PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
·
2025
·Vol. 122
·期 13
·e2426006122
·
IF 9.1
Fengwei Li,Mengmeng Zhang,Chao Liu,Jie Cheng,Yawen Yang,Xiangda Peng,Zhifeng Li,Wenfeng Cai,Haipeng Yu,Junjie Wu,Yuyu Guo,Hongkun Geng,Yun Fa,Youming Zhang,Dalei Wu,Yizhen Yin
Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant (KD) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC50) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.
研究领域:
药物化学
·
癌症生物学
·
结构生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Biomedical Nanotechnology
·
2017
·Vol. 13
·期 11
·1500-1511
·
IF 4.521
Liu Gongyan,Chen Xiaobing,Zhuang Weihua,Nie Yu,Zhang Kai,Yang Li,Wang Yunbing
Zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) is a promising alternative for poly(ethylene glycol) (PEG) as micelle shell-forming block. Three different PMPC-based polymeric micelles were designed and compared with PEGylated micelles. Cholesterol-conjugated and
disulfide-modified poly(D, L-lactide)-SS-poly(2-methacryloyloxyethyl phosphorylcholine) (CPLA-SS-PMPC) micelles, cholesterol-conjugated CPLA-PMPC micelles without disulfides, and PLA-PMPC micelles without cholesterol-conjugation were compared to PLA-PEG micelles. These PMPC-based micelles
showed better hydrophilicity and less protein adsorption. In cellular uptake evaluation, PMPC-based micelles exhibited much better cellular uptake than that of the PLA-PEG, which might reflect strong interaction between the biomimetic PMPC surface and the cellular membrane. In addition, although
there was no statistical difference in cellular internalization behavior among these three PMPC-based micelles, the anticancer activity of paclitaxel (PTX)-loaded CPLA-SS-PMPC micelles was significantly higher than those of the other two kinds of micelles. This superiority was attributed to
the rapid release of the anticancer drug under the redox environment inside cancer cells.
研究领域:
生物材料学
·
药剂学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Ping Wang,Chen Liu,Weiqiang Tang,Shixue Ren,Zhijun Chen,Yuanru Guo,Rahele Rostamian,Shuangliang Zhao,Jian Li,Shouxin Liu,Shujun Li
Carbon dots have wide applications in bioimaging, encryption, sensing, and light-emitting devices, but most preparations of carbon dots require complicated separation and purification steps. Here, a clustering-induced emission luminogen, sodium alginate, was covalently “glued” by ethylenediamine to prepare carbon dots on a 100 g scale, without any separation or purification. The conversion yield was as high as 94.7%. Theoretical calculations suggested that the fluorescence emission of as-prepared carbon dots (N-CDs) was mainly attributable to through-space conjugation between oxygen atoms and carbonyl moieties. The N-CDs were shown to have applications as a fluorescent ink for encryption and as a phosphor for white light-emitting diodes. This work provides a convenient method for the large-scale preparation of carbon dots and a new understanding of fluorescent emission of carbon dots.
研究领域:
材料科学
·
生物成像
·
化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2013
·
IF 3.554
Ping Luo,Yu Luo,Jin Huang,Wei Lu,Dajun Luo,Jiahui Yu,Shiyuan Liu
In this research, a reduction-degradable supramolecular micelle delivery system of camptothecin (CPT) was developed to enhance the stability of CPT in aqueous media. Firstly, Michael addition polymerization occurred between N, N ’-bis(acryloyl) cystamine (BAC) and mono(6-(2-aminoethyl)amino-6-deoxy)-β-cyclodextrin (CDen) to produce the reduction-degradable polymer of BAC-CDen. And adamantyl-modified polyethylene glycol monomethyl ether (mPEG-Ad) was further encapsulated into it to gain supramolecular micelles of mPEG-Ad@BAC-CDen. Then mPEG-Ad@BAC-CDen/CPT supramolecular micelles could be easily obtained by incorporation of CPT into mPEG-Ad@BAC-CDen via dialysis method. The particle size of supramolecular micelles increased from 106 nm (bare micelles) to 142 nm (CPT loaded micelles), suggesting their passive targeting potential to tumor tissue. Owing to the reduction degradability of disulfide linker in main chain of BAC-CDen, the CPT could be sustainably released from the above micelles with the gradual cleavage of polymer in the presence of dithiothreitol (DTT) at the concentration of simulating the intracellular condition. It was noted that the stability of CPT in aqueous media was remarkably improved in the mPEG-Ad@BAC-CDen supramolecular micelles, which effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Besides, compared with free CPT, the CPT-loaded supramolecular micelles showed much lower cytotoxicity against L929 cell line. All these results suggested the potential utilization of the mPEG-Ad@BAC-CDen supramolecular micelles as the carriers of hydrophobic drugs with better stability and lower cytotoxicity. And the resulted anti-tumor CPT supramolecular micelles can be delivered to tumor cells with a high selectivity.
研究领域:
药剂学
·
肿瘤学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Jinxian Shan,Feiyun Li,Hongming Lou,Yanjun Tang
The cost of enzymolysis is a major bottleneck for the industrialisation of lignocellulosic enzymatic hydrolysis technology, and recycling cellulase can reduce this cost. Herein, a sulfobetaine prepolymer (CPS) with terminal chlorine was grafted onto enzymatic hydrolysis residual lignin (EHL) from corncob to construct thermosensitive lignin-based “molecular glues” (lignin-based sulfobetaine polymers, L-CPS) that were used to recover and recycle cellulase. L-CPS 2 (1.0 g/L) was added to the corncob residue (CCR) enzymolysis system (50 °C, pH 4.5). After hydrolysis, L-CPS 2 co-precipitated with cellulase through hydrophobic binding when cooling to 25 °C. This co-precipitation decreased the amount of cellulase by 40 %. In summary, a thermally responsive lignin-based molecular glue was constructed for green recycling of cellulase, providing a new approach to decreasing the cost of lignocellulosic enzymolysis and high value utilisation of industrial lignin.
研究领域:
生物化学
·
可再生资源工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
POLYMER
·
2020
·
IF 4.231
Xue Liang,Xiaojie Li,Xiang Gao,Yifan Zhang,Wei Wei,Xiaoya Liu
Unimolecular micelles are an attractive type of nanocarriers for drug delivery, but developing unimolecular micelle-based nanomedicine with high drug loading capacity and excellent unimolecular stability is challenging. Herein, we report the design and synthesis of hyperbranched polymers containing both terminal and internal reactive groups for fabricating the unimolecular micelle-based nanocarriers with high drug loading ability and superior unimolecular stability using selective modification. Specifically, we synthesized hyperbranched poly(amino ester)s containing terminal acrylate groups and internal R groups (named HBPAE-R) via the Michael addition polymerization of A 2 + BʹB 2 -R monomers , wherein A represents acrylate, and B, Bʹ represents the hydrogen in primary amine and secondary amine group, respectively, whereas R represents hydroxy, alkene or alkyne groups that do not participate in the polymerization process but assist in additional modification. Then, poly(ethylene glycol) (PEG) chains were linked to the surface of HBPAE-OH (representative molecules) with the subsequent conjugation of doxorubicin (DOX, representative drug) to the internal hydroxy groups through an acid-labile hydrazide bond, to afford anti-cancer drug-loaded hyperbranched star copolymers PEG-HBPAE-DOX. The obtained nanomedicines exhibited good unimolecular stability, relatively high drug loading content and a controlled drug release behavior. The in vitro cytotoxicity experiments further demonstrated the anti-tumor efficacy of these unimolecular nanomedicines. Our approach is expected to further boost research on the fabrication of multifunctional unimolecular nanomedicines from hyperbranched polymers containing both terminal and internal reactive groups.
研究领域:
生物材料学
·
药剂学
·
肿瘤学
✓ 已验证
DOI
高影响因子
MATERIALS & DESIGN
·
2016
·
IF 3.997
Yu Xiang,Libin Liu,Ting Li,Zhao Dang
A universal method to fabricate compressible graphene-based aerogel has been developed by using a molecular glue strategy, such as γ-oxo-1-pyrenebutyric acid (OPBA). The OPBA could link the graphene skeleton sheets and dip-coated polymer layers, where the graphene skeleton could be obtained by hydrothermal or chemical reduction. In contrast to the brittle pristine graphene aerogel, the resulting polymer-coated graphene aerogel demonstrates high elastic properties. The improved compressible properties are attributed to the uniform coating of polymer on the graphene sheet and the effective stress transfer between the graphene sheet and polymer layers, which are enabled by OPBA molecular glue. In addition, this type of strong integrated graphene-based aerogel could be used in practical applications, such as hydrophilic and oleophilic intelligence and compressible electrical sensor.
研究领域:
材料科学
·
化学工程
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Wei Chen,Peng Liu
Unimolecular micelles have attracted intense interests as drug carriers for tumor chemotherapy owing to their superior stability in comparison with the self-assembled supramolecular ones. Among them, the dendritic polymers with the polar frameworks could favour the loading of chemotherapeutic drugs rather than the hyperbranched polymers via radical polymerization, by enhancing the interaction with drugs. While the tedious synthesis procedure for dendritic polymers could be simplified with the construction principle on urethane chemistry. Here, the PEGylated dendritic polyurethanes, Ph-DPU Gly -PEG and Ph-DPU TEA -PEG, were designed with glycerol or triethanolamine as monomer, respectively. The effect of the molecular architecture of the Ph-DPU-PEGs unimolecular micelles on the controlled drug releasing performance was compared. It was found that the Ph-DPU TEA -PEG with tertiary amine as branching points could efficiently endow the pH-triggered drug release, due to its protonation.
研究领域:
药学
·
生物医学工程
·
高分子化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2016
·Vol. 17
·期 3
·1600258
·
IF 3.68
Shan Zhang,Jianbin Xu,Heng Chen,Zhangfa Song,Yalan Wu,Xingyi Dai,Jie Kong
In this contribution, amphiphilic star copolymers (H40- star -PCL- a -PEG) with an H40 hyperbranched polyester core and poly(ε-caprolactone)- a -poly(ethylene glycol) copolymer arms linked with acetal groups are synthesized using ring-opening polymerization and a copper (I)-catalyzed alkyne-azide cycloaddition click reaction. The acid-cleavable acetal groups between the hydrophilic and hydrophobic segments of the arms endow the amphiphilic star copolymers with pH responsiveness. In aqueous solution, unimolecular micelles can be formed with good stability and a unique acid degradability, as is desirable for anticancer drug carriers. For the model drug of doxorubicin, the in vitro release behavior, intracellular release, and inhibition of proliferation of HeLa cells show that the acid-cleavable unimolecular micelles with anticancer activity can be dissociated in an acidic environment and efficiently internalized by HeLa cells. Due to the acid-cleavable and biodegradable nature, unimolecular micelles from amphiphilic star copolymers are promising for applications in intracellular drug delivery for cancer chemotherapy.
研究领域:
材料科学
·
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2018
·
IF 4.485
Jianyue Feng,Qiang Luo,Yun Chen,Bing Li,Kui Luo,Jingbo Lan,Yunlong Yu,Shiyong Zhang
Herein, a new theranostic nanoplatform was built by introducing DOTA on the surface of the cross-linked small molecular micelles. This nanoplatform consisted of three parts: (1) Hydrophobic alkyl chain functioned with alkenes as cross-linkable part to ensure the robust stability in vivo; (2) Hydrophilic DOTA for not only gadolinium ions complexion as MR imaging contrast agents but also platinum ions complexion as drug carriers; (3) Cisplatin as antitumor drug and MR imaging amplifier simultaneously. The metal loading content of the resulting Pt/Gd@DOTA-CSMs was up to 12 and 14 wt % for Gd(III) and Pt(II), respectively. The longitudinal relaxation rate of Gd@DOTA-CSMs (8.46 mM–1 s–1) was 2.6 times than that of the clinical Gd-DTPA (3.23 mM–1 s–1). When cisplatin was involved, not only great antitumor efficiency was achieved, but higher longitudinal relaxation rate of Pt/Gd@DOTA-CSMs (11.17 mM–1 s–1) was carried out due to the extension of rotational correlation time. The experiments of Balb/c mice bearing 4T1 xenograft indicated that Pt/Gd@DOTA-CSMs had better antitumor activity, lower side effect than clinically used cisplatin, and greater MR imaging than Gd-DTPA. All the results proved that the nanoplatform of DOTA-CSMs held remarkable potential in the field of therapeutics.
研究领域:
纳米医学
·
生物材料
·
肿瘤学
·
影像医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Chemistry
·
2022
·
IF 7.613
W. Chen,P. Liu
Ultrasound has been recognized as an exciting tool to enhance the therapeutic efficacy in tumor chemotherapy owing to the triggered drug release, facilitated intracellular drug delivery, and improved spatial precision. Aiming for a precise localized drug delivery, novel dendritic polyurethane-based prodrug (DOX-DPU-PEG) was fabricated with a drug content of 18.9% here by conjugating DOX onto the end groups of the functionalized dendritic polyurethane via acid-labile imine bonds. It could easily form unimolecular micelles around 38 nm. Compared with the non-covalently drug-loaded unimolecular micelles (DOX@Ph-DPU-PEG), they showed excellent pH/ultrasound dual-triggered drug release performance, with drug leakage of only 4% at pH 7.4, but cumulative release of 14% and 88% at pH 5.0 without and with ultrasound, respectively. The ultrasound responsiveness was attributed to the unique strawberry-shaped topological structure of the DOX-DPU-PEG, in which DOX was embedded in the skin layer of the hydrophobic DPU cores. With ultrasound, the DOX-DPU-PEG unimolecular micelles possessed enhanced tumor growth inhibition than free DOX but showed no obvious cytotoxicity on the tumor cells without ultrasound. Such feature makes them promising potential for precise localized drug delivery.
研究领域:
药学
·
生物医学工程
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2017
·
IF 3.887
He-Lin Xu,Zi-Liang Fan,De-Li ZhuGe,Bi-Xin Shen,Bing-Hui Jin,Jian Xiao,Cui-Tao Lu,Ying-Zheng Zhao
Severe toxicity and poor tumour penetration are two intrinsic limited factors to hinder the broad clinical application for most of first-line chemotherapeutics. In this study, a novel vitamin E succinate-grafted ε-polylysine (VES-g-PLL) polymer was synthesized by using ε-polylysine as backbone. By adjusting VES graft ratio, VES-g-PLL (50) with a theoretic VES graft ratio of 50% could self-assemble into a supermolecular micelle with a hydrodynamic diameter (D h ) of ca.20 nm, and Zeta potential of 19.6 mV. VES-g-PLL micelles themselves displayed a strong anti-tumour effect on glioma. The poorly water-soluble curcumin was effectively encapsulated in VES-g-PLL micelles with the drug loading amount and entrapment efficiency reaching 4.32% and 82.27%, respectively. In a physiologic medium, curcumin-loaded VES-g-PLL micelles (Cur-Micelles) not only remained stable without obvious drug leakage but also sustained the release of its encapsulated curcumin for a long time. Because of the ultra-small size and positively-charged surface, Cur-Micelles penetrated the deeper tumour zone than free curcumin, resulting in a significant inhibition of tumour spheroids growth. Moreover, in vivo strong antitumor effect of Cur-Micelles was also exhibited at assistance of ultrasound-targeted microbubble destruction and the real-time MRI imaging demonstrated a nearly complete suppression of glioma after 28 days of treatment. TUNEL staining showed that the therapeutic mechanism of Cur-Micelles was relevant to the apoptosis of tumour cells. Finally, in vivo nontoxicity of Cur-Micelles against normal organs including heart, liver, spleen, lung and kidney tissues was also demonstrated by the HE staining. In conclusion, VES-g-PLL micelles may serve as a potential carrier for curcumin to enhance tumour penetration and improve therapeutic effect on glioma.
研究领域:
药学
·
肿瘤学
·
生物材料学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）