MOLECULAR PHARMACEUTICS
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2017
·
IF 4.44
Yujie Zhang,Yifei Lu,Yu Zhang,Xi He,Qinjun Chen,Lisha Liu,Xinli Chen,Chunhui Ruan,Tao Sun,Chen Jiang
Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear–dendritic polymer–drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear–dendritic PEG–PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 ± 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG–PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR–PEG–PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO–PEG–PTX8/PTX micelles. Furthermore, iNGR–PEG–PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy.
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JOURNAL OF MOLECULAR LIQUIDS
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2016
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IF 2.74
Wei Lin,Zhengming Yang,Juan Wang,Ting Chen,Xingwang Shi
The pH-induced rheological property of octadecy trimethyl ammonium bromide with anthranilic acid was investigated. The viscoelasticity property and structural transformation of molecular self-assembly were comprehensively discussed by means of rheological measurements, dynamic light scattering and cryogenic-transmission electron microscopy. On the basis of surface tension results, the change of viscoelasticity was explained by calculating the packing parameter of P . UV–vis results confirmed that the pH-dependent interaction between the aromatic ring of anthranilic acid and the head group result in the transition between WLMs and spherical micelles, thus altering the viscoelasticity of WLMs.
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Polymer Chemistry
·
2017
·Vol. 8
·期 7
·1223-1232
·
IF 5.375
Yuanfeng Gao,Chang-Ming Dong
The dynamic instability, premature burst drug release, and lack of intracellular stimuli-sensitivity of current polymeric nanocarriers still hinder them from potential clinical applications. To address these challenges, a novel type of reduction- and thermo-sensitive core-cross-linked polypeptide hybrid micelle (CCM) was developed. The trimethoxysilane-terminated and disulfide-bond-centered polyglutamate with pendant diethylene glycol was synthesized from ring-opening polymerization followed by an amino-epoxy ring-opening reaction. FT-IR, 1H NMR, and thermo-gravimetric analyses verified the formation of Si–O–Si cross-linking networks in the CCMs, which have an approximately 6.6-fold lower critical aggregation concentration than the non-cross-linked counterparts. Their size, morphology and dual stimuli-sensitivity were fully characterized by DLS, TEM, and AFM. The CCMs presented a similar thermo-reversibility to non-cross-linked ones; but their size and morphology remained unchanged in 10 mM DTT at 37 °C while non-cross-linked micelles reassembled into smaller ones. The cross-linking effect in the CCMs greatly attenuated the premature burst-release behavior compared to the non-cross-linked counterparts although a reduction-triggered accelerating drug release profile was similarly observed. Furthermore, flow cytometry and CLSM confirm that the anticancer drug doxorubicin-loaded CCMs can efficiently enter the HeLa cells. Hence, this work establishes a facile platform for the fabrication of stimuli-sensitive silica-cross-linked polypeptide hybrid micelles, which hold promise to overcome the above-mentioned challenges for advanced drug delivery systems.
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Journal of Biomedical Nanotechnology
·
2017
·Vol. 13
·期 4
·393-408
·
IF 4.521
Tan LiWei,Ma BuYun,QianZhao .,LanZhang .,Chen LiJuan,Peng JinRong,Qian ZhiYong
In this work, docetaxel (DTX) was encapsulated in monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) micelles and monomethoxy poly(ethylene glycol)-poly(D, L-lactic acid) (mPEG-PLA) micelles, respectively. For the further application, the acute/genetic toxicity
evaluation and pharmacokinetic/pharmacodynamic study of the two kinds of micellar nanomedicines were performed. In the study of anticancer activity in vitro and in vivo, DTX micelles showed better tumorgrowth inhibition than free DTX. The pharmacokinetic and tissue distribution
studies showed that the DTX incorporated in micelles (especially in DTX-mPEG-PCL) retained significantly higher concentration in plasma and tumor tissue compared with free DTX. The acute toxicity and genotoxicity studies indicated that DTX micelles were safer than the docetaxel injection in
cancer therapy and DTX-mPEG-PCL had less damage to DNA than DTX-mPEG-PLA. So the micelles had a pronounced effect on reducing acute toxicity and genotoxicity of docetaxel. In conclusion, DTX micelles were efficient and safe on breast carcinoma chemotherapy.
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RSC Advances
·
2016
·Vol. 6
·期 107
·105957-105968
·
IF 3.289
Shaoping Yin,Liang Chang,Tie Li,Guangji Wang,Xiaochen Gu,Juan Li
It is still a major challenge for successful cancer chemotherapy to design drug delivery systems with desirable extracellular stability and intracellular drug release. Here, novel pH-sensitive hybrid micelles were constructed by introducing positively charged arginine (Arg) into negatively charged micelles formed from a ternary graft copolymer (mPAL) comprising poly(acrylic acid) (PAA) as the backbone and methoxy poly(ethylene-glycol) (mPEG) and poly(lactide) (PLA) as the grafts to balance the extracellular stability and intracellular drug release. Paclitaxel (PTX) loaded hybrid micelles (PTX@mPAL/Arg) exhibited a desirable particle size (62.8 ± 2.9 nm), and a high entrapment efficiency (93.3 ± 2.9%). AFM and TEM images demonstrated the smooth surface and distinct spherical shape of the micelles. PTX@mPAL/Arg displayed high stability against dilution and serum, impeded drug release at physical conditions, and accelerated PTX release in mildly acidic medium. Blank micelles possessed satisfactory compatibility and would be safe for biomedical applications. PTX@mPAL/Arg micelles demonstrated much higher antitumor activity with low IC50 values of 0.67 and 0.20 μg mL−1 for A549 and HepG2 cells following 48 h incubation, respectively. A cellular internalization experiment indicated that the micelles could deliver and release cargo into the cytoplasm of HepG2 cells. Pharmacokinetic study in rats proved that PTX loaded micelles enhanced the AUC of PTX and prolonged circulation time in comparison to Taxol. These intelligent micelles with improved stability and drug release could be further studied as a promising delivery carrier for anticancer agents to improve therapeutic efficacy and to minimize adverse effects.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Ying Lu,Xiangzhou Li,Jun Zhou,Peng Zhou,Jiajia Lai,Yanhong Yang,Liqun Shen
The unique structure of chitosan-based micelles can be loaded with essential oil, so it is significant to study the modification of chitosan and the interactions between chitosan and essential oil, while molecular dynamics (MD) simulation and density functional theory (DFT) provide a solution. In this study, three kinds of amphiphilic chitosan derivatives (CSDs) were constructed by grafting of different hydrophilic and hydrophobic groups. Amphiphilic chitosan micelles loaded with Chinese fir essential oil (CFEO) were prepared by self-assembly. The aggregation behavior of CFEO component (cedrol and α-cedrene) in the solutions of chitosan and three CSDs were simulated using MD, and the mean square displacement was calculated. DFT analyzed the mechanism for regulating the molecular properties of CSDs by different modification methods, and explored the intensity and type of interaction force between cedrol/α-cedrene and three CSDs. The results show that cedrol and α-cedrene were more easily aggregated near the modified CSDs, with CS-g-PLA showing the strongest trapping ability. The grafting of polylactic acid on chitosan resulted in a significant decrease in HOMO-LUMO energy gap and an increase in reactivity activity. Widely distributed hydrogen bonding and van der Waals forces were confirmed to be the key to enhanced loading capacity.
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JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 2.713
Haojun Ma,Chen Jiang
In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as lack of potency of tumor penetration. In this work, we developed actively tumor-targeting micelles with pH-sensitive linker as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable poly(ethylene glycol)-poly(aspartate) polymers, in which paclitaxel can be covalently conjugated to pAsp via an acid-labile acetal bond to form pH-responsive structures. In vitro drug release studies showed that these structures were stable in physiological condition, whereas collapsed once internalized into cells due to the mildly acidic environment in endo/lysosomes, resulting in facilitated intracellular paclitaxel release. In addition, dehydroascorbic acid and guanidinopropyl methacrylamide polymers were decorated on the surface of micelles to achieve specific tumor accumulation and tumor penetration. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo . Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.
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Drug Delivery and Translational Research
·
2024
·
IF 5.7
Zhang Wei,Zhang Qian,Yang Yuhan,Chen Yangyi,Wei Jinbin,Lu Fenglai,Li Dianpeng
A novel multi-functional micelle delivery system was developed for enhancing the oral absorption of paclitaxel (PTX). The delivery carriers were constructed by modifying chitosan-stearic acid (CS-SA) micelles with L-carnitine (LC) and co-encapsulating quercetin (Que), and the PTX-loaded micelles were prepared by film-sonication dispersing technique. The as-prepared micelles showed homogeneous spherical shapes with a small particle size of 148.3 ± 1.7 nm, high drug loading of 7.05% and low critical micelle concentration (CMC) of 16.89 µg/ml. Compared to the in-house PTX formulation similar to the commercial injection Taxol™, the target PTX-loaded micelles had obvious sustained-release effects and exhibited an oral relative bioavailability of 168.08%. The cellular uptake studies of Caco-2 cells confirmed the micellar modification of LC and the co-loading of Que played important roles in promoting the absorption of drug loaded in micelles. The CYP3A4 enzyme test demonstrated the micelles had an inhibitory effect on the metabolic enzyme due to the presence of Que. These findings confirmed the potential of the multi-functional chitosan polymeric micelles based on synergistic effect as an effective oral delivery system. Graphical abstract
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ACS Applied Nano Materials
·
2024
·
IF 5.3
Fanqi Meng,Lei Chen,Haoran Chen,Meili Shen,Guangyi Wang,Yulei Chang
Combined phototherapy with other therapeutic strategies can improve the therapeutic outcomes of tumors and reduce the side effects. However, shaping multiple modalities for combination therapy remains challenging. Herein, multiple stimuli-responsive drug-loaded micelles are presented, which are self-assembled from cypate-conjugated pH-sensitive poly(ethylene glycol)–poly(2-(diisopropylamino) ethyl methacrylate)–poly(2-aminoethyl methacrylate hydrochloride) and redox-responsive poly(glycidyl methacrylate)–poly(propylene sulfide) copolymer and loaded with chemo agents doxorubicin (DOX) and sorafenib (SRF, also a ferroptosis inducer) for enhanced tumor therapy. The DOX and SRF chemo drugs were encapsulated into the hydrophobic core of PPS and PDPA to enable multiple stimuli-responsive controlled drug delivery. In vivo and in vitro experiments are carried out to investigate the potential application for controlled drug release and systemic chemo-phototherapy. This study highlights the rational design of cypate-based drug-loaded micelles, offering multiple stimuli-responsive drug releases and synergistic photo-, ferro-, and chemotherapy in colorectal cancer.
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MACROMOLECULAR BIOSCIENCE
·
2018
·Vol. 18
·期 3
·1700312
·
IF 3.392
Tao Chen,Yuanhong Xu,Wenrong Yang,Aihua Li,Yao Wang,Jing Sun,Jingquan Liu
Concavo-convex micelles with controllable sizes and nanostructures are prepared via self-assembling polymer–enzyme (e.g., shellac enzyme) conjugates with heterogeneous polymer chains, which exhibit higher enzyme stability (300%) and bioactivity (760%) comparing with the well-defined ones. The applied amphiphilic and negatively charged copolymer, poly (methyl methacrylate)-block-poly (sodium p-styrene sulfonate), is synthesized via reversible addition–fragmentation chain transfer polymerization to modify shellac enzyme and immobilize the enzyme bioactivity inducer by covalent conjugation and electrostatic attraction, respectively. The degradation test of catechol confirms the application potential of as-prepared micelles as an efficient and economical decontaminant.
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Polymer Chemistry
·
2012
·Vol. 3
·期 9
·2403-2412
·
IF 5.321
Lesan Yan,Wenbin Wu,Wei Zhao,Ruogu Qi,Dongmei Cui,Zhigang Xie,Yubin Huang,Ti Tong,Xiabin Jing
A functionalized six-membered cyclic carbonate monomer containing a protected thiol group, 2-(2,4-dinitrophenylthio)ethyl-5-methyl-2-oxo-1,3-dioxane-5-carboxylate (MTC), was prepared. Ring-opening polymerization (ROP) of MTC and L-lactide (LA) initiated by monohydroxyl poly(ethylene glycol) (mPEG) was successfully performed with controlled polymer molecular weight and molecular weight distribution. The structures of the obtained monomer and copolymers were confirmed by NMR and FTIR. After deprotection under mild conditions, the amphiphilic block copolymer was self-assembled into micelles in aqueous solution. By oxidation of the free thiol groups in the PMTC segments, the micelles with the cross-linked core were formed, and the enhanced stability against disruptive conditions was demonstrated by dynamic light scattering (DLS) measurement in the presence of DMF. Doxorubicin (DOX) was loaded into the micelles as a model drug. The in vitro DOX release behaviors indicated that cross-linking of the micelle cores resulted in a slow drug release and this process was greatly accelerated by adding glutathione (GSH) solution with comparable concentrations to intracellular levels in tumor cells. The cross-linked micelles were demonstrated to be efficiently internalized into the cells. Faster intracellular DOX release was observed by confocal laser scanning microscopy (CLSM) in the GSH pretreated MCF-7 cells than in the unpretreated MCF-7 cells. In vitro MTT assay revealed that the cross-linked micelles were biocompatible with L929 cells and MCF-7 cells. As expected, DOX-loaded cross-linked micelles showed higher cellular proliferation inhibition towards glutathione pretreated MCF-7 cells than that towards the unpretreated ones at various GSH concentrations. These results indicated that the bioreducible core-cross-linked micelles can be used as drug carriers for intelligent drug delivery.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yanan Gao,Xue Hu,Haiying Zhang,Simin Chen,Jiaqi Yu,Deqiao Dong,Haihe Zhan,Bingmiao Gao,Dingguo Li,Zhenmiao Qin,Yan Liu
Myocardial infarction (MI) is a critical heart disease with a high mortality rate, posing a serious risk to human health. Injectable hydrogels possess considerable therapeutic promise for managing MI through the application of tissue-engineered scaffolds for cell delivery. However, the oxidative stress microenvironment of MI lesions leads to low cell retention and survival. In this study, a thermo-sensitive resveratrol micelles (RES-M) loaded chitosan hydrogel (RM-CH) was developed against oxidative stress injury in cardiomyocytes (CMs). RM-CH had better scavenging ability against DPPH and ABTS radicals compared to industry-standard ascorbic acid. RM-CH had good biodegradability, histocompatibility and cytocompatibility. The injection process of the hydrogel did not cause cell injury. DHE and DCFH-DA staining showed that it can improve the survival of CMs by fighting against the oxidative stress microenvironment. Live/Dead staining of CMs in hydrogels showed that the addition of RES-M could rescue cell survival under oxidative stress. Hence, this work highlights the potential clinical applications of RM-CH which may present an ideal scaffold material for injectable cardiac tissue engineering.
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