ACS Applied Materials & Interfaces
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2022
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IF 10.383
Li Xiang,Xin Wang,Yaru Shao,Qiangqiang Jiao,Jiang Cheng,Xiaotong Zheng,Shaobing Zhou,Yuping Chen
As the central cellular player in fibrogenesis, activated hepatic stellate cells (aHSCs) are the major target of antifibrotic nanomedicines. Based on our finding that activated HSCs increase the expression of folate receptor alpha (FRα), we tried to apply folic acid (FA) decoration to generate an active drug-targeting at aHSCs and suppress hepato-fibrogenesis. FA-conjugated poly(ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) were synthesized and self-assembled into the spherical micelles that owned a uniform size distribution averaging at 60 nm, excellent hemo- and cyto-compatibility, and pH-sensitive stability. These FA-modified micelles were preferentially ingested by aHSCs as expected and accumulated more in acutely CCl4 injured mouse livers compared to nondecorated counterparts. Such an aHSC targetability facilitated the loaded medicinal camptothecin (CPT) to achieve a greater therapeutic efficacy and inhibition of MF phenotypic genes in aHSCs. Encouragingly, though free CPT and nontargeting CPT micelles produced negligible curative outcomes, FA-decorated CPT micelles yielded effectively remedial effects in chronically CCl4-induced fibrotic mice, as represented by a significant shrinkage of aHSC population, suppression of fibrogenesis, and recovery of liver structure and function, clearly indicating the success of the folate decoration-supported aHSC-targeted strategy for antifibrotic nanomedicines in fibrosis resolution.
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JOURNAL OF PHARMACEUTICAL SCIENCES
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2022
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IF 3.784
Meixuan Liu,Sha Liu,Xiaosu Zhu,Yiying Sun,Linyu Su,Hairong Yu,Deshuai Liu,Ying Li,Yuan Du,Rongxia Liu,Kaoxiang Sun
Rosmarinic acid (RA) and tanshinone IIA (TA) which are effective components in Salvia miltiorrhiza show anti-inflammatory potential against atherosclerosis . Based on polysulfated propylene-polyethylene glycol (PPS-PEG), RA was grafted onto this polymer via amide bonds to form a micelle carrier for TA encapsulation: [email protected] A potent inhibitory effect on lipopolysaccharide (LPS) -induced proliferation of endothelial cells with significant intracellular uptake was observed with this system. This could have been the result of release of TA in a reactive oxygen species (ROS) environment and stronger antioxidant effect of RA. The synergistic effect was optimized when the combination was used in a molar ratio of 1:1. Mechanistic studies showed that, compared with PPS-PEG-RA and TA+RA, [email protected] micelles could more effectively regulate the nuclear factor-kappa B (NF-κB) pathway to reduce expression of vascular cell adhesion molecule-1 (VCAM-1), inhibit the inflammatory cascade and reduce endothelial-cell injury. One month after intravenous injection of [email protected] micelles, the plaque area in murine aortic vessels was reduced significantly, and serious toxic side-effects were not observed in vivo , along with excellent biocompatibility . In summary, [email protected] micelles could achieve synergistic treatment of atherosclerosis.
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LANGMUIR
·
2023
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IF 3.9
Fang Chen,Li Yin,Teng He,Tao Chen,Hangbo Yue,Chufen Yang
To enhance the stability of the polymeric micelles and optimize their drug-controlled release ability, three disulfide-linked polyethylene glycol methyl ether methacrylate–disulfide–poly(ε-caprolactone-co-γ-amine−ε-caprolactone) (PPEGMA-SS-P(CL-co-ACL)) polymers were synthesized and characterized by 1H NMR, GPC, and FT-IR successfully, and their dual pH/reduction-responsive cross-linked polymeric micelles were prepared for paclitaxel (PTX) delivery by using 2,3-dimethylmaleic anhydride (DMMA) as the cross-linking agent. The PTX loading capacity (LC) and encapsulation efficiency (EE) values of the cross-linked micelles formed by PPEGMA8-SS-P(CL47-co-ACL15) achieved were 23.96% and 71.58%, slightly higher than those of un-cross-linked micelles. Both particle sizes of blank micelles and in vitro drug release of PTX-loaded micelles confirmed that compared with those un-cross-linked micelles, the cross-linked micelles were more stable at pH 7.4 + 0 mM DTT, with a PTX cumulative release of 13% at 120 h, while the PTX cumulative release of the cross-linked micelles at pH 5.0 + 10 mM DTT were close to that of un-cross-linked micelles after 60 h, indicating the successful reversible cross-linking and smooth drug release of the cross-linked micelles. The cytotoxicity assay showed that PPEGMA8-SS-P(CL47-co-ACL15) and its cross-linked micelles had low cell cytotoxicity, and both PTX-loaded micelles revealed a certain inhibitory effect on HepG2 cells. These results revealed that the dual pH/reduction-responsive cross-linked polymeric micelles prepared from PPEGMA8-SS-P(CL47-co-DCL15) were a promising candidate for PTX delivery.
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JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Ke Wang,Bingbing Zhao,Yuli Ao,Jinyu Zhu,Changshun Zhao,Wei Wang,Yan Zou,Dechun Huang,Yinan Zhong,Wei Chen,Hongliang Qian
Glioblastoma multiforme (GBM) remains incurable in clinical, nanotechnology-based drug delivery strategies show promising perspective in alleviating GBM, while limited blood-brain-barrier (BBB) permeation, short blood half-live accompanied by the poor tumor accumulation and penetration, significantly restrict the therapeutic outcomes. Herein, a versatile super-small zwitterionic nano-system (M CB (S)) based on carboxybetaine (CB) zwitterion functionalized hyperbranched polycarbonate (HP CB ) is developed to overcome the brain delivery challenges. After grafting with amino-functionalized IR780 (free IR780), the ultimate paclitaxel (PTX)-encapsulated micelles (M CB (S)-IR@PTX) are precisely activated by near-infrared (NIR) for accelerated drug release and effective combinational GBM therapy. Importantly, M CB (S)-IR@PTX with the crosslinked structure and CB zwitterion prolongs blood-circulation, and CB-zwitterion further facilitates BBB-traversing through betaine/γ-aminobutyric acid (GABA) transporter-1 (BGT-1) pathway. Combined with the benefit of super small-size, M CB (S)-IR@PTX highly accumulates at tumor sites and penetrates deeply, thus efficiently inhibiting tumor growth and strikingly improving survival time in U87MG orthotopic GBM-bearing mouse model. The ingenious nanoplatform furnishes a versatile strategy for delivering therapeutics into the brain and realizing efficient brain cancer therapy.
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BIOMACROMOLECULES
·
2023
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IF 6.2
Yingping Zeng,Guangtao Song,Shufen Zhang,Sufen Li,Tingting Meng,Hong Yuan,Fuqiang Hu
The tumor microenvironment (TME) of breast cancer is hypoxic, which can promote tumor progression, including invasion and metastasis, and limit the efficacy of anti-tumor treatment. Nitric oxide (NO) can dilate blood vessels, effectively alleviate hypoxia, and regulate the TME, which has the potential to improve the anti-tumor therapeutic efficacy. Here, chitosan (CO) and octadecylamine (ODA) were linked by the disulfide bond, and the LinTT1 peptide was linked onto CO–SS–ODA for targeting tumor cells and endothelial cells in tumors. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) was connected to CO. Doxorubicin (DOX) was encapsulated, and GSH hierarchically responsive polymer micelles (TSCO–SS–ODA/DOX) were constructed for the treatment of breast cancer. The micelles had differently responsive drug release in different GSH concentrations. In endothelial cells, the micelles rapidly responded to release NO. In tumor cells, the disulfide bond rapidly broke and released DOX to effectively kill tumor cells. The disulfide bond was not sensitive to GSH concentration in endothelial cells, which had less release of DOX. The killing effect of the micelles to endothelial cells was much lower than that to tumor cells. The cell selective drug release of the drug delivery systems enabled safe and effective treatment of drugs. TSCO–SS–ODA/DOX, which had the excellent ability to target tumors, can alleviate tumor hypoxia, decrease the infiltration of M2 macrophages in tumors, increase the infiltration of M1 macrophages in tumors, and remodel the TME. Notably, TSCO–SS–ODA/DOX can significantly inhibit the growth of the primary tumor and effectively inhibit tumor metastasis. The drug delivery system provided a potential solution for effectively treating breast cancer.
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REACTIVE & FUNCTIONAL POLYMERS
·
2023
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IF 5.1
Yang Yang,Zifan Song,Weiguo Qi,Ningning Zhang,Ying Gao,Jin Liang,Ao Zhang,Yimin Song
To develop a natural polysaccharide targeted nanomicelles drug delivery system loaded with the broad-spectrum anti-tumor drug adriamycin (ADM), FA-LNT-OA polymer was synthesized, the ADM/FA-LNT-OA polymer nanomicelles was prepared, and response surface approach was used to optimize the drug loading procedure of the ADM/FA-LNT-OA nanomicelles. Under the optimum conditions, the drug loading ratio was 14.36 ± 0.12% while the entrapment efficiency was 95.17 ± 0.13%. The drug-loaded micelles were spherical, with the size about 170 nm, and the size distribution was uniform. The CMC of ADM/FA-LNT-OA nanomicelles was 48 ± 0.46 μg/mL, their release was more sensitive to pH than that of ADM, and they had good stability. The FA-LNT-OA nanomicelles had good blood compatibility and cell compatibility. In vitro anti-tumor pharmacodynamic studies proved that the IC 50 of ADM/FA-LNT-OA nanomicelles on Hela, ES-2 and A549 cells were 48.49 ± 0.25, 63.56 ± 0.68 and 105.93 ± 17.03 μg/mL respectively. Moreover, the plasma elimination half-life of ADM/FA-LNT-OA nanomicelles was 5.341 h, the T max was 0.083 h, the CL was 0.017 L/h/kg. Compared with the common ADM formulation, the ADM/FA-LNT-OA nanomicelles prolonged the clearance half-life of ADM, decreased the clearance rate, and extended the retention time of ADM in vivo. In conclusion, the above results laid the foundation for the increase of therapeutic effects and reduction of the clinical toxic and side effects of ADM.
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ACS Applied Polymer Materials
·
2023
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IF 5
Linrui Jiang,Wenpeng Li,Qingshan Miao,Jing Yang,Shaoyun Shan,Hongying Su
Introducing hydrophobic microstructures into polymer hydrogels has been considered recently as an effective strategy to design multifunctional hydrogel-based carriers for hydrophobic drug delivery. Herein, fluorescent micelle–hydrogel composites by combining aggregation-induced emission (AIE)-active polyethylenimine (PEI) micelles into a dextran hydrogel matrix for improving the delivery of doxorubicin (DOX) are presented. A synthetic protocol based on the mercaptoacetic acid locking imine (MALI) reaction was explored to effectively modify the side-chains of alkylated polyethylenimine (PEI-C12) with AIEgens (aldehyde-functionalized tetraphenylethene, TPE-CHO). DOX-loaded micelle nanoparticles with AIE fluorescent properties and fluorescence resonance energy transfer (FRET) phenomenon were obtained via the self-assembly of the resulting amphiphilic TPE-PEI-C12 and then encapsulated into dextran hydrogels formed by the disulfide-containing Schiff base reaction. The stimuli-sensitive release of the DOX-loaded AEI micelles from the hydrogel matrix and the following DOX release via demicellization was finally investigated by in vitro release and cell-labeling studies. The above results suggest that the AIE micelle–hydrogel system can be considered as a valuable carrier of hydrophobic drugs with potential in intracellular imaging and drug release tracing, especially for local drug delivery.
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International Journal of Nanomedicine
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2023
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IF 8
Yan Liang,Ping-Yu Wang,Ze-Yun Liu,Hong-Fang Sun,Qin Wang,Guang-Bin Sun,Xia Zhang,You-Jie Li,Shu-Yang Xie
Introduction As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies.Methods In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core.Results In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities.Conclusion In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.
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Soft Matter
·
2023
·Vol. 20
·期 4
·804-812
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IF 3.4
Zhengrong Lin,Hongye Li,Jinpeng Zhang,Xiaomei Pei,Zhao Chen,Zhenggang Cui,Binglei Song
Innovation in surfactant structures is an effective way to prepare new soft materials with novel applications. In this study, we synthesized a double-tailed surfactant containing two quaternary ammonium head groups (Di-C12-N2). The Di-C12-N2 solution behavior was investigated by surface tension, fluorescence, rheology, and cryo-TEM methods. Although Di-C12-N2 contained a large double-tailed hydrophobic group, the solubility of Di-C12-N2 was ∼90 mmol L−1 at 25 °C with a Krafft temperature of ∼1 °C. The increase in Di-C12-N2 concentration in the solutions led to the formation of various aggregates, including spherical micelles, worm-like micelles, multi-layered vesicles, and a rare type of small toroidal micelles. The two quaternary ammonium head groups in Di-C12-N2 led to strong electrostatic interactions between molecules, which was critical for the formation of toroidal micelles. Moreover, with an added NaCl concentration of 40 mmol L−1, the viscosity of the 5 mmol L−1Di-C12-N2 solution increased by ∼1000 times compared to the pure 5 mmol L−1Di-C12-N2 solution, revealing the high sensitivity of the unique head groups to ionic strength. This study enriches the research on the self-assembly principles of surfactants and brings new potential applications for new soft materials.
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Journal of Materials Chemistry B
·
2023
·Vol. 11
·期 31
·7478-7489
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IF 7
Lingling Lei,Haibo Wang,Qihan Jia,Yali Tian,Shuang Wang
Due to the rapid development of multi-functional flexible wearable sensors, the development prospects of ionohydrogels with excellent mechanical properties and high sensitivity are necessary. In this work, a novel waterborne polyurethane (WPU) micelle with reactive groups on the surface has been prepared as a crosslinker and then reacted with polyacrylamide (PAM) to obtain a polyacrylamide–polyurethane/ionic liquid (PAM-WPU/IL) ionohydrogel. With the aid of ion–dipole interaction and crosslinks in the composite, the ionohydrogel exhibited ultrastretchability (up to 2927%), good mechanical resilience, and excellent self-adhesion strength (46.01 kPa). Furthermore, the ionohydrogel was used as a strain sensor for monitoring human movement with high strain sensitivity (gauge factor = 35). It is believed that this study provides a new idea for designing a multifunctional ionohydrogel for use in wearable electronics.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
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IF 8.2
Duo Li,Xiaoli Wang,Kaishuo Han,Yaqian Sun,Ting Ren,Guohui Sun,Na Zhang,Lijiao Zhao,Rugang Zhong
Carmustine (BCNU) is a typical chemotherapy used for treatment of cerebroma and other solid tumors, which exerts antitumor effect by inducing DNA damage at O 6 position of guanine. However, the clinical application of BCNU was extremely limited due to the drug resistance mainly mediated by O 6 -alkylguanine-DNA alkyltransferase (AGT) and absence of tumor-targeting ability. To overcome these limitations, we developed a hypoxia-responsive nanomicelle with AGT inhibitory activity, which was successfully loaded with BCNU. In this nano-system, hyaluronic acid (HA) acts as an active tumor-targeting ligand to bind the overexpressing CD44 receptors on the surface of tumor cells. An azo bond selectively breaks in hypoxic tumor microenvironment to release O 6 -benzylguanine (BG) as AGT inhibitor and BCNU as DNA alkylating agent. The obtained HA-AZO-BG NPs with shell core structure had an average particle size of 176.98 ± 11.19 nm and exhibited good stability. Meanwhile, HA-AZO-BG NPs possessed a hypoxia-responsive drug release profile. After immobilizing BCNU into HA-AZO-BG NPs, the obtained HA-AZO-BG/BCNU NPs exhibited obvious hypoxia-selectivity and superior cytotoxicity in T98G, A549, MCF-7 and SMMC-7721 cells with IC 50 at 189.0, 183.2, 90.1 and 100.1 μm, respectively, under hypoxic condition. Near-infrared imaging in HeLa tumor xenograft models showed that HA-AZO-BG/DiR NPs could effectively accumulate in tumor site at 4 h of post-injection, suggesting its good tumor-targetability. In addition, in vivo anti-tumor efficacy and toxicity evaluation indicated that HA-AZO-BG/BCNU NPs was more effective and less harmful compared to the other groups. After treatment, the tumor weight of HA-AZO-BG/BCNU NPs group was 58.46 % and 63.33 % of the control group and BCNU group, respectively. Overall, HA-AZO-BG/BCNU NPs was expected to be a promising candidate for targeted delivery of BCNU and elimination of chemoresistance.
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Polymers
·
2023
·Vol. 15
·期 9
·1990
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IF 5
Xinfeng Cheng,Qiyang Li,Xiaomeng Sun,Yuxin Ma,Huanping Xie,Weiguang Kong,Xianchao Du,Zhenghui Zhang,Dongfang Qiu,Yong Jin
Micellar-nanocarrier-based drug delivery systems possessing characteristics such as an excellent circulation stability, inhibited premature release and on-demand site-specific release are urgently needed for enhanced therapeutic efficacy. Therefore, a novel kind of shell-sheddable core-crosslinked polymeric micelles with pH and oxidation dual-triggered on-demand drug release behavior was facilely constructed. The multifunctional micelles were self-assembled from a carefully designed amphiphilic triblock PEGylated polyurethane (PEG-acetal-PUBr-acetal-PEG) employing an acid-labile acetal linker at the hydrophilic–hydrophobic interface and pendant reactive bromo-containing polyurethane (PU) as the hydrophobic block, followed by a post-crosslinking via oxidation-cleavable diselenide linkages. These well-defined micelles exhibited an enhanced structural stability against dilution, achieved through the incorporation of diselenide crosslinkers. As expected, they were found to possess dual pH- and oxidation-responsive dissociation behaviors when exposure to acid pH (~5.0) and 50 mM H2O2conditions, as evidenced using dynamic light-scattering (DLS) and atomic force microscopy (AFM) analyses. An in vitro drug release investigation showed that the drug indomethacin (IND) could be efficiently encapsulated in the micelles, which demonstrated an inhibited premature release compared to the non-crosslinked ones. It is noteworthy that the resulting micelles could efficiently release entrapped drugs at a fast rate in response to either pH or oxidation stimuli. Moreover, the release could be significantly accelerated in the presence of both acid pH and oxidation conditions, relative to a single stimulus, owing to the synergetic degradation of micelles through pH-induced dePEGylation and oxidation-triggered decrosslinking processes. The proposed shell-sheddable core-crosslinked micelles with a pH and oxidation dual-response could be potential candidates as drug carriers for on-demand drug delivery.Keywords:shell-sheddable;core-crosslinking;pH-responsive;oxidation-responsive;drug delivery
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