The response surface method was used to optimize formulation to enhance the encapsulation efficiency (EE%) of nifedipine. The particle size of nifedipine proliposomes after rehydration was 114 nm. Surface morphology of nifedipine proliposomes was observed by a scanning electron microscope (SEM) and interaction of formulation ingredients was assessed by differential scanning calorimetry (DSC). The solubility of nifedipine is improved 24.8 times after forming proliposomes. In vitro release experiment, nifedipine proliposomes had a control release effect, especially in simulated gastric fluid. In vivo, nifedipine proliposomes significantly improved the bioavailability of nifedipine. The area under the concentration-time curve (AUC) of nifedipine proliposomes was about 10 times than nifedipine after oral administration. The elimination half-life (T) of nifedipine was increased from 1.6 h to 6.6 h. In conclusion, proliposomes was a promising system to deliver nifedipine through oral route and warranted further investigation.
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http://dx.doi.org/10.3390/molecules25020338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024191PMC
January 2020

The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.

Nat Commun 2019 11 25;10(1):5351. Epub 2019 Nov 25.

The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA.

Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.
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http://dx.doi.org/10.1038/s41467-019-13259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877618PMC
November 2019

Biocompatible co-loading vehicles for delivering both nanoplatin cores and siRNA to treat hepatocellular carcinoma.

Int J Pharm 2019 Dec 26;572:118769. Epub 2019 Oct 26.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China. Electronic address:

Bmi-1 is a gene related to malignant transformation in hepatocellular carcinoma (HCC). The liver cancer cells developed the ability to tolerate CDDP treatment with the elevation of Bmi-1. Bmi-1 is also an oncogene promoting malignance of tumor and an anti-cancer target in many studies. Herein, a biocompatible nanocarrier was designed in the study to deliver a chemotherapeutical agent CDDP and Bmi-1 siRNA to kill cancer cells and silence drug resistance related gene simultaneously. Calciumphosphate (CaP) was applied to coat both nanoplatin cores and siRNA as a shell for the purpose of delivering cargos to the cytosol of the tumor cells. Nanoplatin and siRNA co-loaded CaP nanoparticles (NPSC) enhanced cell uptake of CDDP and showed elevated drug accumulation in tumor. NPSC achieved considerable anti-cancer efficacy and counter-regulated drug tolerance, therefore, warranted a further investigation as a novel therapeutic nanosystem to improve cancer therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118769DOI Listing
December 2019

Folate Receptor-Targeted Albumin Nanoparticles Based on Microfluidic Technology to Deliver Cabazitaxel.

Cancers (Basel) 2019 Oct 16;11(10). Epub 2019 Oct 16.

School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.

Microfluidic technology (MF) has improved the formulation of nanoparticles (NPs) by achieving uniform particle size distribution, controllable particle size, and consistency. Moreover, because liquid mixing can be precisely controlled in the pores of the microfluidic chip, maintaining high mixing efficiency, MF exerts higher of NP encapsulation efficiency (EE) than conventional methods. MF-NPs-cabazitaxel (CTX) particles (MF-NPs-CTX) were first prepared by encapsulating CTX according to MF. Folate (FA)- Polyethylene glycol (PEG)-NPs-CTX particles (FA-PEG-NPs-CTX) were formulated by connecting FA to MF-NPs-CTX to endow NPs with targeted delivery capability. Accordingly, the mean particle size of FA-PEG-NPs-CTX increased by approximately 25 nm, as compared with MF-NPs-CTX. Upon morphological observation of FA-PEG-NPs-CTX and MF-NPs-CTX by transmission electron microscopy (TEM), all NPs were spherical and particle size distribution was uniform. Moreover, the increased delivery efficiency of CTX in vitro and its strong tumor inhibition in vivo indicated that FA-PEG-NPs-CTX had a powerful tumor-suppressive effect both in vitro and in vivo. In vivo imaging and pharmacokinetic data confirmed that FA-PEG-NPs-CTX had good drug delivery efficiency. Taken together, FA-PEG-NPs-CTX particles prepared using MF showed high efficient and targeted drug delivery and may have a considerable driving effect on the clinical application of targeting albumin NPs.
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http://dx.doi.org/10.3390/cancers11101571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827099PMC
October 2019