State Key Laboratory of Natural and Biomimetic Drugs

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State Key Laboratory of Natural and Biomimetic Drugs

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Shi N.-Q.,Peking University | Shi N.-Q.,Jilin University | Qi X.-R.,Peking University | Qi X.-R.,State Key Laboratory of Natural and Biomimetic Drugs
ACS Applied Materials and Interfaces | Year: 2017

Cell-penetrating peptide (CPP), also called "Trojan Horse" peptide, has become a successful approach to deliver various payloads into cells for achieving the intracellular access. However, the "Trojan Horse" peptide is too wild, not just to "Troy", but rather widely distributed in the body. Thus, there is an urgent need to tame the wildness of "Trojan Horse" peptide for targeted delivery of antineoplastic agents to the tumor site. To achieve this goal, we exploit a masked CPP-doxorubicin conjugate platform for targeted delivery of chemotherapeutic drugs using charge-guided masking and protease-triggered demasking strategies. In this platform, the cell-penetrating function of the positively CPP (d-form nonaarginine) is abrogated by a negatively shielding peptide (masked CPP), and between them is a cleavable substrate peptide by the protease (MMP-2/9). Protease-triggered demasking would occur when the masked CPP reached the MMP-2/9-riched tumor. The CPP-doxorubicin conjugate (CPP-Dox) and the masked CPP-Dox conjugate (mCPP-Dox) were used as models for the evaluation of masking and demasking processes. It was found that exogenous MMP-2/9 could effectively trigger the reversion of CPP-cargo in this conjugate, and this trigger adhered to the Michaelis-Menten kinetics profile. This conjugate was sensitive to the trigger of endogenous MMP-2/9 and could induce enhanced cytotoxicity toward MMP-2/9-rich tumor cells. In vivo antitumor efficacy revealed that this masked conjugate had considerable antitumor activity and could inhibit the tumor growth at a higher level relative to CPP-cargo. Low toxicity in vivo showed the noticeably decreased wildness of this conjugate toward normal tissues and more controllable entry of antitumor agents into "Troy". On the basis of analyses in vitro and in vivo, this mCPP-cargo conjugate delivery system held an improved selectivity toward MMP-2/9-rich tumors and would be a promising strategy for tumor-targeted treatment. © 2017 American Chemical Society.


Su H.-T.,Peking University | Li X.,Peking University | Liang D.-S.,Peking University | Qi X.-R.,Peking University | Qi X.-R.,State Key Laboratory of Natural and Biomimetic Drugs
Oncotarget | Year: 2016

Low density lipoprotein (LDL), which is a principal carrier for the delivery of cholesterol, has been used as a great candidate for the delivery of drugs to tumor based on the great requirements for cholesterol of many cancer cells. Mimicking the structure and composition of LDL, we designed a synthetic low-density lipoprotein (sLDL) to encapsulate paclitaxel-alpha linolenic acid (PALA) for tumor therapy. The PALA loaded sLDL (PALA-sLDL) and PALA-loaded microemulsion (PALA-ME, without the binding domain for LDLR) displayed uniform sizes with high drug loading efficiency (> 90%). In vitro studies demonstrated PALA-sLDL exhibited enhanced cellular uptake capacity and better cytotoxicity to LDLR over-expressed U87 MG cells as compared to PALA-ME. The uptake mechanisms of PALA-sLDL were involved in a receptor mediated endocytosis and macropinocytosis. Furthermore, the in vivo biodistribution and tumor growth inhibition studies of PALA-sLDL were investigated in xenograft U87 MG tumor-bearing mice. The results showed that PALA-sLDL exhibited higher tumor accumulation than PALA-ME and superior tumor inhibition efficiency (72.1%) compared to Taxol® (51.2%) and PALA-ME (58.8%) but with lower toxicity. These studies suggested that sLDL is potential to be used as a valuable carrier for the selective delivery of anticancer drugs to tumor with low systemic toxicity.


Yang F.,State Key Laboratory of Natural and Biomimetic Drugs | Zheng X.-J.,State Key Laboratory of Natural and Biomimetic Drugs | Huo C.-X.,State Key Laboratory of Natural and Biomimetic Drugs | Wang Y.,State Key Laboratory of Natural and Biomimetic Drugs | And 2 more authors.
ACS Chemical Biology | Year: 2011

The abnormal glycans expressed on the surface of tumor cells, known as tumorassociated carbohydrate antigens, increase the chance to develop carbohydrate-based anticancer vaccines. However, carbohydrate antigens pose certain difficulties, and the major drawback is their weak immunogenicity. To tackle this problem, numerous structurally modified STn antigens were designed and synthesized in this work. These synthetic antigens were screened in vitro by using competitive ELISA method, and the antigens with positive response were conjugated to the protein carrier for vaccination. The vaccination results on mice showed that some fluorine-containing modifications on the STn antigen can significantly increase the anti-STn IgG titers and improve the ratios of anti-STn IgG/IgM. The antisera can recognize the tumor cells expressing the native STn antigen. © 2011 American Chemical Society.


Qin J.-H.,Anhui Agricultural University | Li N.,State Key Laboratory of Natural and Biomimetic Drugs | Tu P.-F.,State Key Laboratory of Natural and Biomimetic Drugs | Ma Z.-Z.,Peking University | Zhang L.,Anhui Agricultural University
Journal of Agricultural and Food Chemistry | Year: 2012

The aim of this study was to evaluate tea polyphenol and purine alkaloid contents of pu-erh tea (Camellia assamica) in a fermentation solid system with Aspergillus niger and Aspergillus fumigatu. In addition, the objective was to find the major intermediate product during fermentation by HPLC-MS n analysis. The results showed the change of catechin, ester-catechins and gallic acid by quantitative analysis. In the early stages, the contents of ester-catechins were lightly increased. Then, ester-catechins were gradually degraded to produce catechins and gallic acid. Furthermore, a major metabolic intermediate compound of catechins was observed and elucidated by HPLC-DAD-MS n analysis. This study provided a reliable dynamic data description and metabolic pathway of tea polyphenols for postfermented pu-erh tea. © 2012 American Chemical Society.


Ma L.-Y.,State Key Laboratory of Natural and Biomimetic Drugs | Yang X.-W.,State Key Laboratory of Natural and Biomimetic Drugs
Chinese Traditional and Herbal Drugs | Year: 2016

Objective: To study the chemical constituents of alkaline hydrolysates of total saponins from the stems and leaves of Panax ginseng. Methods: The chemical constituents were isolated and purified by various chromatographic methods, and the chemical structures were identified by NMR and MS spectra analyses. Results: A total of 30 compounds were isolated and identified. Among them, 28 were determined as 20(S)-protopanaxadiol (1), 20(R)-protopanaxadiol (2), dammar-20(21),24-diene-3β,6α,12β-triol (3), dammar-20(22)E,24-diene-3β,6α,12β-triol (4), 20(S)-protopanaxatriol (5), 20(R)-protopanaxatriol (6), 20(S)-ginsenoside Rh2 (7), 20(R)-ginsenoside Rh2 (8), ginsenoside Rh16 (9), isoginsenoside Rh3 (10), 20(S)-dammar-3β,6α,12β,20,25-pentol (11), 20(R)-dammar-3β,6α,12β,20,25-pentol (12), ginsenoside Rk3 (13), 20(S)-ginsenoside Rh1 (14), 20(R)-ginsenoside Rh1 (15), ginsenoside F1 (16), ginsenoside Rh19 (17), 20(R)-ginsenoside Rh19 (18), dammar-20(22)E-ene-3β,6α,12β,25-tetrol (19), notoginsenoside T2 (20), ginsenoside Rg6 (21), 20(22)E-ginsenoside F4 (22), ginsenoside Rk1 (23), 20(S)-ginsenoside Rg3 (24), 20(R)-ginsenoside Rg3 (25), 20(S)-ginsenoside Rg2 (26), 20(R)-ginsenoside Rg2 (27), and 3β,6α,12β,25-tetrahydroxy-dammar-20(22)E-ene-6-O-α-L-rhamno- pyranosyl-(1→2)-β-D-glucopyranoside (28). Conclusion: Compound 18 is a new saponin. Compounds 3, 4, 11, 12, and 19 are rare dammarane-type triterpenes, and 7-10, 13-18, and 20-28 are rare ginsenosides. © 2016, Editorial Office of Chinese Traditional and Herbal Drugs. All right reserved.


Yang X.-B.,Chinese Academy of Sciences | Yang X.-B.,Beijing University of Chinese Medicine | Yang X.-B.,State Key Laboratory of Natural and Biomimetic Drugs | Yang X.-W.,State Key Laboratory of Natural and Biomimetic Drugs | And 2 more authors.
Zhongguo Zhongyao Zazhi | Year: 2014

Corydalis Rhizoma, the dried tuber of Corydalis yanhusuo (Papaveraceae) distributed traditionally mainly in southeastern and now cultivated in northwestern and other district in China, is one of the commonly used and well-known traditional Chinese medicine. It has been widely used to treat spastic pain, abdominal pain, pain due to injury, and promote blood circulation. Its main chemical constituents were alkaloids, which were divided into the two types of protoberberines and aporphines. Among them, some alkaloids were found to elicit profound effects on the dopaminergic system in the central nervous system, which plays an important role in regulating nociception. In this article, the chemical composition and structure-types, new methods of qualitative and quantitative analysis as well as characteristics of biotransformation, absorption, distribution, metabolism, excretion, pharmacokinetic, and drug-drug interaction for the alkaloids were revealed. These results would greatly contribute to the establishment of bioactive material base of Corydalis Rhizoma.


Li Y.-P.,State Key Laboratory of Natural and Biomimetic Drugs | Li Z.-J.,State Key Laboratory of Natural and Biomimetic Drugs | Meng X.-B.,State Key Laboratory of Natural and Biomimetic Drugs
Carbohydrate Research | Year: 2011

A series of 4,5-substituted chiral γ-lactams were synthesized through a highly diastereoselective addition-rearrangement approach from 2,3-unsaturated sugar lactones. The single-crystal X-ray structure of one product indicated that the sugar ring was attacked from the axial side. Partial reduction of the nitro group produced N-hydroxy-γ-lactams, which were further reduced with TiCl 3 to yield the 4,5-substituted chiral γ-lactams. The absolute configuration of C5 of the γ-lactam was determined by NOESY spectra. © 2011 Elsevier Ltd. All rights reserved.


Huo M.,China Pharmaceutical University | Zou A.,China Pharmaceutical University | Yao C.,China Pharmaceutical University | Zhang Y.,Jiangsu Chia Tai Tianqing Pharmacy Co. | And 5 more authors.
Biomaterials | Year: 2012

In this study, a ligand-PEG-lipid conjugate, octreotide-polyethene glycol-deoxycholic acid (OCT(Phe)-PEG-DOCA, or OPD) was successfully synthesized and used as a targeting molecule for N-deoxycholic acid-O, N-hydroxyethylation chitosan (DAHC) micelles for efficient cancer therapy. DAHC micelles exhibited good loading capacities for doxorubicin (DOX), a model anti-cancer drug, and the modification of OPD showed no significant effect on drug load while slightly increasing the particle size and partly shielding the positive charges on the surface of micelles. Accelerated release rate of DOX from micelles were also observed after OPD modification and the release profile exhibited pH-sensitive properties. Compared with DAHC-DOX micelles, OPD-DAHC-DOX micelles exhibited significantly stronger cytotoxicity to MCF-7 cells (SSTRs overexpression) but with hardly any difference from WI-38 cells (no SSTRs expression). The results of flow cytometry and confocal laser scanning microscopy further revealed that OPD-DAHC-DOX micelles could be selectively taken into tumor cells by SSTRs-mediated endocytosis. In vivo investigation of micelles on nude mice bearing MCF-7 cancer xenografts confirmed that OPD-DAHC micelles possessed much higher tumor-targeting capacity than the DAHC control and exhibited enhanced anti-tumor efficacy and decreased systemic toxicity. These results suggest that OPD-DAHC micelles might be a promising anti-cancer drug delivery carrier for targeted cancer therapy. © 2012 Elsevier Ltd.


Li J.,China Pharmaceutical University | Huo M.,China Pharmaceutical University | Wang J.,China Pharmaceutical University | Zhou J.,China Pharmaceutical University | And 6 more authors.
Biomaterials | Year: 2012

A targeted intracellular delivery system of paclitaxel (PTX) was successfully developed based on redox-sensitive hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates. The conjugates self-assembled into nano-size micelles in aqueous media and exhibited excellent drug-loading capacities (34.1%) and entrapment efficiency (93.2%) for PTX. HA-ss-DOCA micelles were sufficiently stable at simulated normal physiologic condition but fast disassembled in the presence of 20m. m reducing agent, glutathione. Invitro drug release studies showed that the PTX-loaded HA-ss-DOCA micelles accomplished rapid drug release under reducing condition. Intracellular release of fluorescent probe nile red indicated that HA-ss-DOCA micelles provide an effective approach for rapid transport of cargo into the cytoplasm. Enhanced cytotoxicity of PTX-loaded HA-ss-DOCA micelles further confirmed that the sensitive micelles are more potent for intracellular drug delivery as compared to the insensitive control. Based on flow cytometry and confocal microscopic analyses, observations revealed that HA-ss-DOCA micelles were taken up to human breast adenocarcinoma cells (MDA-MB-231) via HA-receptor mediated endocytosis. Invivo investigation of micelles in tumor-bearing mice confirmed that HA-ss-DOCA micelles possessed much higher tumor targeting capacity than the insensitive control. These results suggest that redox-sensitive HA-ss-DOCA micelles hold great potential as targeted intracellular delivery carriers of lipophilic anticancer drugs. © 2011.


Zhong W.,State Key Laboratory of Natural and Biomimetic Drugs | Yang J.,State Key Laboratory of Natural and Biomimetic Drugs | Meng X.,State Key Laboratory of Natural and Biomimetic Drugs | Li Z.,State Key Laboratory of Natural and Biomimetic Drugs
Journal of Organic Chemistry | Year: 2011

Selective syn and anti diacetoxylations of alkenes have been achieved using a PhI(OAc) 2/BF 3·OEt 2 system in the presence and absence of water, respectively. A broad range of substrates including electron-deficient alkenes (such as α,β-unsaturated esters) could be elaborated efficiently at room temperature with this methodology, furnishing the desired products in good to excellent yields and diastereoselectivity. In particular, a multigram-scale diastereoselective diacetoxylation of methyl cinnamate (5.00 g) was also accomplished in a few hours, maintaining the same efficiency as small-scale reaction. This novel methodology provides an alternative approach for the preparation of various 1,2-diols. © 2011 American Chemical Society.

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