JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2014
·
IF 1.357
Yan-Ling Luo,Jing-Yu Fu,Feng Xu,Ya-Shao Chen,Bin Zhang
Thermo-sensitive poly(N-isoproplacrylamide)m-block-hydroxyl-terminated polybutadiene-block-poly(N-isoproplacrylamide)m (PNIPAMm-b-HTPB-b-PNIPAMm, m = 1 or 2) block copolymers, AB4 four-armed star multiblock and linear triblock copolymers, were synthesized by ATRP with HTPB as central blocks, and characterization was performed by 1H NMR, Fourier transform infrared, and size exclusion chromatography. The multiblock copolymers could spontaneously assemble into more regular spherical core–shell nanoscale micelles than the linear triblock copolymer. The physicochemical properties were detected by a surface tension, nanoparticle analyzer, transmission electron microscope (TEM), dynamic light scattering, and UV–vis measurements. The multiblock copolymer micelles had lower critical micelle concentration than the linear counterpart, TEM size from 100 to 120 nm, and the hydrodynamic diameters below 150 nm. The micelles exhibited thermo-dependent size change, with low critical solution temperature of about 33–35 °C. The characteristic parameters were affected by the composition ratios, length of PNIPAM blocks, and molecular architectures. The camptothecin release demonstrated that the drug release was thermo-responsive, accompanied by the temperature-induced structural changes of the micelles. MTT assays were performed to evaluate the biocompatibility or cytotoxicity of the prepared copolymer micelles.
研究领域:
高分子化学
·
药物递送系统
·
生物材料
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 8
·3277-3286
·
IF 5.251
Jun Li,Zu-E. Hu,Xian-Ling Yang,Wan-Xia Wu,Xiu Xing,Bo Gu,Yan-Hong Liu,Na Wang,Xiao-Qi Yu
Dual stimuli-responsive camptothecin polymeric prodrugs (CPT Prodrugs) with grafted structures were designed via chemoenzymatic methods and combined with doxorubicin (DOX) for synergistic drug delivery to improve anticancer efficiency. The CPT Prodrugs loaded DOX with a high efficiency through the cooperative contribution of several interaction forces. The produced amphiphilic polymeric prodrugs loaded with DOX, referred to as DOX@CPT Prodrugs, formed homogeneous spherical micelles of appropriate sizes (sub-50 nm). The DOX@CPT Prodrug micelles showed excellent stability in release experiments under in vitro physiological conditions and maintained over 80% drug loading after 4 weeks when stored at 4 °C. Under weakly acidic pH and reduced glutathione (GSH) conditions, the DOX@CPT Prodrugs with high disulfide and tertiary amine content achieved synergistic release of the two loaded drugs and biodegraded into low-molecular-weight compounds. The cell experiments confirmed that the internalization of DOX@CPT Prodrugs into cancer cells was greatly improved by nearly 30% compared with that of free drugs. Furthermore, the synergistic drug delivery system exhibited superior anticancer efficiency with highly improved cell selectivity ratios (up to 127.0%) and greatly enhanced synergistic effects (up to 23.9%) benefiting from good long-term stability, better internalization by cells and sensitive pH and GSH dual-responsivity. In addition, the DOX@CPT Prodrugs with suitable sizes and good water solubility also exhibited a greater penetrability in the case of simulating solid tumors than the free drugs. These results demonstrate the potential of DOX@CPT Prodrugs as biodegradable, dual-responsive combination therapy nanocarriers for synergistic anticancer treatment.
研究领域:
药学
·
肿瘤学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2022
·
IF 5.062
Fei Wang,Xuyang Li,Xialin Hu,Wenya Zhuang,Jiewei Lai,Wenchao Wang,Xuanrong Sun,Hong Wang,Qingyong Li
FLQY2 is a camptothecin derivative modified by FL118 and proved to be good antitumor activity in vitro . However, its poor solubility leads to the low therapeutic efficacy in vivo . Here, the injectable FLQY2 lyophilized powder was prepared with Kolliphor® HS 15 (HS 15), which was called HS 15-FLQY2. The preparation process of HS 15-FLQY2 was optimized by orthogonal design and the lyophilization process was investigated by single factor experiment. Moreover, the formulation was characterized, the pharmacokinetics study and the antitumor activity were carried out in vivo . As the results, HS 15-FLQY2 (1:1500, w/w) containing 5% mannitol as cryoprotectant showed good appearance and 70% entrapment efficiency. HS 15-FLQY2 revealed low particle size (<16 nm), better homogeneity (PDI <0.2) and remained stable for 24 h in water. In addition, the data of the DSC , XRD and FTIR demonstrated that FLQY2 was distributed within micelles . In vivo , the bioavailability of HS 15-FLQY2 (i.p.) was improved significantly compared with oral CD-FLQY2 (a cyclodextrin inclusion complex of FLQY2). In addition, HS 15-FLQY2 demonstrated higher tumor inhibition effect than capecitabine , confirming the possibility of treatment cancer by the delivery of FLQY2.
研究领域:
药剂学
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肿瘤学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF DRUG TARGETING
·
2014
·
IF 2.723
Qingyong Li,Tianyu Liu,Yunchao Li,Shuyue Luo,Qiaochu Zhu,Li Zhang,Tengfei Zhao
Camptothecin-20(s)-O-glycine ester-[N-(3′α, 12′α-dihydroxy-24′-carbonyl-5′β-cholan)] (A2), 10-(3′α,12′α-dihydroxy-5′β-cholan-24′-carboxyl)-(20 s)-camptothecin (C2), and 10-O-(3-O-(3′α, 12′α-dihydroxy-24′-carbonyl-5′β-cholan)-propyl)-(20S)-camptothecin (D2) are novel camptothecin-deoxycholic acid analogues. MTT assays were performed to assess the anticancer activity of these compounds against hepatocellular carcinoma SMMC-7721, breast carcinoma MCF-7, and colorectal carcinoma HCT-116 cells. A2 had a high killing ability on SMMC-7721 cells selectively, but C2 and D2 did not exhibit selectivity with regard to SMMC-7721 killing. Uptake assays were performed in an effort to elucidate the transport mechanisms of A2 into SMMC-7721 cells. A2 increased the mRNA expression of OATP1B3 (an organic anion-transporting polypeptide) and uptake of A2 was inhibited by rifampin (inhibitor of OATP1B3), which indicated that the transporter-mediated transport of A2 was mediated by OATP1B3. In addition, according to the western blot and apoptosis assays, we found that A2 killed SMMC-7721 cells by inducing cell apoptosis mainly via an AIF (apoptosis-inducing factor) pathway and a caspase-dependent mitochondria apoptosis pathway.
研究领域:
药理学
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肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2016
·
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
·
纳米技术
·
癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Longbing Ling,Muhammad Ismail,Yawei Du,Qing Xia,Wei He,Chen Yao,Xinsong Li
Nanomedicines in polymeric therapeutics present a potential treatment for cancers. However, their clinical effectiveness still has room to be improved. Herein, reduction-responsive reversibly core-cross-linked micelles based on the poly(ethylene glycol)-dihydrolipoic acid (MeO-PEG2k-DHLA) conjugate were developed for triggered intracellular release of camptothecin (CPT). Coupling two molecules of dihydrolipoic acid (DHLA) to methyl-terminated PEG (Mw 2000) through a labile ester bond was performed by solution-phase condensation reaction. Due to the amphiphilic property, the MeO-PEG2k-DHLA conjugate formed micelles that were readily cross-linked with disulfide formation dispersed in water. These sole cross-linked micelles were 74.9 nm in hydrodiameter, as analyzed by dynamic light scattering (DLS). The nanostructures demonstrated excellent stability against extensive dilution, while rapidly dissociating under 10 mM glutathione (GSH), highlighting their potential for drug delivery. Interestingly, CPT was modified with a disulfide linkage and subsequently conjugated to the MeO-PEG2k-DHLA polymer scaffold. Core-cross-linking of the micelles achieved high drug loading of CPT (31.81%, wt %) and demonstrated that CPT release at pH 7.4 was significantly declined by cross-linking (i.e., less than 15% release in 24 h), whereas more than 90% of CPT was released under 10 mM GSH condition. In vitro cellular uptake and MTT assays showed that CPT-conjugated MeO-PEG2k-DHLA micelles were effectively internalized into tumor cells to induce the cytotoxic effects against HepG-2 and MCF-7 cells. Importantly, in vivo pharmacokinetics analysis demonstrated the nanoscale feature of micelles makes CPT to present longer retention time, resulting in a higher accumulation at tumor sites. Taken together, the disulfide core-cross-linked MeO-PEG2k-DHLA multifunctional micelles with high drug loading and excellent stability are potential candidates for tumor-targeting drug delivery.
研究领域:
药学
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纳米技术
·
生物医学工程
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癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2015
·
IF 4.513
Minxi Hu,Ping Huang,Yao Wang,Yue Su,Linzhu Zhou,Xinyuan Zhu,Deyue Yan
Combination chemotherapy has been widely applied in cancer treatment; however, the cocktail administration of combination chemotherapy could cause the nonuniform biodistribution of anticancer agents, thus impairing the therapeutic efficacy. In the present study, to address this concern, we proposed a novel strategy of preparing self-assembled nanoparticles from amphiphilic drug–drug conjugate for synergistic combination chemotherapy. The conjugate was synthesized by two-step esterification of hydrophobic camptothecin (CPT) and hydrophilic floxuridine (FUDR) through a linker compound. Because of its amphiphilic nature, the CPT-FUDR conjugate self-assembled into stable nanoparticles which could simultaneously release fixed dosage of the two drugs in cancer cells. In vitro studies demonstrated synergistic anticancer efficacy of the CPT-FUDR nanoparticles including improved cell apoptosis, varied cell cycle arrest, as well as effective inhibition of cancer cell proliferation.
研究领域:
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2019
·
IF 8.355
Yunfeng Hu,Shi Wu,Yong He,Liehua Deng
A redox prodrug consisting of camptothecin-conjugating PEG through the diselenide bond was synthesized, and the resultant amphiphilic prodrug was then used to load the curcumin to form the co-delivery system for the synergetic B16 melanoma cells inhibition. The co-delivery system showed a good response to glutataione, and the prodrug could be degraded and the two loaded drugs were then released. Both camptothecin and curcumin could induce the obvious cytotoxicity to B16 melanoma cells. Particularly, the co-delivery strategy showed a synergetic inhibition effect to B16 melanoma cells through an in vitro assay. In vivo assay also showed that the co-delivery system could inhibit B16 tumor growth and showed much better inhibition effect than that of only camptothecin or curcumin used. Moreover, as an injectable drug delivery system, the biocompatibility including the blood compatibility of the co-delivery system was confirmed, suggesting that the redox co-delivery system have a potential application in B16 tumor therapy.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY
·
2019
·Vol. 96
·期 1
·169-179
·
IF 1.429
Ma Mingfang,Shang Wenqing,Jia Ruxiao,Chen Ruijiao,Zhao Min,Wang Chaoqun,Tian Mingyan,Yang Shulei,Hao Aiyou
Abstract Folic acid, as a significant vitamin, is essential for human bodies, especially for pregnant women. However, folic acid hydrogel for drug delivery has not been reported until now. Herein, folic acid hydrogel was prepared by ion inducing method firstly. Then β-cyclodextrin/camptothecin inclusion complex was loaded into folic acid hydrogel successfully by co-assembly. Camptothecin loading folic acid hydrogel has good rheological mechanical property and thermodynamic stability. Moreover, the possible mechanism of hydrogel formation was proposed by energy dispersive spectrometer and small-angle X-ray scattering. Besides, compared to camptothecin itself, camptothecin release rate from camptothecin loaded hydrogel was prolongated remarkably through dialysis experiment. Finally, the cell inhibitory rate of camptothecin loading folic acid hydrogel was increased observably compared to camptothecin itself. Hence, as a green drug delivery system, our folic acid hydrogel has important potential application in medical engineering material. Graphic Abstract Herein, a novel β-cyclodextrin/camptothecin inclusion complex loaded folic acid hydrogel was constructed by elaborate design and preparation, which can load camptothecin into folic acid hydrogel effectively. Moreover, compared to camptothecin itself, camptothecin release rate from camptothecin loaded hydrogel was prolongated remarkably through dialysis experiment. Finally, the cell inhibitory rate of camptothecin loading folic acid hydrogel was increased observably compared to camptothecin itself. Hence, as a green drug delivery system, our folic acid hydrogel has important potential application in medical engineering material.
研究领域:
材料科学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-15
·
IF 9.429
Wang Yi,Wang Wenchao,Yu Endian,Zhuang Wenya,Sun Xuanrong,Wang Hong,Li Qingyong
Background 7-p-trifluoromethylphenyl-FL118 (FLQY2) is a camptothecin analog with excellent antitumor efficacy against various solid tumors. However, its poor solubility and low bioavailability limited the development of the drug. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), an emerging carrier for preparing solid dispersion (SD), encapsulated FLQY2 to circumvent the above limitations.Results In this project, FLQY2-SD was prepared by solvent evaporation method and self-assembled into micelles in aqueous solutions owing to the amphiphilic nature of Soluplus®. The physicochemical characterizations demonstrated that FLQY2 existed in a homogeneous amorphous form in SD and was rapidly dissolved. The micelles did not affect cytotoxicity or cellular uptake of FLQY2 in vitro, and the oral bioavailability was increased by 12.3-fold compared to the FLQY2 cyclodextrin suspension. The pharmacokinetics of FLQY2-SD showed rapid absorption, accumulation in the intestine, and slow elimination via fecal. Metabolite identification studies showed 14 novel metabolites were identified, including 12 phase I metabolites (M1–M12) and 2 phase II metabolites (M13–M14), of which M2 (oxidation after decarboxylation) and M7 (dioxolane ring cleavage) were the primary metabolites in the positive mode and negative mode, respectively. The tumor growth inhibition rate (TGI, 81.1%) of FLQY2-SD (1.5 mpk, p.o./QW) in tumor-bearing mice after oral administration was higher than that of albumin-bound Paclitaxel (15 mpk, i.v./Q4D) and Irinotecan hydrochloride (100 mpk, i.p./QW).Conclusion sThe successful preparation, pharmacokinetics, and pharmacodynamics studies of FLQY2-SD showed that the solubility and bioavailability of FLQY2 were improved, which facilitated the further druggability development of FLQY2.Graphical Abstract
研究领域:
药学
·
药物递送系统
·
癌症研究
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Research Express
·
2022
·Vol. 9
·期 11
·115011
·
IF 2.025
Yu Zeng,Huihui Chen,Fan Yang,Huiyong Li,Pengxiang Yang
Malignant gliomas are the most prevalent and deadly primary brain tumors. The life expectancy of people with gliomas only slightly increases through surgical procedures, radiation, and chemotherapy. Magnetic nanocarriers must be developed to enable drug delivery using a magnetic field. A utilized to fabricate holmium ferrite nanoparticles is described herein. β-Cyclodextrin-polyethylene glycol (PEG) conjugate is used as a coat for the holmium ferrite nanoparticles. X-ray diffraction, energy dispersive x-ray spectroscopy, and x-ray photoelectron spectroscopy are all used to study the nanoparticles. This size range of nanoparticles is optimal for efficient drug delivery. The in vitro cytotoxicity of the fabricated nanoparticles was examined using U87MG and LN229 glioma cancer cells. The acridine orange/ethidium bromide and nuclear staining methods examined the morphological changes in the U87MG and LN229 glioma cells. The mode of cell death mechanism was investigated by Annexin V-FITC/PI flow cytometry methods. The possibility for successful SN38 delivery for the treatment of glioma cancer exists with the SN38@HF-β-CD-PEG.
研究领域:
肿瘤学
·
纳米医学
·
药物递送
✓ 已验证
产品关联
DOI
高影响因子
Letters in Drug Design & Discovery
·
2019
·Vol. 16
·期 12
·1378-1386
·
IF 0.953
Cai Xingchen,Huang Weiwei,Huang Yi,Xia Lihua,Liu Miao,Wang Mengke,Wang Wenchao,Li Qingyong
Background: The single-agent therapy was unable to provide an effective control of the malignant process, a well-established strategy to improve the efficacy of antitumor therapy is the rational design of drug combinations aimed at achieving synergistic effects. Objective: The
objective of this study is generating the new potential anticancer agents with synergistic activity. Owing to the unique mechanism of action of Camptothecin (CPT), it has shown abroad spectrum of anti-cancer activity against human malignancies, and growing evidence revealed that Nonsteroidal
Anti-Inflammatory Drugs (NSAIDs) reduce the risk of different kinds of cancers. So four CPT-NSAIDs conjugates were synthesized and evaluated. Methods: In this study, a series of novel CPT - NSAIDs derivatives were synthesized by esterification. These new compounds were evaluated for in
vitro antitumor activity against tumor cell lines A549, Hela, HepG2, HCT116 by MTT assay. To probe the required stabilities as prodrugs, stability tests were studied in human plasma. To further evaluate the stability of Ketoprofen-CPT in vivo, the female SD rats were used to determine the
pharmacokinetics following a single oral dose. Results: In vitro results showed that Ketoprofen-CPT and Naproxen-CPT conjugates possessed nice efficacy. In a molecular docking model, the two conjugates interacted with Topo I-DNA through hydrogen bonds, - stacking and
so on.In human plasma results showed that the prodrug was converted to ketoprofen and another compound. The female SD rats were used to determine the pharmacokinetics following a single oral dose, the half-life (t1/2) of Ketoprofen-CPT was approximately 12 h which was much longer than that
of CPT. Conclusion: Good activity was noted for some compounds will be helpful for the design of dualaction agents with most promising anti-cancer activity.
研究领域:
肿瘤学
·
药物化学
·
药理学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）