Publications by authors named "Conglian Yang"

15 Publications

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Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design.

Acta Pharm Sin B 2021 May 7. Epub 2021 May 7.

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

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.
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http://dx.doi.org/10.1016/j.apsb.2021.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102084PMC
May 2021

L-EGCG-Mn nanoparticles as a pH-sensitive MRI contrast agent.

Drug Deliv 2021 Dec;28(1):134-143

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, PR China.

This study aimed to synthesize and characterize L-epigallocatechin gallate (EGCG) complexed Mn nanoparticle (L-EGCG-Mn), a proof-of-concept pH-sensitive manganese core nanoparticle (NP), and compare its magnetic resonance (MR) properties with those of Gd-DTPA, both and . Reverse microemulsion was used to obtain the L-EGCG-Mn NPs. The physicochemical properties of L-EGCG-Mn were characterized using dynamic light scattering, transmission electron microscopy, and near-infrared fluorescence small animal live imaging. The relaxivity of L-EGCG-Mn incubated with different pH buffer solutions (pH = 7.4, 6.8, 5.5) was evaluated. The T1-weighted MR imaging (MRI) properties were evaluated using hypoxic H22 cells as well as in H22 tumor-bearing mice. Cytotoxicity tests and histological analysis were performed to evaluate the safety of L-EGCG-Mn. L-EGCG-Mn showed good biocompatibility, stability, pH sensitivity, and tumor-targeting ability. Moreover, when the pH was decreased from 7.4 to 5.5, the relaxivity of L-EGCG-Mn was shown to gradually increase from 1.79 to 6.43 mM·s. Furthermore, after incubation with L-EGCG-Mn for 4 h, the T1 relaxation time of hypoxic H22 cells was significantly lower than that of normoxic H22 cells (1788 ± 89 vs. 1982 ± 68 ms, =.041). The analysis showed that after injection, L-EGCG-Mn exhibited a higher MRI signal compared to Gd-DTPA in H22 tumor-bearing mice ( < .05). Furthermore, L-EGCG-Mn was found to have a good safety profile via cytotoxicity tests and histological analysis. L-EGCG-Mn has a good safety profile and pH sensitivity and may thus serve as a potential MRI contrast agent.
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http://dx.doi.org/10.1080/10717544.2020.1862363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782420PMC
December 2021

Reshaping Tumor Immune Microenvironment through Acidity-Responsive Nanoparticles Featured with CRISPR/Cas9-Mediated Programmed Death-Ligand 1 Attenuation and Chemotherapeutics-Induced Immunogenic Cell Death.

ACS Appl Mater Interfaces 2020 Apr 30;12(14):16018-16030. Epub 2020 Mar 30.

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

Blocking immune checkpoints with monoclonal antibody has been verified to achieve potential clinical successes for cancer immunotherapy. However, its application has been impeded by the "cold" tumor microenvironment. Here, weak acidity-responsive nanoparticles co-loaded with CRISPR/Cas9 and paclitaxel (PTX) with the ability to convert "cold" tumor into "hot" tumor are reported. The nanoparticles exhibited high cargo packaging capacity, superior transfection efficiency, well biocompatibility, and effective tumor accumulation. The CRISPR/Cas9 encapsulated in nanoparticles could specifically knock out cyclin-dependent kinase 5 gene to significantly attenuate the expression of programmed death-ligand 1 on tumor cells. More importantly, PTX co-delivered in nanoparticles could significantly induce immunogenic cell death, reduce regulatory T lymphocytes, repolarize tumor-associated macrophages, and enhance antitumor immunity. Therefore, the nanoparticles could effectively convert cold tumor into hot tumor, achieve effective tumor growth inhibition, and prolong overall survival from 16 to 36 days. This research provided a referable strategy for the development of combinatorial immunotherapy and chemotherapy.
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http://dx.doi.org/10.1021/acsami.9b23084DOI Listing
April 2020

The novel platinum(IV) prodrug with self-assembly property and structure-transformable character against triple-negative breast cancer.

Biomaterials 2020 02 31;232:119751. Epub 2019 Dec 31.

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, PR China. Electronic address:

Herein, a small library of Pt(IV) prodrugs based on cisplatin and chemosensitizer adjudin (ADD) were explored for efficient cisplatin resistant triple-negative breast cancer (TNBC) treatment. We further elucidated the detail relationship of chemical structure, alkyl chain length (ethyl to dodecyl) and ADD substituted degree, with respect to the self-assembly ability and cytotoxic effect of prodrugs. It demonstrated that all prodrugs could self-assemble into nanomedicine, which was in consist with the molecule structure building and self-assembly simulation. All nanomedicines possessed small particle size, uniform morphology and ultra-high drug loading content (84.0%-86.5%). Moreover, the length of alkyl chain was of great importance for the structure-transformable character and cytotoxicity of nanomedicines. Interestingly, ADD monosubstituted with butyl or hexyl contralateral substituted prodrug (C-Pt-ADD or C-Pt-ADD) assembled nanomedicine could convert to wire or sheet structure. These transformable nanoparticles showed great potential in improving the sensitivity of cisplatin to TNBC with up to 266-fold lower IC value and significantly enhanced in vivo tumor growth inhibition. Therefore, the self-assembled nanomedicine based on Pt(IV)-ADD could be a promising strategy for TNBC therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119751DOI Listing
February 2020

Green tea extract-assembled nanoclusters for combinational photothermal and chemotherapy.

J Mater Chem B 2019 10;7(39):5972-5982

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.

"Green chemistry" is a newly developed approach that uses natural products to fabricate drug delivery systems; it has many advantages, such as low cost, simplicity, rapidity and environmental friendliness. In this study, we fabricated doxorubicin-loaded gold nanoclusters via a "green chemistry" method, involving the use of green tea extract to realize combinational photothermal and chemotherapy against melanoma. Green tea extract acted as a reducing agent of chloroauric acid and a stabilizer of the nanoclusters, and it also provided a co-polymerization site for doxorubicin. Gold nanoclusters were formed in the presence of the reductive polyphenols in the green tea extract. The accordingly converted polyphenol oxides could assemble into oligomers to stabilize the formulated nanoclusters while co-polymerizing with doxorubicin through π-π stacking and electrostatic interactions. This drug delivery system showed good stability, pH-sensitive drug release properties and enhanced cellular uptake. In vitro and in vivo experiments both demonstrated that our system with combinational photothermal and chemotherapy could achieve significantly enhanced tumor growth inhibition compared to monotherapy. Overall, this platform may provide a safe and efficient strategy for cancer treatment and new insight into green, natural extracts for nanoparticle fabrication.
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http://dx.doi.org/10.1039/c9tb01546aDOI Listing
October 2019

Intracellularly Generated Immunological Gold Nanoparticles for Combinatorial Photothermal Therapy and Immunotherapy against Tumor.

Nano Lett 2019 09 12;19(9):6635-6646. Epub 2019 Aug 12.

Gold nanoparticle (AuNP) has been widely used in cancer photothermal therapy (PTT) for ablating accessible tumor, while it is insufficient for inhibiting tumor metastasis and relapse in current stage. Here, we first developed a novel immunological AuNP through intracellular generation and exocytosis for combinatorial PTT and immunotherapy. Melanoma B16F10 cells were employed to generate AuNPs first and then shed nanoparticle trapped vesicles to extracellular environment with retained tumor antigens ([email protected]). By further introducing the nanoparticles into dendritic cells (DCs), DC-derived AuNPs ([email protected]) were generated with enhanced biosafety, which can induce hyperthermia and provoke antitumor immune responses. This immunological nanoplatform demonstrated efficient inhibition or even eradication of primary tumor, tumor metastasis, as well as tumor relapse, with significantly improved overall survival of mice. With our design, the intracellularly generated AuNPs with immunological property could act as an effective treatment modality for cancer.
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http://dx.doi.org/10.1021/acs.nanolett.9b02903DOI Listing
September 2019

A sequentially responsive and structure-transformable nanoparticle with a comprehensively improved 'CAPIR cascade' for enhanced antitumor effect.

Nanoscale 2019 Jan;11(3):1177-1194

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

An intravenously administered drug delivery system should undergo a five-step 'CAPIR' cascade (circulation, accumulation, penetration, internalization and release), and the maximal efficiency of each step is of great importance to obtain the improved final therapeutic benefits and overall survival rate. Here, a pH/matrix metalloproteinase-9 (MMP9) sequentially responsive and continuously structure-transformable nanoparticle assembled from a doxorubicin (DOX)-conjugated peptide was exploited for comprehensively improving the 'CAPIR cascade' and eventually enhancing the therapeutic efficacy. The chimeric peptide can self-assemble into spherical nanoparticles (RGD-sNPs) at pH 7.4 with a particle size of 45.7 ± 5.4 nm. By a combination of passive and active targeting mechanisms, RGD-sNPs achieved efficient accumulation at the tumor site (∼15.1% ID g-1 within 24 h). Both in vitro and in vivo experiments revealed that RGD-sNPs can be transformed into rod-like nanoparticles (S-NFs) triggered by MMP9 that overexpressed in the tumor microenvironment, demonstrating remarkable advantages of deep tumor penetration, prolonged drug retention with ∼3.7% ID g-1 at 96 h, and 2-fold enhanced internalization. Subsequently, S-NFs would respond to the intracellular weakly acidic stimuli to rapidly release DOX for induction of cytotoxicity and apoptosis. Meanwhile, the remaining peptide was further converted into long fibers (length >5 μm) with significant cytotoxicity, thereby exerting a synergistic antitumor effect. Thus RGD-sNPs displayed superior antitumor efficacy and extended the median survival period to 55 days. This provides a new horizon for the exploration of high-performance antitumor nanomedicines.
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http://dx.doi.org/10.1039/c8nr08781dDOI Listing
January 2019

Tumor Lysate-Loaded Lipid Hybrid Nanovaccine Collaborated with an Immune Checkpoint Antagonist for Combination Immunotherapy.

Adv Healthc Mater 2019 01 3;8(1):e1800837. Epub 2018 Dec 3.

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

Cancer vaccines have shown great potential for treating different types of cancer. However, the application of vaccination still presents two major challenges. One is efficiency of antigen delivery, and the other is dealing with immune tolerance accompanied with tumor development. Lipid zinc phosphate hybrid nanoparticles (LZnP NPs) with a unique material structure can realize efficient delivery of antigens to dendritic cells (DCs) and also serve as an adjuvant to promote immune responses. Herein, ZnP NPs are introduced to load toll-like receptor 4 agonist (monophosphoryl lipid A) and B16F10 melanoma cell-derived tumor lysate (TLS) for vaccination. To regulate immune tolerance, the immune checkpoint antagonist, d-peptide antagonist ( PPA-1), is involved in treatment. TLS-loaded LZnP nanovaccine can efficiently prime DCs and induce cytotoxic T lymphocytes response. The explored combination treatment further exhibits the anticipated tumor inhibition on therapeutic and prophylactic melanoma models with extended survival time. It demonstrates the possibility to combine TLS-loaded LZnP nanovaccine with PPA-1 against melanoma and provides support to optimize the combination treatment based on nanovaccine and immune checkpoint therapy.
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http://dx.doi.org/10.1002/adhm.201800837DOI Listing
January 2019

Star-shaped polymer of β‑cyclodextrin-g-vitamin E TPGS for doxorubicin delivery and multidrug resistance inhibition.

Colloids Surf B Biointerfaces 2018 09 1;169:10-19. Epub 2018 May 1.

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, PR China; Hubei Engineering Research Center for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan 430030, PR China. Electronic address:

Multidrug resistance (MDR) remains as an obstacle for effective cancer treatment. Herein, we developed a novel and efficient nanomedicine by virtue of the carrier characters and MDR inhibition effects of β-cyclodextrin (β-CD) and d-α-tocopheryl polyethylene glycol succinate (TPGS). A series of star-shaped polymers CD-g-TPGS with different TPGS substitution degree were synthesized for doxorubicin (DOX) delivery, where β-CD was identified as a core and TPGS as branches. These star polymers can self-assemble into nanoparticles with DOX. These nanoparticles showed no significant differences in size, zeta potential and morphology except for in vitro stability. They demonstrated good biocompatibility and enhanced cellular uptake in both drug sensitive and resistant cancer cells. Notably, the nanoparticles exhibited superiority of cytotoxicity in drug resistant cancer cells against free DOX. In vivo antitumor effect also demonstrated the improved cancer inhibition effect. This work suggests that star-shaped polymers CD-g-TPGS are promising drug carriers to overcome MDR in cancer treatment.
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http://dx.doi.org/10.1016/j.colsurfb.2018.05.001DOI Listing
September 2018

A facile doxorubicin-dichloroacetate conjugate nanomedicine with high drug loading for safe drug delivery.

Int J Nanomedicine 2018 6;13:1281-1293. Epub 2018 Mar 6.

Tongji School of Pharmacy.

Background: Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns.

Methods: An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor.

Results: Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG, leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model.

Conclusion: This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.
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http://dx.doi.org/10.2147/IJN.S154361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846746PMC
May 2018

Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

Mol Pharm 2018 03 9;15(3):1005-1016. Epub 2018 Feb 9.

Tongji School of Pharmacy , Huazhong University of Science and Technology , Wuhan 430030 , P.R. China.

The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00922DOI Listing
March 2018

Biomimetic Nanovesicles for Enhanced Antitumor Activity of Combinational Photothermal and Chemotherapy.

Mol Pharm 2018 03 9;15(3):1341-1352. Epub 2018 Feb 9.

The combination of multiple modalities has shown great potential in cancer treatment with improved therapeutic effects and minimized side effects. Here, we fabricated a type of doxorubicin-encapsulated biomimetic nanovesicle (NV) by a facile method with near-infrared dye insertion in the membrane for combinatorial photothermal and chemotherapy. With innate biomimetic properties, NVs enhanced the uptake by tumor cells while reducing the phagocytosis of macrophages. Upon laser irradiation, NVs can convert the absorbed fluorescent energy into heat for effective tumor killing. Hyperthermia can further induce membrane ablation of NVs to accelerate the release of chemotherapeutic drug for potent cytotoxicity to tumor cells. The NVs improved drug accumulation and showed a more efficient in vivo photothermal effect with a rapid temperature increase in tumors. Moreover, the NV-based combinational photothermal and chemotherapy exhibited significant tumor growth suppression with a high inhibitory rate of 91.6% and negligible systemic toxicity. The results indicate that NVs could be an appealing vehicle for combinational cancer treatment.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b01142DOI Listing
March 2018

pH-sensitive micelles with charge-reversible property for tumor growth inhibition and anti-metastasis.

J Mater Chem B 2018 Jan 5;6(3):458-468. Epub 2018 Jan 5.

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

Physical properties, such as surface charge, of nanomedicines play a crucial role in their in vivo behaviors, which could eventually determine the tumor inhibition effect. Although drug delivery systems with positive charge are effective for cell internalization, this property is universally applicable to the lack of selectivity of both tumors and normal tissues, resulting in rapid blood clearance and undesired side effects. By employing charge-reversible strategies, the dilemma can be overcome and enhanced cellular uptake, prolonged circulation time and high biocompatibility can be realized. Here, we constructed Vitamin E-based micelles with charge-reversible property for the delivery of the antineoplastic agent paclitaxel. In the slightly acidic tumor microenvironment, the micelles converted from negative to positive charge due to the cleavage of the pH-sensitive bond, leading to enhanced cellular uptake and subsequently enhanced drug release. The micelles demonstrated improved antitumor efficiency both in vitro and in vivo and improved anti-metastasis effect in 4T1 orthotopic tumor model compared with those of clinically formulated Taxol and non-sensitive micelles. Besides, the micelles showed high biocompatibility and reduced side effects. Overall, these findings highlight that the micelles with charge-reversible property have great potential for cancer therapy in clinic.
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http://dx.doi.org/10.1039/c7tb02439hDOI Listing
January 2018

Recent Advances in the Application of Vitamin E TPGS for Drug Delivery.

Theranostics 2018 1;8(2):464-485. Epub 2018 Jan 1.

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.

D-ɑ-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) has been approved by FDA as a safe adjuvant and widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its applications in drug delivery like high biocompatibility, enhancement of drug solubility, improvement of drug permeation and selective antitumor activity. Notably, TPGS can inhibit the activity of ATP dependent P-glycoprotein and act as a potent excipient for overcoming multi-drug resistance (MDR) in tumor. In this review, we aim to discuss the recent advances of TPGS in drug delivery including TPGS based prodrugs, nitric oxide donor and polymers, and unmodified TPGS based formulations. These potential applications are focused on enhancing delivery efficiency as well as the therapeutic effect of agents, especially on overcoming MDR of tumors. It also demonstrates that the clinical translation of TPGS based nanomedicines is still faced with many challenges, which requires more detailed study on TPGS properties and based delivery system in the future.
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http://dx.doi.org/10.7150/thno.22711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743561PMC
December 2018

LC-MS/MS analysis of pramipexole in mouse plasma and tissues: elimination of lipid matrix effects using weak cation exchange mode based solid-phase extraction.

J Chromatogr B Analyt Technol Biomed Life Sci 2015 Apr 2;988:157-65. Epub 2015 Mar 2.

Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China. Electronic address:

Intranasal delivery is emerging as a promising alternative for oral or intravenous administration of central nervous system (CNS) drugs, such as pramipexole which is widely used for the treatment of Parkinson's disease. To evaluate the effectiveness of intranasal delivery of pramipexole, preclinical pharmacokinetic and tissue distribution studies following intranasal administration need to be investigated. In this paper, we developed and validated a robust and sensitive LC-MS/MS assay without matrix effect for accurate measurements of pramipexole in mouse plasma and tissue samples. Pramipexole and its stable isotope labeled internal standard (d3-pramipexole) were extracted from biological samples by protein precipitation (PPT) coupled with solid phase extraction (SPE) using weak cation exchange SPE cartridges. Matrix effects were studied using post-column infusion and post-extraction addition experiments by direct monitoring of typical phospholipids including glycerophosphocholines (GPChos) and lysoglycerophosphocholines (Lyso-GPChos). Chromatographic separation was achieved on a Welch Ultimate(®) XB-CN column using isocratic elution with a run time of 3.0 min. The assay was linear in the concentration range of 0.05-100 ng/mL and the intra- and inter-day precision and accuracy met the acceptance criteria. Compared with previous reported assays, the current sample preparation approach exhibited significant reduction of matrix effects due to the dramatically decreased levels of residual matrix components such as GPChos and Lyso-GPChos. This method has been successfully applied to pharmacokinetic and tissue distribution studies of pramipexole in mice following a single intravenous or intranasal dose of 50 μg/kg.
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http://dx.doi.org/10.1016/j.jchromb.2015.02.032DOI Listing
April 2015