CARBOHYDRATE POLYMERS
·
2022
·
IF 10.723
Min Li,Yinan Zhao,Jiao Sun,Huiying Chen,Zhanbiao Liu,Kexin Lin,Pengfei Ma,Wenjun Zhang,Yuhong Zhen,Shufen Zhang,Shubiao Zhang
Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are in great demand for enhanced cancer treatment. Hyaluronic acid (HA), which has excellent biocompatibility and targeting ability for cluster determinant 44 (CD44), has been proposed for delivering drugs that have poor solubility and high toxicity. Herein, podophyllotoxin (PPT) was conjugated to HA via ester and disulfide linkages to construct a pH- and reduction-responsive prodrug (HA-S-S-PPT). The micelles self-assembled from HA-S-S-PPT prodrug efficiently accumulated at tumor site due to HA receptor-mediated endocytosis . HA-S-S-PPT micelles exhibited 33.1% higher cumulative release than HA-NH-CO-PPT micelles (sensitive only to pH) owing to their dual responsiveness to pH and reduction. HA-S-S-PPT micelles achieved excellent antitumor activity in vivo , with the tumor inhibition rate reaching 92%, significantly higher than that of HA-NH-CO-PPT micelles (65%), and negligible systemic toxicity. This controllable-targeting nanoparticle system provides a potential platform for clinical application of PPT.
研究领域:
药物学
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癌症研究
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纳米技术
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药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
DRUG DELIVERY
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2017
·
IF 6.402
Jian Hou,E. Sun,Zhen-Hai Zhang,Jing Wang,Lei Yang,Li Cui,Zhong-Cheng Ke,Xiao-Bin Tan,Xiao-Bin Jia,Huixia Lv
The aim of this study was to establish a paclitaxel (PTX)-loaded mixed micelle delivery system (PTX-TP-M) with vitamin E-TPGS (TPGS) and Plasdone®S-630 Copovidone (PVPS630) as carriers to improve the solubility, oral absorption, and anti-tumor activity of PTX against lung cancer. In this study, PTX-TP-M was prepared using the ethanol thin-film dispersion method followed by characterization of the binary mixed micelles system. The average size of the PTX-TP-M was 83.5 ± 1.8 nm with a polydispersity index of 0.265 ± 0.007 and the drug loading (DL%) and entrapment efficiency (EE%) were 3.09 ± 0.09% and 95.67 ± 2.84%, respectively, which contributed to a high solubility of PTX about 24947-fold increase in water (4.78 ± 0.14 mg/mL). In addition, TEM analysis showed that the PTX-TP-M appeared spherical in structure and was well dispersed without aggregation and adhesion. In vitro release studies showed that the PTX-TP-M displayed a sustained release compared to free PTX in the dialysis bag. The efflux ratio of PTX reduced from 44.83 to 3.52 when formulated as PTX-TP-M; a 92.15% reduction, studied using the Caco-2 monolayer model. The oral bioavailability of PTX also improved by 4.35-fold, suggesting that PTX-TP-M can markedly promote the absorption in the gastrointestinal tract. Using in vitro MTT assays, it was observed that cytotoxicity was markedly increased, and IC50 values of PTX-TP-M (3.14 ± 0.85 and 8.28 ± 1.02 μg/mL) were lower than those of PTX solution (5.21 ± 0.93 and 14.53 ± 1.96 μg/mL) in A549 and Lewis cell, respectively. In vivo anti-tumor studies showed that PTX-TP-M achieved higher anti-tumor efficacy compared with PTX in Lewis bared C57BL/6 mice. Furthermore, a gastrointestinal safety assay also proved the safety of PTX-TP-M. All results demonstrated that the PTX-TP-M exhibited great potential for delivering PTX with increased solubility, oral bioavailability, and anti-cancer activity and this binary mixed micelles drug delivery system has potential to be used clinically.
研究领域:
药学
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肿瘤学
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药物递送系统
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药代动力学
✓ 已验证
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2022
·
IF 6.978
Yuejia Ji,Yuxin Sun,Mingyang Hei,Di Cheng,Bin Wang,Yao Tang,Yun Fu,Weiping Zhu,Yufang Xu,Xuhong Qian
The balance between drug efficiency and its side effects on normal tissues is still a challenging problem to be solved in current cancer therapies. Among different strategies, cancer therapeutic methods based on nanomedicine delivery systems have received extensive attention due to their unique advantages such as improved circulation and reduced toxicity of drugs in the body. Herein, we constructed dual-responsive polymeric micelles DOX&ALS@MFM based on an upper critical solution temperature (UCST) polymer to simultaneously combine chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT). Amphiphilic block copolymer P(AAm-co-AN)-b-PEI-ss-PEG-FA with a critical point of 42 °C was able to self-assemble into polymeric micelles under physiological conditions, which further encapsulated anticancer drug doxorubicin (DOX) and photosensitizer ALS to obtain drug-loaded micelles DOX&ALS@MFM. Micelles aggregated at tumor sites due to folate targeting and an enhanced permeability retention (EPR) effect. After that, the high intracellular concentration of glutathione (GSH) and near-infrared (NIR) light prompted disassembly of the polymer to release DOX and ALS. ALS not only plays a role in PTT but also produces singlet oxygen, therefore killing tumor cells by PDT. Both in vitro and in vivo studies demonstrated the photothermal conversion and reactive oxygen species generation ability of DOX&ALS@MFM micelles, at the same time as the excellent inhibitory effect on tumor growth with NIR light irradiation. Thus, our research substantiated a new strategy for the biomedical application of UCST polymers in the cited triple modal tumor therapy.
研究领域:
纳米医学
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癌症治疗
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药物递送系统
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聚合物材料
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光疗
✓ 已验证
DOI
PubMed
高影响因子
Colloid and Interface Science Communications
·
2021
·
IF 4.914
Shuting Wang,Yu Fang,Zequn Zhang,Qiao Jin,Jian Ji
Because of the severe antibiotic resistance , photodynamic therapy is considered as a potent method for the treatment of bacterial infection with bare drug resistance. However, its therapeutic efficacy is not always satisfactory in practical treatment. In this study, pH-responsive prodrug micelles were prepared by conjugation of chlorin e6 to polyethylene glycol- b -poly(2-(hexamethyleneimino) ethyl methacrylate- co -aminoethyl methacrylate) for improving the antimicrobial activity of photodynamic therapy. The micelles were negatively charged in normal physiological environment, which was very important for long blood circulation. However, the micelles could turn to be positively charged in bacterial infection microenvironment and then adhere to negatively charged bacterial membranes, which could significantly improve their antibacterial activity against both methicillin-resistant Staphylococcus aureus and Escherichia coli after laser irradiation. The in vivo experiment showed excellent antibacterial effect of pH-sensitive micelles in a subcutaneous infection model. The micelles showed great potential in the photodynamic therapy of stubborn bacterial infections.
研究领域:
药学
·
生物医学工程
·
微生物学
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
AAPS PHARMSCITECH
·
2020
·Vol. 21
·期 6
·1-13
·
IF 2.401
Zhang Jisen,Su Meiling,Yin Zongning
Currently, there is no specific treatment for acute lung injury (ALI) in clinical practice. In order to efficiently and accurately treat ALI, the advantages of cationic carriers were combined to accelerate the cell uptake. Polycaprolactone-polyethylene glycol carrier (PCL-PEG-COOH, PPC) with good biocompatibility, polycaprolactone-polyethylmethacrylate cationic carrier (PCL-PDMAEMA, PCD), and polycaprolactone-polyethylene glycol carrier connected with high-affinity targeting peptide (Esbp) targeting inflammatory endothelial cells (PCL-PEG-Esbp, PPE) were used to construct the high-molecular polymer micelles (PCD/PPC/PPE). The particle size of the prepared DEX-loaded micelles was 130 ± 4.41 nm, and the Zeta potential was 28.3 ± 0.76 mV. The CMC value of the prepared polymer micelles was 0.643 μg/mL, and it was not easy to depolymerize in the blood circulation. Only about 40% DXM was released from the drug-loaded polymer micelles after 12 h compared with free DXM, indicating that the micelle material had a certain sustained-release performance in vitro release experiments. The safe concentration range of polymer was determined by biocompatibility test. It was recommended that the concentration of polymer micelles should not exceed 0.40 mg/mL to obtain a good compatibility in organisms. The results of cytotoxicity measurement showed that when the content of PCD increased to 50%, the concentration of blank micelles should not exceed 500 μg/mL and the concentration of DXM-loaded micelles should not be higher than 100 μg/mL. It was proved in the cell uptake experiment that the cation carrier of the micelles accelerated the cell uptake. The targeting ability of the targeted micelle group was higher compared with the non-targeted micelle group ( P < 0.01, **). Meanwhile, the targeting ability of the non-targeted micelle group was higher compared with the free group ( P < 0.001, ***). The targeting ability of the non-targeted micelle group was about 2.30 times and the targeted micelle group was about 3.16 times larger than that of the free group. It was also proved in the in vivo targeting experiments that the targeted micelles had a good targeting ability. The results of in vivo imaging of mice showed that the DXM of the micelle group gathered more in the lungs, and the micelle group had a better targeting ability compared with the free DID group. The order of lung targeting intensity was targeted micelles > non-targeted micelles >> free DID group. The targeting ability of polypeptide Esbp to ALI was confirmed. In conclusion, the prepared PCD/PPC/PPE polymer micelles had obvious in vitro and in vivo targeting ability and good biocompatibility. They could be used as a new targeted delivery system for the treatment of ALI in the future.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2020
·
IF 5.115
Yun-Chun Zhao,Hai-Li Zheng,Xiao-Rong Wang,Xiao-Ling Zheng,Yue Chen,Wei-Dong Fei,Yong-Quan Zheng,Wen-Xi Wang,Cai-Hong Zheng
Background Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N′,N′-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.Materials and Methods DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.Results In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100–120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX.Conclusion These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.
研究领域:
药剂学
·
皮肤病学
·
生物材料
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2019
·Vol. 19
·期 4
·1800364
·
IF 2.895
Yang Ming,Yao Xiao,Yuan Tian,Shaobing Zhou
Considerable efforts have been devoted to enhancing the cell penetration of nanoparticles by coating cell-penetrating peptides (CPPs) on the surface. However, the internalization mechanism for a CPP at different concentrations varies a lot. It is acknowledged that the mechanism is restricted to endocytic pathway at relatively low concentrations; however, direct translocation becomes dominant at high concentrations. This raises an interesting question on how the surface Tat coating density of the nanoparticles would influence their cell–membrane interaction and the consequent internalization behavior. This study systematically investigates the effect of Tat peptides on the internalization behavior of polymeric micelles by tuning surface Tat coating density, incubation concentrations, incubation time, and other factors using poly(ethylene glycol)–poly(ε-caprolactone) copolymer (PEG-PCL) micelles. It is found that both energy-dependent and energy-independent pathways are involved in the cellular uptake process, and the Tat-conjugated polymeric micelles strongly accumulated on the cell surface at initial stage. The membrane-anchoring and internalization rate increase with the increasing Tat coating density. Furthermore, the increasing of Tat coating density accelerates the energy-independent pathway. It is envisioned that this finding will further shed light on the surface modification of nanoparticles for enhanced cell penetration and direct translocation into cell cytoplasm.
研究领域:
生物医学工程
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药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2011
·Vol. 11
·期 11
·1570-1578
·
IF 3.458
Taihang Li,Ruiyan Han,Mingzhe Wang,Changbai Liu,Xiabin Jing,Yubin Huang
PEG-PLA copolymers with dumbbell- and Y-shaped structures are prepared. They can self-assemble from nanoparticles to micro-sized fusiform micellar particles in aqueous solution. In particular the micelles formed by the (PLA) 2 -PEG-(PLA) 2 particles show a better drug loading capacity and encapsulation efficiency than those formed by linear MPEG-PLA. In vitro studies show that the particles formed by Y-shaped copolymers show a particularly quick drug release. The copolymers have good biocompatibility with low cytotoxicity. These unique self-assembled systems thus have many possible biomedical applications, such as a sustained delivery of high-dosed water insoluble drugs, quick effective drugs for trauma, controlled delivery of the oral-administration drugs, and so forth.
研究领域:
生物材料学
·
药剂学
·
生物医药工程
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
·
2016
·
IF 2.101
Zhang Jing,Li Mengfei,Yuan Zhefan,Wu Dan,Chen Jia-da,Feng Jie
Abstract A novel type of stepwise-activable multifunctional peptide-guided prodrug micelles (MPPM) was fabricated for cancerous cells intracellular drug release. Deca-lysine sequence (K 10 ), a type of cell-penetrating peptide, was synthesized and terminated with azido-glycine. Then a new kind of molecule, alkyne modified doxorubicin (DOX) connecting through disulfide bond (DOX-SS-alkyne), was synthesized. After coupling via Cu-catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry reaction, reduction-sensitive peptide-guided prodrug was obtained. Due to the amphiphilic property of the prodrug, it can assemble to form micelles. To prevent the nanocarriers from unspecific cellular uptake, the prodrug micelles were subsequently modified with 2,3-dimethyl maleic anhydride to obtain MPPM with a negatively charged outer shell. In vitro studies showed that MPPM could be shielded from cells under psychological environment. However, when arriving at mild acidic tumor site, the cell-penetrating capacity of MPPM would be activated by charge reversal of the micelles via hydrolysis of acid-labile β -carboxylic amides and regeneration of K 10 , which enabled efficient internalization of MPPM by tumor cells as well as following glutathione- and protease-induced drug release inside the cancerous cells. Furthermore, since the guide peptide sequences can be accurately designed and synthesized, it can be easily changed for various functions, such as targeting peptide, apoptotic peptide, even aptamers, only need to be terminated with azido-glycine. This method can be used as a template for reduction-sensitive peptide-guided prodrug for cancer therapy. Graphical abstract A novel type of stepwise-activable multifunctional peptide-guided prodrug micelles (MPPM) was fabricated for selective drug delivery in cancerous cells. MPPM could be shielded from cells under psychological environment. However, when arriving at mild acidic tumor site, the cell-penetrating capacity of MPPM would be activated by charge reversal of the prodrug micelles via hydrolysis of acid-labile β -carboxylic amides and regeneration of K 10 . The cell-penetrating peptide, K 10 , would enable efficient internalization of MPPM by tumor cells, and the drug would be rapidly released induced by concentrated glutathione and numerous proteases inside the cancerous cells, resulting in the inhibited effect of the cells .
研究领域:
药学
·
癌症研究
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
BIOMACROMOLECULES
·
2016
·
IF 5.583
Yuejing Xi,Tao Song,Songyao Tang,Nuosha Wang,Jianzhong Du
Traditional antibiotics usually sterilize in chemical ways, which may lead to serious drug resistance. By contrast, peptide-based antibacterial materials are less susceptible to drug resistance. Herein we report the preparation of an antibacterial peptide-based copolymer micelle and the investigation of its membrane-penetration antibacterial mechanism by transmission electron microscopy (TEM). The copolymer is poly(l-lactide)-block-poly(phenylalanine-stat-lysine) [PLLA31-b-poly(Phe24-stat-Lys36)], which is synthesized by ring-opening polymerization. The PLLA chains form the core, whereas the polypeptide chains form the coronas of the micelle in aqueous solution. This micelle boasts excellent antibacterial efficacy against both Gram-positive and Gram-negative bacteria. Furthermore, TEM studies clearly reveal that the micelles pierce and then destroy the cell membrane of the bacteria. We also compared the advantages and disadvantages of two general methods for measuring the Minimal Inhibitory Concentration (MIC) values of antibacterial micelles. Overall, this study provides us with direct evidence for the antibacterial mechanism of polypeptide-based micelles and a strategy for synthesizing biodegradable antibacterial nanomaterials without antibiotic resistance.
研究领域:
生物材料学
·
微生物学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2018
·
IF 13.709
Xuanrong Sun,Guowei Wang,Hao Zhang,Shiqi Hu,Xin Liu,Jianbin Tang,Youqing Shen
Polymer micelles are one of the most investigated nanocarriers for drug delivery; many have entered clinical trials and some are in clinic use, but their delivery systems have not yet shown the expected high therapeutic efficacy in clinics. Further understanding their in vivo behaviors, particularly how quickly and by what mechanism polymer micelles are cleared (i.e., via micelles or unimers) once injected, is key to solving this dilemma. Herein, we hope to answer these questions for the clinically relevant polyethylene glycol-block-poly(ε-caprolactone) (PEG-PCL) and PEG-block-poly(d,l-lactide) (PEG-PDLLA) micelles. A small fraction of the hydrophobic chain ends was conjugated with a pair of fluorescence resonance energy transfer (FRET) dyes, Cy5 and Cy5.5, and used to fabricate FRET micelles whose FRET efficiency was correlated to the percentage of polymer chains in the micelles, the micelle degree. In vitro, serum proteins induced PEG-PCL micelle dissociation to some extent; mouse serum or blood surprisingly did not induce micelle dissociation but once with shear applied by a microfluidic channel caused most PEG-PCL micelles dissociated. After intravenous administration in mice, the PEG-PCL or PEG-PDLLA micelles were quickly sequestered into the liver as unimers, and the micelle degree in the blood quickly decreased to about 20%. The FRET-imaging experiments showed that in blood vessels the micelles quickly dissociated into unimers, which were found associated with albumin in blood and in liver. Thus, it is concluded that, upon intravenous injection, the shear and the bloodborne proteins (particularly albumin) induced the most (∼80%) PEG-PCL and PEG-PDLLA micelles to quickly dissociate into unimers, which were sequestered by Kupffer cells, while intact micelles were difficult to clear. These micelles were able to penetrate tumors and were very stable with cell membranes, but dissociated gradually inside cells. These findings on in vivo micelle fate and the clearance mechanism are directional for the rational design of polymer micelles for improved therapeutics; particularly, improving micelle stability in blood is the prerequisite for surface functionalizations such as introducing targeting ligands.
研究领域:
药剂学
·
生物医学工程
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2018
·
IF 4.37
Xin Jin,Qing Yang,Ning Cai
Introduction Ginsenoside compound K (CK) has effects on cell-cycle regulation, tumor growth inhibition, and apoptosis induction. However, it has limited applications in clinical settings because of its low solubility and poor absorption. Methods To overcome these limitations, we aimed to develop a mixed micellar system composed of phosphatidylcholine (PC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol 2000 (DSPE PEG 2000; DP). CK encapsulated in PC/DP mixed micelles had enhanced solubility, permeability, and retention effects. Results Compared to free CK, the CK PC/DP micellar system exhibited improved anticancer effects in vitro, including cell-cycle arrest, apoptosis, and anti-invasion in human lung carcinoma A549 cells. The significant proapoptotic effect was reflected by increased chromosomal condensation, annexin V/propidium iodide staining, and related protein expression. In vitro cellular uptake and optical mouse imaging in vivo suggested that the improved antitumor effect was caused primarily by enhanced uptake and tumor targeting. Furthermore, an in vivo antitumor efficacy study indicated that the CK mixed micelles significantly inhibited tumor growth, thereby decreasing tumor volume at the end of the experiment as compared with that in the control mice. Histological analysis confirmed the antitumor effect with low toxicity. Conclusion The PC/DP micellar system was an effective drug delivery system for CK in tumor therapy.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）