JOURNAL OF DRUG TARGETING
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2026
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IF 4.7
Pingping Zhao,Wenhao Yuan,Yuhong Xu,Caifei Jin,Chu Chu,Yan Yang
The transdermal delivery of poorly water-soluble drugs is limited by low aqueous solubility and the stratum corneum permeability barrier. In this study, curcumin was formulated into self-assembled micelles using Tween 20 and polyethylene glycol 400, which exhibited a particle size of 12.5 nm, a zeta potential of −12.5 mV, and a 170-fold increase in solubility. The curcumin micelles (CM) were combined with constant-current iontophoresis (0.45 mA/cm2), to investigate the synergistic enhancement effects and underlying mechanisms. The results showed a 44.2-fold increase in cumulative release over 60 min, with a linear flux–current density relationship (R2 = 0.99). CM exhibited electro-responsive release with an approximate 20-min lag. Under a fixed 2 h total stimulation, pulsed current (4 pulses) nearly doubled the 8-h cumulative release compared to continuous current. Furthermore, both current density and electrode configuration were shown to influence penetration depth and width. Iontophoresis enabled CM to penetrate rat skin to a depth of 270 μm and increased intradermal retention by 258%. In a rat second-degree burn model, the combination therapy significantly accelerated wound healing via promoting angiogenesis, downregulating inflammatory cytokines, and enhancing collagen deposition.
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ACS Applied Nano Materials
·
2023
·
IF 5.9
Jiaojiao Chen,Yarong Song,Wenqian Yang,Jianhui Guo,Saihui Zhang,Dong Wan,Yonghui Liu,Jie Pan
Chemotherapy remains the primary treatment for cancer; however, conventional chemotherapeutic drugs have several shortcomings, including poor solubility, lack of targeting, low bioavailability, and high toxicity to healthy tissues. In order to overcome these limitations, drug delivery systems (DDS) have emerged as a promising alternative. In this study, we synthesized TPGS3350-PVGLIG-SS-DOX polymeric micelles that incorporate both extracellular MMP2/9 enzyme response and intracellular reduction response at a nanoscale level. The micelles remained stable throughout the blood circulation and only aggregated at the tumor sites, thanks to the enhanced permeability and retention (EPR) effect. Moreover, the tumor tissue showed a high expression of MMP2/9 enzymes, which resulted in the cleavage of the PVGLIG peptide sequence, ultimately leading to an improved phagocytosis efficiency. Under the action of high intracellular GSH concentration, the disulfide bond was broken and DOX was released to induce tumor cell death. The TPSD&D micelles exhibited good tumor inhibitory activity in vivo and significantly reduced toxic side effects on normal tissues. Our work provides a simple method to assemble tumor-targeted prodrug micelles to improve cancer therapy, which holds potential for clinical applications in antitumor therapy.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
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IF 5.8
Jinyu Liu,Yanhao Zhang,Chao Liu,Yuhao Jiang,Zihao Wang,Xinsong Li
Polypeptides are a highly promising carrier for delivering hydrophobic drugs, due to their excellent biocompatibility , non-toxicity, and non-immunogenicity. Herein, a redox and pH dual-responsive poly(ethylene glycol)-SS-b-polypeptide micelles encapsulated with disulfide bridged paclitaxel-pentadecanoic acid prodrug was developed for cancer chemotherapy . First of all, disulfide bridged paclitaxel-pentadecanoic acid prodrug (PTX-SS-COOH) and poly(ethylene glycol)-SS-b-polylysine-b-polyphenylalanine (mPEG-SS-b-PLys-b-PPhe, ESLP) were synthesized and confirmed via NMR, MS, FT-IR or GPC. After that, PTX-SS-COOH (PSH) embedded mPEG-SS-b-PLys-b-PPhe (ESLP/PSH) micelles were prepared by mixing method based on electrostatic interactions and hydrophobic forces. For comparison, mPEG-b-PLys-b-PPhe (ELP) was mixed with PTX-SS-COOH to generate another kind of micelles (ELP/PSH). The characterization of ESLP/PSH micelles through dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed a spherical structure with a diameter of approximately 170 nm . It is noteworthy that ESLP/PSH micelles displayed a high drug-loading rate of 22.84%, and excellent stability, which can be attributed to the specific interactions between the prodrug and copolymer . Drug release analysis demonstrated that the micelles exhibited a substantial release of PTX in the presence of GSH at pH 5.0, indicating a pH and redox dual responsiveness. In vivo pharmacokinetic study revealed the ESLP/PSH micelles had increased bioavailability and an extended circulation time. Ultimately, antitumor efficacy and systemic toxicity evaluation in 4 T1 tumor-bearing mice confirmed that ESLP/PSH micelles achieved the highest level of tumor growth inhibition (ca. 83%) and the lowest systemic toxicity in comparison with ELP/PSH micelles and commercialized Taxol®. Taken together, the dual responsive micelles represent a promising PTX formulation with potential clinical application in cancer chemotherapy.
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AAPS PHARMSCITECH
·
2023
·Vol. 24
·期 2
·1-16
·
IF 3.3
Wu Wenting,Ding Quan,Zhou Zhiwei,Kuang Wenliang,Jiang Lipeng,Liu Peng,Ai Weiping,Zhu Weifeng
In order to better promote the application of the polymeric mixed micelles (PMMs) in oral delivery, in addition to focusing on the improvement of micellar structural stability, it is necessary to obtain the absorption characteristics of the intact micellar particles. In this work, the transport behavior across Caco-2 cells of FS/PMMs composed of Pluronic F127 and Solutol HS15 was tracked by encapsulating an environment-responsive probe into the particles. The specific property of the probe is the water-initiated aggregation-caused quenching (ACQ) ability, by which integral particles can be identified accurately. The influence of polymeric ratios (FS) on the transcellular behavior of FS/PMMs was explored and the single pass intestinal perfusion experiment was used to further illustrate it. Moreover, pharmacokinetics parameters were detected to analyze the relationship among FS ratios, transport behavior, and pharmacokinetic parameters. FS ratios were found to hardly affect the endocytosis pathways and intracellular itinerary of FS/PMMs, but do affect the proportion of each path. FS/PMMs with high HS15 content, namely System-I, were found to primarily undergo receptor-mediated endocytosis pathway and be less susceptible to lysosomal degradation, which would lead to more absorption and higher Cmax and AUC than drug suspension. In contrast, despite System-II with high F127 content cannot contribute to drug plasma concentration, it can prolong the in vivo retention time. These findings provided evidence for the role of polymeric ratios in modulating the transcellular absorption and pharmacokinetic parameters of the drug-loaded PMMs, and would be a step forward in helping PMMs’ design to enhance oral drug delivery. Graphical Abstract
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International Journal of Nanomedicine
·
2023
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IF 8
Yanhai Xi,Tingwang Jiang,Yinglan Yu,Jiangmin Yu,Mintao Xue,Ning Xu,Jiankun Wen,Weiheng Wang,Hailong He,Yan Shen,Daquan Chen,Xiaojian Ye,Thomas J Webster
Introduction Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity.Methods The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied.Results The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR.Conclusion The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.
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Drug Design Development and Therapy
·
2023
·
IF 4.8
Qin Guo,Jie Cai,Pengyu Li,Dongling Xu,Xiaomin Ni,Hui Wen,Dan Liu,Suizhen Lin,Haiyan Hu
Androst-3β,5α,6β-triol (Triol) is a promising neuroprotective agent, but its poor solubility restricts its development into parenteral preparations. In this study, Triol is significantly solubilized by bile salt/phosphatidylcholine mixed micelles (BS/PC-MM). All BS/PC-MM systems are tested to remarkably improve the drug solubility with various stabilities after drug loading. Among them, the sodium glycocholate (SGC)/egg phosphatidylcholine (EPC) system with 2:1 ratio in weight and the total concentration of SGC and EPC of 100 mg/mL is proved to produce stable mixed micelles with high drug loading. It is found that the stability of drug-loaded mixed micelles is quite different, which might be related to the change in critical micelle concentration (CMC) after incorporating drugs. SGC/EPC and SGC/soya phosphatidylcholine (SPC) remain transparent under accelerated conditions and manifest a decreased CMC (dropping from 0.105 to 0.056 mg/mL and from 0.067 to 0.024 mg/mL, respectively). In contrast, swine bile acid-sodium salt (SBA-Na)/PC and sodium deoxycholate (SDC)/PC are accompanied by drug precipitation and reached the maximum CMC on the first and the third days, respectively. Interestingly, the variation of CMC under accelerated testing conditions highly matches the drug-precipitating event in the primary stability experiment. In brief, the bile salt/phosphatidylcholine system exists as a potential strategy of improving sterol drug solubility. CMC variation under accelerated testing conditions might be a simple and easy method to predict the stability of drug-loaded mixed micelles.
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Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Liu Zhanbiao,Chen Xuejun,Jin Qian,Li Min,Zhu Siqing,Zhang Yi,Zhi Defu,Zhao Yinan,Li Liqin,Zhang Shubiao
Although many carriers for the delivery of chemotherapeutic drugs have been investigated, the disadvantages of passive targeting and uncontrolled drug release limit their utility. Herein, hyaluronic acid (HA) was hydrophobically modified to serve as a carrier for binding to cluster determinant 44 (CD44) overexpressed on tumor cell surfaces. Specifically, after deacetylation, HA was grafted to dodecylamine or tetradecylamine to afford amphiphilic zwitterionic polymer micelles, designated dHAD and dHAT, respectively, for the delivery of paclitaxel (PTX). The micelles were negatively charged at pH 7.4 and positively charged at pH 5.6, and this pH sensitivity facilitated PTX release under acidic conditions. The cell uptake efficiencies of the dHAD-PTX and dHAT-PTX micelles by MCF-7 cells after 4 h of incubation were 96.9% and 95.4%, respectively, and their affinities for CD44 were twice that of HA. Furthermore, the micelles markedly inhibited tumor growth both in vitro and in vivo, with IC50 values of 1.943 μg/mL for dHAD-PTX and 1.874 μg/mL for dHAT-PTX for MCF-7 cells; the tumor inhibition rate of dHAD-PTX (92.96%) was higher than that of dHAT-PTX (78.65%). Importantly, dHAD and dHAT micelles showed negligible systemic toxicity. Our findings suggest that these micelles are promising delivery vehicles for antitumor drugs.
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Nanomedicine-Nanotechnology Biology and Medicine
·
2023
·
IF 5.4
Chunjing Guo,Min Cao,Ningning Diao,Wenxin Wang,Hongxu Geng,Yanguo Su,Tianying Sun,Xinyue Lu,Ming Kong,Daquan Chen
Diabetic nephropathy (DN) is an important complication of diabetes and is the main cause of end-stage renal disease. The pathogenesis of DN is complex, including glucose and lipid metabolism disorder , inflammation, and so on. Novel hybrid micelles loaded Puerarin (Pue) based on Angelica sinensis polysaccharides (ASP) and Astragalus polysaccharide (APS) were fabricated with pH-responsive ASP-hydrazone-ibuprofen (BF) materials (ASP-HZ-BF, SHB) and sialic acid (SA) modified APS-hydrazone-ibuprofen materials (SA/APS-HZ-BF, SPHB) by thin-film dispersion method. The SA in hybrid micelles can specifically bind to the E -selectin receptor which is highly expressed in inflammatory vascular endothelial cells . The loaded Pue could be accurately delivered to the inflammatory site of the kidney in response to the low pH microenvironment . Overall, this study provides a promising strategy for developing hybrid micelles based on natural polysaccharides for the treatment of diabetic nephropathy by inhibiting renal inflammatory reactions, and antioxidant stress.
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2023
·
IF 4.6
Dan Shen,Tingyu Jin,Yin Xiao,Xingyi Zhu,Yunfen Hua
Pazopanib (PZ) is a multikinase inhibitor, which is mainly used in the treatment of soft tissue sarcoma and advanced renal cancer. However, because of its water insolubility, oral bioavailability is poor. At the same time, photo lability and high dose oral administration lead to severe hepatotoxicity, which is limited in clinical application. In this paper, the novel pazopanib-fumarate disodium glycyrrhizinate nanocrystalline micelles are successfully prepared by liquid-assisted ball milling. The prepared cocrystals and nanocrystalline micelle structures are systematically characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectrometer (FTIR) analysis. In vitro solubility and dissolution experiments show that the solubility and dissolution of nanocrystalline micelles are significantly improved under different simulated physiological conditions. The accelerated stabilization experiments show that the nanocrystalline micelles have good physical and chemical stability and showed excellent stability in water (Zeta potential was 62.39 mV). In addition, the in vivo bioavailability of nanocrystalline micelles is 3 times higher than that of PZ, and the therapeutic threshold (> 20 μg/mL) is up to 30 h. This new strategy provides a feasible solution to the undesirable properties of PZ.
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CARBOHYDRATE POLYMERS
·
2022
·
IF 10.723
Yang Li,Qunyu Gao
A new micellization method was applied to produce the nano octenyl succinic anhydride (OSA) modified starch micelles with controllable size. The underlying mechanism was explored by using Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), zeta-potential, surface tension, fluorescence spectra and transmission electron microscope (TEM). Due to the new starch modification method, the electrostatic repulsion between the deprotonation carboxyl groups prevented the aggregation of starch chains. With the progress of protonation , the weaken electrostatic repulsion and enhanced hydrophobic interaction driven the self-assembly of micelles. The size of micelles increased gradually with the increase of the protonation degree (PD) and concentration of OSA starch. However, a V-shaped trends were observed in the size as the increase of substitution of degree (DS). Curcuma loading test indicated that micelles had good encapsulated capability and the maximum value was 52.2 μg/mg. The understanding of the self-assembly behavior of OSA starch micelles can facilitate and improve the starch-based carrier designs used to synthesis complex and smart micelle delivery system with good biocompatibility.
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AAPS PHARMSCITECH
·
2022
·Vol. 23
·期 7
·1-13
·
IF 4.026
Cao Xia,He Qing,Adu-Frimpong Michael,Shen Xinyi,Rong Wanjing,Li Xiaoxiao,Zhang Jian,Xia Xiaoli,Shi Feng,Ji Hao,Toreniyazov Elmurat,Wang Qilong,Yu Jiangnan,Xu Ximing
Pinocembrin (PCB) is 5,7-dihydroxyl flavanone and has multiple pharmacological activities, namely, anti-inflammation, anti-osteoporotic, and so on. However, low water solubility and bioavailability have hindered its application. Herein, we aimed to increase its bioavailability through preparation of F127/MPEG-PDLLA polymer micelles (PCB-M). We characterized the micelles through appropriate attributes such as analysis of particle size (PS), polydispersity (PDI), transmission electron microscopic (TEM) image, stability test, and evaluation of in vitro release of drug. After physical characterization, the respective PS, PDI, and entrapment efficiency (EE) of PCB-M were estimated to be 27.63 ± 0.17 nm, 0.055 ± 0.02, and 90.53 ± 0.01%. Fluorescence probe method was employed to measure critical micelle concentration (CMC) of PCB-M, we observed CMC was low, thereby suggesting that PCB-M had good stability. In vitro release analysis indicated that the rate of cumulative PCB release from PCB-M was greater than 90% in each medium compared with free PCB, which was less than 40%, thus pointing to a significantly improved solubility of PCB. In vivo pharmacokinetic results showed that oral biological availability of PCB-M increased 5.3 folds comparable to free PCB. The effects of PCB on osteoblasts and ALP activities were investigated; subsequently, zebrafish osteoporotic model was established with prednisolone to study the anti-osteoporotic effects of PCB and PCB-M. The results showed that PCB improved osteoporosis with PCB-M being more effective than free PCB. Finally, PCB-M can be used as a promising method to improve the solubility of PCB, while the bioavailability and anti-osteoporotic effect of PCB could be improved, thus laying a foundation for clinical use in the future. Graphical Abstract
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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.
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