Acta Biomaterialia
·
2016
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IF 6.008
Zhoujiang Chen,Nan He,Maohua Chen,Long Zhao,Xiaohong Li
Micelles self-assembled from drug-conjugated polymers indicate advantages in alleviating the premature release before reaching the intended site. Hyaluronic acid (HA) is known to specifically bind with a transmembrane glycoprotein CD44 , overexpressed in many types of cancerous cells, and can also be served as micelle carriers. However, an excess amount of drug conjugation to HA backbone may be detrimental to the receptor-mediated cellular uptake. Up to now, the effect of conjugation densities of drugs has never been determined on the physical properties and biological performance of resulting micelles. In the current study, camptothecin (CPT) was conjugated on HA through 3,3′-dithiodipropionic acid to self-assemble into reduction-sensitive micelles. The substitution degrees of CPT on HA backbone were tuned from around 4–20%, to clarify the effects on the cellular uptake efficiency and cytotoxicities of micelles, as well as the tumor accumulation and antitumor efficacy. The CPT substitution degree of around 15% on HA resulted in micelles with a higher cytotoxicity to 4T1 cells and achieved a better balance between the cellular uptake and reduction-triggered drug release, compared with other micelles. In contrast to a fast kidney clearance and an even distribution in major organs after intravenous injection of free CPT, the optimized micelles were accumulated in tumors, livers and lungs. The micelle content indicated a significant decrease in livers after 24 h, while that in tumors displayed a significant increase to 4.9% of the injection dose. The tumor accumulation of micelles led to strong tumor suppression with minimal systemic toxicity. The in situ tumor inhibition and the accumulation of micelles in liver and lungs inhibited tumor metastasis to these tissues. It demonstrates a feasible strategy to develop drug-HA conjugate micelles with a concise and tunable structure for tumor targeting and reduction-triggered release. Statement of Significance Hyaluronic acid (HA) can be served as micelle carriers and targeting ligands to tumor cells. However, the effects of drug conjugation densities on the physical profile and biological performance of resulting micelles have never been investigated. In the current study, camptothecin is conjugated on HA with reduction-sensitive linkers, and the substitution degrees of camptothecin on HA backbone vary from around 4–20%. The micelles with a substitution degree of around 15% achieve a better balance between the cellular uptake and reduction-triggered drug release and a higher cytotoxicity than others. It demonstrates a feasible strategy to develop drug-HA conjugate micelles with a concise and tunable structure for tumor targeting and reduction-triggered release.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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DOI
PubMed
高影响因子
AAPS PHARMSCITECH
·
2022
·Vol. 24
·期 1
·1-14
·
IF 4.026
Wang Xiaoling,Du Jiangyue,Zhou Feng,Ye Qing,Chen Ying,Sun Dujuan,Chen Haimin,Lv Yuanyuan,Sun Xiaoyi
Adequate delivery of therapeutic agents to their intended molecular targets is crucial in tumor therapy. Versatile drug carriers need to overcome the challenges coming from the systemic circulation, membrane barriers, and endo-lysosomal degradation. Herein, hyaluronic acid-conjugated polydopamine (HA-PDA)-shelled mesoporous silica nanoparticles encapsulated with doxorubicin (MSNs-DOX) were successfully fabricated for targeted tumor therapy. Compared with reported studies focusing on the pH-sensitive release in tumors, we especially revealed the significant role of lysosomal release in DOX nuclear accumulation. After active targeting and CD44-mediated endocytosis in tumor cells, the PDA layer of the nanoparticles would be peeled off to trigger drug release owing to MSNs gatekeeper in acidic lysosomes. Subsequently, DOX molecules passively diffused into nuclei. The intracellular DOX transportation was evidenced by DOX accumulation in nuclei, lysosomal location of nanoparticles, and lysosome acidification inhibition test. After discharging of the cargoes from nanoparticles, PDA shells from residual nanoparticles were able to produce localized hyperthermia under NIR irradiation entrapped in lysosomes, inducing synergistic chemo-photothermal effect. Under NIR treatment, HA-PDA@MSNs-DOX presented a prominent tumor inhibition rate without obvious side effects. This study indicated the potent nuclear delivery and synergetic chemo-photothermal therapy achieved by HA-PDA-shelled MSNs. Graphical Abstract
研究领域:
癌症治疗
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纳米医学
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2022
·
IF 5.999
Yuhui Wang,Shilong Ma,Xuanyu Liu,Yan Wei,Haofeng Xu,Ziwei Liang,Yinchun Hu,Xiaojie Lian,Di Huang
Hepatocellular carcinoma (HCC) is one of the deadliest tumors in the world with a high rate of recurrence and metastasis. Therefore, the most pressing issue today is the development of new drugs, diagnostic and therapeutic approaches for effective cancer treatment. Cancer stem cells (CSCs) play a pivotal role in tumor recurrence, tumor resistance, and tumor metastasis, which provides a new perspective on the development of liver cancer. In the study, a high-temperature thermal breakdown approach was used to create composite magnetic nanocubes modified by polyethyleneimine (PEI) and hyaluronic acid (HA). The Fe 3 O 4 nanocubes can recognize HCC stem cells via receptor−ligand binding of HA and CD44 (HA receptor). While loading a small molecule LDN193189 inhibited the expression of stemness-related genes OCT4 and Nanog . More crucially, the Fe 3 O 4 nanocubes significantly suppressed HCC cell proliferation and migration by regulating the expression of epithelial-mesenchymal transition (EMT) process markers E-cadherin, Vimentin , and N-cadherin. Dual targeting using magnetic and receptor-mediated targeting improved the uptake of the drug delivery system. Our findings imply that the medication delivery method might be a potential therapeutic strategy for HCC.
研究领域:
癌症生物学
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纳米技术
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR CHEMISTRY AND PHYSICS
·
2023
·
IF 2.5
Xiupeng Zhong,Gangyuan Bi,Hai Yang,Ying Liu,Qi Zhao,Wenjing Song,Sa Liu,Renjian Xie,Li Ren
Cartilage repair is currently an inevitable and significant issue due to the prevalence of cartilage defects or osteoarthritis. However, it remains a big challenge worldwide because of the avascular and aneural nature of cartilage. In this paper, a novel biomimetic pericellular microniche (BPM), inspired by chondron composed of chondrocyte and its surrounding pericellular matrix (PCM), is proposed to offer a promising solution to achieve cartilage repair. BPM, with a diameter ≈64 µm, not only mimicked the structure of the chondron but also mimicked the key components of the PCM by artificially synthesizing brush-like molecules (HA/PA and HA/PM). Chondrocyte-laden BPM is constructed successfully through microfluidic and showed excellent injectability. The encapsulated chondrocyte showed high viability in BPM. F-Actin and H&E reflected that chondrocytes would grow out of BPM and adhere to the BPM surface through the interaction between CD44 and hyaluronic acid. RT-qPCR and immunofluorescence staining indicated that the gene expression of type II collagen and aggrecan are upregulated significantly in the BPM. Therefore, the construction of BPM provides a promising strategy for cartilage tissue engineering. This article is protected by copyright. All rights reserved
研究领域:
组织工程
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生物医学工程
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再生医学
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材料科学
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产品关联
DOI
高影响因子
POLYMERS FOR ADVANCED TECHNOLOGIES
·
2023
·Vol. 34
·期 7
·2340-2354
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IF 3.4
Ping Zhang,Chaoqun Zhang,Jie Song,Shuxin Wang,Qian Li,Feng Su,Suming Li
A novel nanoprobe was developed for the detection of hyaluronidase as cancer marker, using fluorescein 5-isothiocyanate (FITC) as fluorescence indicator, hyaluronic acid (HA), and polyethyleneimine (PEI) functionalized graphene oxide (GO) as quencher. PEI was attached to GO through amide bonding, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N -hydroxysuccinimide (NHS) as coupling agents. Aminated hyaluronic acid (HA) was then linked to GO-PEI (GOP) via the same route. Nuclear magnetic resonance, ultraviolet–visible–near infrared spectroscopy, Fourier transform infrared spectroscopy, scanning electron microscope, and thermogravimetric analysis analyses confirmed the successful synthesis of GOP-HA. Finally, FITC was attached to GOP-HA through reaction between the isothiocyanate group of FITC and the amine group of aminated HA. The fluorescence of FITC is quenched in the resulted GOP-HA-FITC nanoprobe. Addition of hyaluronidase can cleave HA chains into small fragments, releasing FITC to emit fluorescence. Importantly, the nanoprobe is highly sensitive and selective, and can enter cells by specifically binding to the CD44 receptor on the surface of Hela cells. Therefore, GOP-HA-FITC nanoprobe could be used in targeted tumor cell imaging for the early diagnosis of cancers.
研究领域:
纳米技术
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生物医学工程
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癌症研究
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分子生物学
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材料科学
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产品关联
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2023
·
IF 5.8
Ziwei Liang,Yuhui Wang,Jiapu Wang,Tao Xu,Shilong Ma,Qi Liu,Liqin Zhao,Yan Wei,Xiaojie Lian,Di Huang
Ferroptosis is a novel form of regulated cell death induced by iron-dependent lipid peroxidation imbalance. It has emerged as a promising antitumor therapeutic strategy in recent years. In this work, we successfully synthesized a complex magnetic nanocube Fe 3 O 4 modified with PEI and HA by the thermal decomposition method. While loading a ferroptosis inducer RSL3 inhibited cancer cells through the ferroptosis signal transduction pathway. The drug delivery system could actively target tumor cells through an external magnetic field and HA-CD44 binding. Zeta potential analysis showed that Fe 3 O 4 [email protected] nanoparticles were more stable and uniformly dispersed in tumor acidic environment. Moreover, cellular experiments demonstrated that Fe 3 O 4 [email protected] nanoparticles could significantly inhibit the proliferation of hepatoma cells without a cytotoxic effect on normal hepatic cells. In addition, Fe 3 O 4 [email protected] played a vital role in ferroptosis by accelerating ROS production. The expression of ferroptosis-related genes Lactoferrin, FACL 4, GPX 4 and Ferritin was significantly suppressed with increasing treatment of Fe 3 O 4 [email protected] nanocubes. Therefore, this ferroptosis nanomaterial has great potential in Hepatocellular carcinoma (HCC) therapy.
研究领域:
纳米技术
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癌症生物学
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药学
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分子生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Han Yu,Na Ning,Fujin He,Jiao Xu,Han Zhao,Shaofeng Duan,Yunqi Zhao
Background Targeted delivery systems have been developed to improve cancer treatment by reducing side effects and enhancing drug efficacy. Geraniol, a natural product, has demonstrated promising anti-cancer effects in various cancer types, including prostate cancer, which is the most commonly diagnosed cancer in men. Hyaluronic acid (HA), a natural carrier targeting CD44-positive prostate cancer cells, can be utilized in a targeted delivery system.Purpose This study investigated the efficacy of a conjugate of HA and geraniol linked via a disulfide bond linker (HA-SS-Geraniol) in prostate cancer.Materials and Methods The cytotoxicity of HA-SS-Geraniol was evaluated on human PC-3 prostate cancer cells. Flow cytometry was used to assess its effects on mitochondrial membrane potential, apoptosis, and cell cycle arrest. Additionally, proteomic analysis was conducted to explore the underlying mechanism of action induced by HA-SS-Geraniol treatment. A subcutaneous xenograft tumor model was established in nude mice to evaluate the toxicity and efficacy of HA-SS-Geraniol in vivo.Results The results demonstrated that HA-SS-Geraniol exhibited potent cytotoxicity against PC-3 prostate cancer cells by inducing mitochondrial membrane potential loss and apoptosis in vitro. The proteomic analysis further supported the hypothesis that HA-SS-Geraniol induces cell death through mitochondria-mediated apoptosis, as evidenced by differential protein expression. The in vivo mouse model confirmed the safety of HA-SS-Geraniol and its ability to inhibit tumor growth.Conclusion HA-SS-Geraniol holds promise as a biologically safe and potentially effective therapeutic agent for prostate cancer treatment. Its targeted delivery system utilizing HA as a carrier shows potential for improving the efficacy of geraniol in cancer therapy.
研究领域:
癌症研究
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药学
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分子生物学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Xin Yu Liu,He Ying Mao,Shuai Hong,Cheng-Hua Jin,Hu-Lin Jiang,Ming Guan Piao
Alcoholic liver injury stands as a predominant pathogenic contributor to the global burden of liver diseases, with alcohol consumption serving as a significant determinant of worldwide morbidity and mortality. Given that liver-targeted therapy for mitigating alcoholic liver injury remains to be a major clinical challenge due to the poor specificity and instability associated with single targeting modification in actively targeted nanomedicine systems, bifunctional targeting modification may serve as a more promising strategy. Here, galactose-functionalized hyaluronic acid (Gal-HA) coated cationic solid lipid nanoparticles carrying silybin (Gal-HA/SIL-SLNPs) featuring dual-targeting hyaluronic acid (HA) and galactose (Gal) moieties, enabled specific liver surface targeting of asialoglycoprotein receptor (ASGPR) and cluster of differentiation 44 (CD44) proteins to enhance silybin uptake, while simultaneously ameliorating the deficiencies of positively charged lipid nanoparticles as drug carriers and preserving their stability in the bloodstream. Based on the findings, Gal-HA/SIL-SLNPs with excellent biocompatibility demonstrated improved cellular internalization and liver distribution, while also displaying ideal curative properties in a mouse model of alcohol-induced liver injury without causing damage to other organs. This work suggests that Gal-HA/SIL-SLNPs with dual modification may represent an encouraging approach for developing more effective liver targeted nano-drug delivery systems to achieve accurate medication for alcoholic liver injury.
研究领域:
药学
·
纳米技术
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肝病学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Li Jinxin,Wu Honghui,Yu Zebin,Wang Qiwei,Zeng Xin,Qian Wenchang,Lu Siqi,Jiang Lingli,Li Jingyi,Zhu Meng,Han Yingli,Gao Jianqing,Qian Pengxu
Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin β2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.
研究领域:
血液学
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药理学
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肿瘤学
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生物材料科学
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产品关联
DOI
PubMed
高影响因子
International Journal of Pharmaceutics-X
·
2024
·
IF 5.2
Lan Cheng,Yanhua Zhang,Qian Xu,Zheng Li,Zulan Liu,Fangyin Dai
Systemic administration of methotrexate (MTX), widely regarded as one of the most effective treatments for psoriasis, poses significant challenges due to its high toxicity, limited solubility, and potential for adverse effects. Consequently, developing a topical form of MTX may offer a safer and more effective strategy for psoriasis management. Silk fibroin (SF), a protein-based biomacromolecule, has shown considerable promise as a nanocarrier for sustained and targeted drug delivery, owing to its exceptional physicochemical and biological properties. This study aimed to develop and characterize a novel drug delivery nanocarrier for MTX using SF nanoparticles modified with hyaluronic acid (HA) and to assess their potential for skin-targeted drug delivery with reduced transdermal permeation. The nanoparticles were thoroughly characterized, demonstrating a uniform particle size, high drug-loading capacity, pH sensitivity, and excellent slow-release properties. In vitro and in vivo experiments further indicated that these nanoparticles effectively reduced psoriasis-induced inflammatory responses, including erythema and scaling, by inhibiting keratinocyte proliferation and decreasing levels of pro-inflammatory cytokines. The inclusion of HA improved nanoparticle targeting, particularly through interactions with overexpressed CD44 proteins in psoriatic skin, resulting in enhanced methotrexate accumulation at the sites of inflammation and improved therapeutic efficacy. Our findings suggest that HA/SF nanoparticles loaded with MTX represent a promising, safe transdermal delivery system for the localized treatment of psoriasis.
研究领域:
药学
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纳米技术
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皮肤病学
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药物递送系统
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炎症研究
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2012
·
IF 7.404
Zhaowei Chen,Zhenhua Li,Youhui Lin,Meili Yin,Jinsong Ren,Xiaogang Qu
Recent insight into the molecular mechanisms of natural biomineralization has enabled biomimetic synthesis of functional organic-inorganic hybrid materials under mild reaction conditions. Here, we describe a novel method to construct organic-inorganic hybrid on mesoporous silica nanoparticles by utilizing electrostatically absorbed hyaluronic acid (HA) as a reaction site for deposition of calcium phosphate (CaP) minerals. The addition of another layer of HA on the CaP surfaces not only stabilizes the nanocomposites but also confers target ability toward CD44 overexpressed cancer cells. The nanomaterials enable controlled release of loaded anticancer drugs in acidic subcellular environments after receptor mediated endocytosis . More importantly, our study demonstrated that the cancer targeting nanomaterials dramatically enhanced cellular uptake and cytotoxicity toward breast carcinoma cells. These results thus open new opportunities for biomineralization guided nanostructure assemblies with great potential for biomedical applications .
研究领域:
材料科学
·
纳米技术
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生物医学工程
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2021
·
IF 9.381
Wenjia Wang,Xiaoqin Zhang,Zhiqian Li,Dayi Pan,Hongyan Zhu,Zhongwei Gu,Jie Chen,Hu Zhang,Qiyong Gong,Kui Luo
To achieve target delivery of anti-tumor drugs with great biocompatibility into tumor tissues, a stimuli-responsive dendronized hyaluronic acid (HA)-docetaxel conjugate (HA-DTX-Dendron, HADD) was designed and prepared. The incorporation of HA in HADD improved the delivery of DTX to tumor cells with rich CD44 receptors. Enhanced biocompatibility and therapeutic outcomes were achieved using glyodendrons-modified HA and tumor microenvironment-responsive linkers in HADD. The glycodendron was connected with HA via GSH-responsive disulfide bonds , and the drug DTX was linked to the carrier via a cathepsin B-responsive tetrapeptide GFLG. This design resulted in self-assembly nanostructures for facilitating uptake of HADD by tumor cells and rapid release of DTX to exert its therapeutic effect. Compared to free DTX, HADD showed much higher tumor growth inhibition in the MDA-MB-231 tumor-bearing mice model (up to 99.71%), and no toxicity was observed. Therefore, HADD could be employed as an efficacious nano-agent for treating triple negative breast cancer (TNBC).
研究领域:
药学
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癌症研究
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纳米技术
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生物医学工程
✓ 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）