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Fundamental Research · 2022 · IF 0

Preparation and cellular uptake behaviors of uniform fiber-like micelles with length controllability and high colloidal stability in aqueous media

Junyu Ma,Chen Ma,Xiaoyu Huang,Pedro Henrique Hermes de Araujo,Amit Kumal Goyal,Guolin Lu,Chun Feng

Fragmentation/disassembly of fiber-like micelles generated by living crystalline-driven self-assembly (CDSA) is usually encountered in aqueous media, which hinders the applications of micelles. Herein, we report the generation of uniform fiber-like micelles consisting of a π-conjugated oligo( p -phenylenevinylene) core and a cross-linking silica shell with grafted poly(ethylene glycol) (PEG) chains by the combination of living CDSA, silica chemistry and surface grafting-onto strategy. Owing to the presence of crosslinking silica shell and the outmost PEG chains, the resulting micelles exhibit excellent dispersity and colloidal stability in PBS buffer, BSA aqueous solution and upon heating at 80 °C for 2 h without micellar fragmentation/disassembly. The micelles also show negligible cytotoxicity toward both HeLa cervical cancer and HEK239T human embryonic kidney cell lines. Interestingly, micelles with L n of 156 nm show the “stealth” property with no significant uptake by HeLa cells, whereas some certain amounts of micelles with L n of 535 nm can penetrate into HeLa cells, showing length-dependent cellular uptake behaviors. These results provide a route to prepare uniform, colloidally stable fiber-like nanostructures with tunable length and functions derived for biomedical applications.

CAS / MDL: 9048-46-8
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PACKAGING TECHNOLOGY AND SCIENCE · 2023 ·Vol. 36 ·期 11 ·941-950 · IF 2.6

Dual natural antioxidant-loaded chitosan-graft-oleic acid micelles by ultrasound-assisted self-assembly: Potential additives for antioxidant active packaging

Wenjiao Ge,Han Yu,Xiaohui Wang

Natural antioxidants are beneficial additives for active packaging due to their ability to resist oxidative damage. Polymeric micelles are effective in delivering natural antioxidants in aqueous environments. However, individual encapsulation of a single antioxidant may not be sufficient to meet the needs of modern food packaging. A dual natural antioxidant-loaded micellar system (i.e., vitamin E [VE] and curcumin [Cur]) was developed to achieve combined functionality and high loading concentration. Chitosan-graft-oleic acid (CSOA) micelles were employed as carriers to co-encapsulate VE and Cur through a facile ultrasound-assisted self-assembly method. The prepared VE and Cur co-loaded micelles (CSOA/VE/Cur) exhibited a uniform spherical structure with an average particle size of 210.6 nm and a zeta potential of +29.5 mV. Moreover, the co-encapsulation of VE and Cur showed a significant enhancement in both entrapment efficiency, loading capacity and stability as compared to the individual encapsulation of either VE or Cur. In addition, the CSOA/VE/Cur micelles showed improved antioxidant activity than free VE/Cur at the same concentrations, as evidenced by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Moreover, the micellar materials were utilized to fabricate regenerated cellulose (RC) films with antioxidant properties, highlighting their potential as additives for antioxidant active packaging.

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CHEMICAL ENGINEERING JOURNAL · 2023 · IF 15.1

Stimuli-responsive polymeric micelles based on cellulose derivative containing imine groups with improved bioavailability and reduced aquatic toxicity of pyraclostrobin

Xiaohong Zhang,Junfan Niu,Zhiyuan Zhou,Gang Tang,Guangyao Yan,Yulu Liu,Jialu Wang,Gaohua Hu,Jianhua Xiao,Weiyao Yan,Yongsong Cao

The low bioavailability of pesticides has resulted in serious resource waste, environmental pollution, and potential threats to human health. Polymeric micelles for the delivery of pesticides can obviously reduce the drift, and photolysis as well as the risks of poisoning during the application of pesticides. Herein, an amphiphilic polymer, octaneacylhydrazone propylcellulose pyruvate (OPP), was prepared by conjugating octanehydrazide with propylcellulose pyruvate and used as a micellar carrier to improve the utilization efficiency of pyraclostrobin (PYR). The results showed that OPP exhibited a lower critical micelle concentration (9.99 mg/L) than classical surfactant Tween. The prepared PYR-loaded OPP micelles (POM) exhibited excellent pH and cellulase dual responsive release properties with a pesticide loading rate of 8.94%, which could efficiently prevent PYR from photolysis to prolong the effective duration. The fungicidal activities of POM against Sclerotinia sclerotiorum and Botrytis cinerea were better than that of PYR in vitro and in vivo . Furthermore, the acute toxicity of POM to zebrafish was decreased more than eleven-fold compared with that of PYR technical. Therefore, the prepared POM with excellent fungicidal activities may be a potential alternative to conventional formulations of PYR, and OPP would be used as a promising polymeric carrier for the highly efficient delivery of pesticides.

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DYES AND PIGMENTS · 2020 · IF 4.613

Preparation of AIE active and thermoresponsive poly(1-ethenyl-4-(1,2,2-triphenylethenyl)-benzene-b-N-isopropylacrylamide) micelles for cell imaging

Chunping Ma,Gaoyi Xie,Yangchun Tao,Hongni Zhu,Yi Zhang,Zhenguo Chi,Siwei Liu,Jiarui Xu

Three diblock copolymers ( PTPEE-PNns ) with controllable polymer structures were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, combining 1-ethenyl-4-(1,2,2-triphenylethenyl)-benzene (TPEE) and N-isopropylacrylamide (NIPAM). All PTPEE-PNns copolymers showed remarkable aggregation-induced emission (AIE) characteristic. Due to the amphiphilic structure of the copolymers, PTPEE-PNn micelles (mainly hollow) were prepared with either “precipitation” or “dialysis” method, respectively. Scanning electron microscopy, transmission electron microscopy , dynamic light scattering and fluorescence methodology were performed to investigate the morphology, size distribution and stability of the micelles, revealing the effects of molecular weight and micelle preparation method on the nanostructure of the micelles. The PTPEE-PN2 hollow micelles prepared by the “dialysis” method had the advantages of small particle size, extremely narrow particle size distribution , remarkable thermal sensitivity, excellent particle stability, and showed good biocompatibility and fluorescence emission capability in cell imaging . This work would inspire more approaches to prepare novel AIE-active, thermoresponsive and biocompatible polymers for biomedical application .

CAS / MDL: 2210-25-5
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MOLECULAR PHARMACEUTICS · 2020 · IF 4.321

Platensimycin-Encapsulated Liposomes or Micelles as Biosafe Nanoantibiotics Exhibited Strong Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus Infection in Mice

Zhe Wang,Xingyun Liu,Ying Peng,Meng Su,Saibin Zhu,Jian Pan,Ben Shen,Yanwen Duan,Yong Huang

Platensimycin (PTM) is a promising natural product drug lead against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), while the clinical development was hampered by problems related to its poor solubility and pharmacokinetic properties. In this study, we used liposomes and micelles as carriers of PTM to prepare PTM nanoformulations for the treatment of MRSA infection in mice. PTM-loaded nanoparticles could effectively reduce residual bacteria in the MRSA-infected macrophage cell model, comparing to free PTM. More importantly, in vivo studies showed that encapsulation of PTM by liposomes or micelles effectively improved the pharmacokinetic properties of PTM in Sprague–Dawley rats and the survival rate of MRSA-infected C57BL/6J mice. Our study has thus suggested that the clinically used nanocarriers, such as liposome and micelle, might also be useful to improve the efficacy of other natural product drug leads to accelerate their in vivo evaluation and preclinical development.

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JOURNAL OF ALLOYS AND COMPOUNDS · 2020 · IF 4.65

Strongly luminescent and highly stable core-shell suprastructures from in-situ growth of CsPbBr3 perovskite nanocrystals in multidentate copolymer micelles

Aizhao Pan,Lihe Yan,Xiaoqin Ma,Youshen Wu,Yanfeng Zhang,Guijiang Zhou,Ling He

Lead halide perovskite nanocrystals (NCs) have shown exceptional optoelectronic characteristics and photovoltaic performance ; however, their instability has limited their use in optoelectronic applications. Herein, we introduce a facile and effective in-situ synthesis strategy to prepare stable core-shell colloidal perovskite nanocrystal-polymer micelle composites (abbr. ap -POSS-PMMA- b -PDMAEMA@CsPbBr 3 ) by using amphiphilic copolymer (abbr. ap -POSS-PMMA- b -PDMAEMA) self-assembled “reverse micelle” templates. The amphiphilic block copolymer with hydrophobic ( ap- POSS and polymethylmethacrylate, PMMA) and hydrophilic blocks (poly 2-(dimethylamino)ethyl methacrylate, PDMAEMA) can be regulated to self-assemble into “reverse” micelles. The micelle serves as a confined nanoreactor during perovskite crystallization, which passivates the perovskite surface by forming a multidentate capping shell and yields the formation of multi-nanocubes with size between 6 and 8 nm and a photoluminescence quantum yield (PLQY) that surpasses 60%. Benefitting from femtosecond transient absorption (fs TA) and time-resolved photoluminescence (PL) spectroscopy studies, the excited carrier dynamics of the obtained composites substantiate fewer internal band-gap trap states from micelle-induced CsPbBr 3 NCs. The films cast from these composites showed enhanced water-resistant properties as compared to bare NCs and previously reported encapsulated NCs. Therefore, the copolymer “reverse” micelle induced in-situ grown NCs provide a potential approach for further engineering the morphology of NC-based composites and open the door to potential scalable and robust optoelectronic applications.

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INTERNATIONAL JOURNAL OF PHARMACEUTICS · 2020 · IF 4.845

Facile nose-to-brain delivery of rotigotine-loaded polymer micelles thermosensitive hydrogels: In vitro characterization and in vivo behavior study

Fangyuan Wang,Zhuanzhuan Yang,Mengli Liu,Yaotian Tao,Zhenbao Li,Zonghao Wu,Shuangying Gui

A rotigotine (ROT)-loaded polymer micelles thermosensitive gel (ROT-PM-TSG) delivery system was engineered to enhance the solubility of the drug, prolong the residence time, and increase the concentration of the drug in the brain tissue. First, ROT-loaded polymer micelles (ROT-PM) were tailored and optimized. The average particle size, encapsulation efficiency, and drug loading of the ROT-PM were (88.62 ± 1.47) nm , (93.5 ± 0.79) %, and (19.9 ± 0.60) %. The optimal ROT-PM-TSG formulation contained 22% P407 and 2% P188 with a gelation temperature of about 32.3 °C and a pH of 5.186. In vivo , the MRT of ROT-PM and ROT-PM-TSG nasal administration was 1.43 and 1.79 times extended than that of the intravenous. In comparison with the intravenous group, the distribution of ROT in olfactory bulb, cerebrum , cerebellum and striatum was 276.6%, 170.5%, 166.5% and 184.4%, respectively. In conclusion, the ROT-PM-TSG system has proven to be a potential application prospect as a ROT nose-to-brain delivery system.

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Theranostics · 2019 · IF 8.063

TMTP1-modified Indocyanine Green-loaded Polymeric Micelles for Targeted Imaging of Cervical Cancer and Metastasis Sentinel Lymph Node in vivo

Rui Wei,Guiying Jiang,MengQin Lv,Songwei Tan,Xueqian Wang,Ying Zhou,Teng Cheng,Xueqin Gao,Xi Chen,Wei Wang,Chenming Zou,Fei Li,Xiangyi Ma,Junbo Hu,Ding Ma,Danfeng Luo,Ling Xi

Metastasis is one of the most threatening aspects of cervical cancer. We developed a method to intraoperatively map the primary tumor, metastasis and metastatic sentinel lymph nodes (SLNs), providing real-time intraoperative guidance in cervical cancer. Methods : TMTP1, a tumor metastasis targeting peptide, was employed to modify the indocyanine green (ICG)-loaded poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PEG-PLGA) micelles. The cervical cancer subcutaneous tumor model and lung metastasis model were established to determine the active targeting of ICG-loaded TMTP1-PEG-PLGA micelles (ITM) for the primary tumor and occult metastasis of cervical cancer. Human cervical cancer HeLa cells engineered by firefly luciferase were injected into the right hocks of BALB/c nude mice to develop the SLN metastasis model. The ITM and control ICG-loaded PEG-PLGA micelles (IM) were injected into the right hind footpads in the SLN metastasis model, and the migration and retention of micelles were recorded under near-infrared fluorescence. K14-HPV16 transgenic mice were also used to detect the image capability of ITM to target cancerous lesions. Results : ITM could actively target imaging of the primary tumor and cervical cancer metastasis. ITM quickly diffused from the injection site to SLNs along lymphatic capillaries and remained in the SLNs for 12 h. Moreover, ITM specifically accumulated in the tumor metastatic SLNs (T-SLNs), which could be successfully distinguished from normal SLNs (N-SLNs). Conclusion : ITM could achieve active targeting of the primary tumor, metastasis and T-SLNs, providing precise and real-time intraoperative guidance for cervical cancer.

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DESIGNED MONOMERS AND POLYMERS · 2020 · IF 1.75

Construction of poly(ethylene glycol)-poly(L-lactic acid)-stearic acid aspirin-loaded reverse micelles and optimization of preparation process

Yunpeng Min,Hang Zhang,Huiru Wang,Yimin Song

This work aims to study the construction of reverse aspirin-loaded micelles prepared from amphiphilic PEG-PLA-SA triblock copolymers and the optimization of the preparation process. Using polyethylene glycol (PEG) as the initiator, ring-opening polymerization of L-lactide (L-LA) was used to prepare PEG-PLA diblock copolymers. Final product PEG-PLA-SA triblock copolymers were prepared by the reaction of stearic acid (SA) and PEG-PLA catalyzed by 4-dimethylaminopyridine (DMAP) and N,N’-Dicyclohexylcarbodiimide (DCC). Fourier transform infrared spectrometer (FT-IR) was used to characterize the product structure. PEG-PLA-SA triblock copolymers self-assembled in toluene/ethanol/water system to form reverse micelles, which could encapsulate aspirin into a hydrophilic core. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to determine the size and morphology of reverse micelles. The results showed that the reverse micelles are spherical, with a particle size of less than 70 nm. Response surface analysis method was applied to optimize the preparation process of PEG-PLA-SA. In vitro drug release was achieved by embedding reverse aspirin-loaded micelles in the biocompatible membrane in phosphate buffer saline (PBS) at 37°C. In the first 8 h, the drug release rate of the triblock copolymers was slower than that of the diblock copolymers. After 8 h, the drug release rate of both tended to be flat. The stability of aspirin-loaded reverse micelles was studied through accelerated test. These results indicate that reverse micelle PEG-PLA-SA may be a promising carrier for hydrophilic drugs like aspirin.

CAS / MDL: 4511-42-6
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BIOMATERIALS · 2018 · IF 8.806

pH protective Y1 receptor ligand functionalized antiphagocytosis BPLP-WPU micelles for enhanced tumor imaging and therapy with prolonged survival time

Zhenqi Jiang,Yuchen Tian,Dingying Shan,Yinjie Wang,Ethan Gerhard,Jianbi Xia,Rong Huang,Yan He,Aiguo Li,Jianchao Tang,Huimin Ruan,Yong Li,Juan Li,Jian Yang,Aiguo Wu

Nanoparticle-based tumor therapies are extensively studied; however, few are capable of improving patient survival time due to premature drug leakage, off target effects, and poor tissue penetration. Previously, we successfully synthesized a novel family of Y 1 receptor (Y 1 R) ligand modified, photoluminescent BPLP nanobubbles and nanoparticles for targeted breast cancer ultrasound imaging ; however, increased accumulation could also be observed in the liver, kidney, and spleen, suggesting significant interaction of the particles with macrophages in vivo . Herein, for the first time, we imparted antiphagocytosis capability to Y 1 R ligand functionalized BPLP-WPU polymeric micelles through the incorporation of a CD47 human glycoprotein based self-peptide. Application of self-peptide modified, DOX loaded micelles in vivo resulted in a 100% survival rate and complete tumor necrosis over 100 days of treatment. In vivo imaging of SPION loaded, self-peptide modified micelles revealed effective targeting to the tumor site while analysis of iron content demonstrated reduced particle accumulation in the liver and kidney, demonstrating reduced macrophage interaction, as well as a 2-fold increase of particles in the tumor. As these results demonstrate, Y 1 R ligand, self-peptide modified BPLP-WPU micelles are capable of target specific cancer treatment and imaging, making them ideal candidates to improve survival rate and tumor reduction clinically.

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Acta Biomaterialia · 2018 · IF 6.383

Lipid-modified cell-penetrating peptide-based self-assembly micelles for co-delivery of narciclasine and siULK1 in hepatocellular carcinoma therapy

Xiaoyun Wang,Fengbo Wu,Guoyou Li,Nan Zhang,Xiangrong Song,Yu Zheng,Changyang Gong,Bo Han,Gu He

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and one therapeutic approach is to target both the AMPK and autophagy pathways in order to synergistically promote programmed cell death. Here, a series of amphiphilic, lipid-modified cell-penetrating peptides were synthesized and allowed to self-assemble into micelles loaded with the AMPK activator narciclasine (Narc) and short interfering RNA targeting the unc-51-like kinase 1 (siULK1). The size of these micelles, their efficiency of transfection into cells, and their ability to release drug or siRNA cargo in vitro were pH-sensitive, such that drug release was facilitated in the acidic microenvironment of the tumor. Transfecting the micelles into HCC cells significantly inhibited protective autophagy within tumor cells, and delivering the micelles into mice carrying HCC xenografts induced apoptosis, slowed tumor growth, and inhibited autophagy. Our results indicate that co-delivering Narc and siULK1 in biocompatible micelles can safely inhibit tumor growth and protective autophagy, justifying further studies into this promising therapeutic approach against HCC. Statement of Significance We have focused on the targeted therapy of HCC via synergistically inhibiting the autophagy and inducing apoptosis. The lipid-modified cell-penetrating peptide can not only aggregate into micelles to load natural product narciclasine and ULK1 siRNA simultaneously, but also facilitate uptake and endosome escape with a pH-sensitive manner in HepG2 cells. HepG2 cell treated with siULK1-M-Narc has increased apoptotic levels and declined autophagy via the targeted regulation of AMPK-ULK1 signaling axis. The in vivo studies have confirmed that siULK1-M-Narc efficiently reduce the growth of tumor on HCC xenograft models with good safety. Thus, we suppose the lipid-modified cell-penetrating peptide has good application prospects in the targeted combinational therapy of HCC.

CAS / MDL: 29477-83-6
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Journal of Materials Chemistry B · 2015 ·Vol. 3 ·期 27 ·5478-5489 · IF 4.726

DOX-encapsulated intelligent PAA-g-PEG/PEG–Fa polymeric micelles for intensifying antitumor therapeutic effect via active-targeted tumor accumulation

Yong Sun,Yaning Wang,Yani Cui,Wen Zou,Yanfei Tan,Jie Liang,Yujiang Fan,Xingdong Zhang

Stimuli-responsive targeted polymeric micelles as drug delivery systems have recently attracted significant attention for the treatment of various cancers, which could improve delivery efficiency by tumor-specific recognition via active targeting strategies. In this research, DOX-incorporated bioreducible polymeric micelles based on PAA-g-PEG/PEG–Fa conjugated polymers were prepared and characterized as nanocarriers for promoting intracellular anti-tumor drug delivery efficiency via folate receptor-mediated endocytosis. The anti-proliferative activity on cancer cells, biodistribution, active-/passive-targeting efficiency, tumor growth inhibition efficiency, and biological toxicity were evaluated in vitro and in vivo. The MTT assay demonstrated that the DOX-encapsulated active-targeting PAA-g-PEG/PEG–Fa micelles had much greater growth inhibition effect against 4T1 and KB than passive-targeting micelles. These active-targeting micelles showed superior tumor accumulation and excellent tumor growth inhibition effect as revealed by the fluorescence optical imaging technique and tumor volume change investigation, as well as the survival study of the tumor-bearing Balb/c mice. Furthermore, the active targeting micelles greatly decreased the toxicity of DOX on the heart and other organs. These potential results encouraged us to further optimize the molecular structure to achieve more excellent targeted therapeutic effect.

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