JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yupeng Wang,Yuwei Cong,Manying Cai,Xiaoling Liang,Lina Wang,Dongfang Zhou
Polyprodrug nanomedicines hold great potential for combating tumors. However, the functionalization of polyprodrug nanomedicines to improve therapeutic efficacy is restricted by conventional polymerization methods. Herein, we fabricated a charge-conversional click polyprodrug nanomedicine system by metal-free azide-alkyne cycloaddition click polymerization (AACCP) for targeted and synergistic cancer therapy. Specifically, Pt(IV) prodrug-backboned diazide monomer , DMC prodrug-pendent diazide monomer, dialkyne-terminated PEG monomer and azide-modified folate were click polymerized to obtain the target polyprodrug (P1). P1 could self-assemble into nano-micelles (1-NM), where PEG was the hydrophilic shell with folate on the surface, Pt(IV) and DMC prodrugs as the hydrophobic core. Taking advantage of PEGylation and folate-mediated tumor cell targeting, 1-NM achieved prolonged blood circulation time and high tumor accumulation efficiency. Tumor acidic microenvironment-responsive cleavage and cascade activation of pendant DMC prodrug induced surface charge conversion of 1-NM from negative to positive, which promoted tumor penetration and cellular internalization of the remaining 1-NM. After internalization into tumor cells, the reduction-responsive activation of Pt(IV) prodrug to Pt(II) further showed synergetic effect with DMC for enhanced apoptosis . This first designed charge-conversional click polyprodrug nanomedicine exhibited targeted and synergistic efficacy to suppress tumor proliferation in living mice bearing human ovarian tumor model.
研究领域:
纳米技术
·
药学
·
肿瘤学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF POLYMER SCIENCE
·
2023
·
IF 4.3
Chen Jia-Wei,Shen Yi,Yu Qing-Song,Gan Zhi-Hua
Nanotheranostics, which combine the therapeutic and diagnostic functions in one integrated system, have received extensive attentions in cancer treatments because they enable non-invasive diagnosis, tumor-targeted drug delivery, and real-time monitoring of therapeutic response. However, due to the high systemic toxicity of commonly used chemotherapeutics, current treatment still has limitations. Herein, to simultaneously achieve safe cancer therapy and therapeutic response monitoring, an iodinated prodrug strategy was proposed. 2,3,5-Triiodobenzoic acid (TIBA) was used to modify both paclitaxel (PTX) and the polymeric vehicle, so that the encapsulation efficiency of PTX could be increased and the systemic toxicity could be reduced. As-prepared prodrug nanoparticles could accumulate passively in the tumor site and promptly release loaded drugs in response to the overexpressed GSH in cancer cells, which then caused efficient cell cycle arrest and apoptosis like that of the parent PTX. With this rational design, safe and efficient antitumor therapy and real-time computer tomography (CT) imaging could be simultaneously realized, facilitating potential CT imaging-guided therapy of metastatic breast cancer.
研究领域:
癌症治疗
·
纳米技术
·
药学
·
医学成像
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药物递送系统
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生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2022
·
IF 9.273
Yaqiao Li,Lingxiao Li,Qianhui Jin,Tian Liu,Jin Sun,Yongjun Wang,Zhijun Yang,Zhonggui He,Bingjun Sun
PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles (prodrug-SANPs). However, the impacts of the amount of PEG on the self-assemble stability, cellular uptake, pharmacokinetics, and antitumor efficacy of prodrug-SANPs are still unknown. Herein, selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug. Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG (W prodrug /W DSPE-mPEG2000 = 10:0, 9:1, 8:2, 7:3 and 6:4), and defined as Pure drug NPs, 9:1NPs, 8:2NPs, 7:3 NPs and 6:4 NPs, respectively. Interestingly, 8:2 NPs formed the most compact nanostructure, thus improving the self-assemble stability and pharmacokinetics behavior. In addition, the difference of these prodrug-SANPs in cellular uptake was investigated, and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details. The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product. Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.
研究领域:
药学
·
纳米技术
·
癌症治疗
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 9
·3652-3661
·
IF 5.251
Yunyan Li,Tong Yan,Wenya Chang,Chongjiang Cao,Dawei Deng
Cancer metastasis is a major cause of high mortality in breast cancer. Despite the progress achieved in nanomaterial-based treatments, the cure rate remains unsatisfactory, owing to their poor biocompatibility and non-specific recognition. Inspired by the cell-mimetic strategy, in this work, we fabricated an intelligent cell-like nano-prodrug (Dox-MPK@MDL) for lung metastasis of breast cancer. Specifically, a DNA tetrahedron dendrimer was selected to act as a rigid internal cytoskeleton, and then sequentially coated with a liposome and macrophage membrane to form cell-like Dox-MPK@MDL via hierarchical self-assembly. Here, it should be noted that pH-sensitive Dox-MPK prodrugs were synthesized and inserted into the DNA-based cytoskeleton (the Dox group is an intercalator of double stranded DNA) in advance for the next anti-metastatic therapy. Our results show that Dox-MPK@MDL specifically targeted the sites of lung metastasis via the biomimetic metastasis-homing effects and intelligently triggered Dox release at the metastatic cancer cells, thereby leading to the significant inhibition of lung metastasis. All these features help to enhance the anti-metastatic therapy efficiency of Dox while maximally reducing side-effects.
研究领域:
纳米技术
·
癌症治疗
·
生物医学工程
·
药物科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2021
·
IF 5.268
Ning Wang,Chenyu Liu,Weihe Yao,Hengjun Zhou,Simiao Yu,Hailiang Chen,Weihong Qiao
Constructing highly efficient and multifunctional nanoparticles to overcome the multiple challenges of targeted drug delivery is a new strategy urgently needed in tumor therapy. Here, we synthesized pH-responsive prodrug ( PEG 2K -NH -N- DOX ), GSH-responsive prodrug ( PEG 2K -S-S-CPT ), folate-receptor targeting polymers ( FA-PEG 2K -L8 , FA-PEG 2K -TOS) and T1-enhanced magnetic resonance imaging contrast agents ( Gd-DTPA-N16−16) , used to encapsulate combrestatinA4 (CA4) to prepare multifunctional nanoparticles ( FTDCAG NPs). Unlike other nanoparticles, FTDCAG NPs contains three drugs with the ability to control the release in time and space, which can maximize the effectiveness of precise cancer chemotherapy. We first confirmed that specific binding between FTDCAG NPs and overexpressed folate-receptor cells by flow cytometry and confocal laser scanning microscopy. We then investigated the spatiotemporally controlled release ability of FTDCAG NPs loaded with doxorubicin (DOX), CA4 and camptothecin (CPT). Relative to pH = 7.4, the release efficiency of CA4 in the pH = 6.5 increased by 63.4 %. The first released CA4 is able to destroy the angiogenesis and help tumor cells to be exposed to the remaining FTDCG NPs. After being internalized into the tumor cells, FTDCG NPs is disassembled and the CPT and DOX were released due to the increase of intracellular GSH concentration and the decrease of pH value. Besides, the relaxation time of FTDCAG NPs is 3.86 times that of clinical Gd-DTPA, and the in vitro and vivo T1-weighted imaging is brighter, which can be used to trace the nanoparticles by MRI. Therefore, FTDCAG NPs provide an efficient strategy for the design of multifunctional drug delivery systems for enhancing antitumor efficacy.
研究领域:
纳米医学
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癌症治疗
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymers
·
2018
·Vol. 10
·期 10
·1127
·
IF 2.935
Yinglei Zhai,Xing Zhou,Zhiqiang Zhang,Lei Zhang,Dianyu Wang,Xinhui Wang,Wei Sun
The side effects of doxorubicin (DOX) extremely limit its application in the treatment of malignant tumors. Nano-sized polymeric drugs based on the acidic microenvironment of tissular- or intra- tumor have attracted ample attention because of their potential in reducing side effects. In this research, an amphiphilic diblock copolymer based on poly (ethylene glycol) (PEG) and functionalized polycaprolactone (PCL) was synthesized and utilized as the drug carrier. DOX was chemically conjugated with the polymer via acid-cleavable imine bonds to obtain a novel pH-sensitive DOX prodrug (mPEG-PCL-Imi-DOX). mPEG-PCL-Imi-DOX (24.2 wt % DOX content) formed micelles with an average diameter of 125 nm through a simple solvent evaporation method. The in vitro release profile demonstrated that DOX release of the prodrug micelles was pH-responsive and able to be accelerated with the decrease of pH. In vitro cytotoxicity assay tests revealed that the pH-sensitive DOX prodrug micelles exhibited relatively lower toxicity and similar antitumor efficacy towards MCF-7 cells compared with free DOX. Hence, the DOX prodrug micelles with imine bonds can offer a carrier with great potential for chemo-therapeutics.Keywords:doxorubicin;pH-sensitive;prodrug;micelles;imine
研究领域:
药学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2018
·
IF 3.095
Jincheng Yang,Qingzhi Lv,Wei Wei,Zhengtao Yang,Jiajun Dong,Ruoshi Zhang,Qiming Kan,Zhonggui He,Youjun Xu
The efficacy of traditional chemotherapy often suffers from rapid clearance and off-target toxicity. Drug delivery systems and controlled release are applied to improve the therapeutic efficiencies of small-molecule drugs. In this work, two novel oxidative/reductive (Ox/Re) -sensitive and one non-sensitive Paclitaxel (PTX) prodrugs were synthesized with a maleimide group, which rapidly conjugates with albumin in vivo. Albumin serves as a good vehicle to deliver more prodrug to tumors due to the enhanced permeation and retention (EPR) effect. PTX was then released from the prodrugs in glutathione(GSH)/ reactive oxygen species(ROS)-rich tumor microenvironments. This bioresponsive prodrug strategy demonstrates potent chemotherapeutic efficiency in vivo and may be utilized in clinical cancer therapy.
研究领域:
药物化学
·
肿瘤学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
·
IF 3.862
Hui-Yun Zhang,Cong-yong Sun,Michael Adu-Frimpong,Jiang-nan Yu,Xi-ming Xu
The anti-tumor efficacy of curcumin can be markedly improved by nano-drug self-delivery systems with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, a type of novel, glutathione (GSH)-responsive, PEGylated prodrug nano-micelles (PPNMs) was prepared by self-assembly of curcumin-s-s-vitamin E/mPEG2k-DSPE mixture. The PPNMs (entrapment efficiency: 96.7%) was acceptably stable in water with a mean particle size of 29.84 nm. Compared with curcumin-loaded mPEG2k-DSPE nano-micelles (CUR-NMs), PPNMs showed a higher drug loading (1.68% vs 27.3%) and remarkably improved the chemical stability of curcumin in phosphate buffer saline (PBS) (pH = 7.4), 10% FBS culture medium, and rat plasma. In vitro release study showed that PPNMs could redox responsively control the release of curcumin from the prodrug. Moreover, PPNMs showed a cytotoxicity in HepG2 cells similar to that of the free curcumin; however, when the HepG2 cells were pretreated with 1 mM GSH, PPNMs displayed a markedly enhanced cytotoxicity and cellular uptake than the free curcumin. After intravenous injection, PPNMs showed an increased half-life in blood circulation (10.6-fold) and bioavailability (107-fold) compared with the free curcumin injection. Altogether, the prodrug nano-micelles represent a promising preparation for sustained and controlled delivery of curcumin with enhanced antitumor activity.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Chemistry
·
2024
·
IF 6.7
Jinyu Wang,Qianqian Qiao,Yuqi Feng,Yuhao Guo,Tao Liao,Linwei Li,Ying Kuang,Bingbing Jiang,Ziqiang Xu,Cao Li
In cancer treatment, although prodrugs have been developed to overcome obstacles such as undesirable pharmacokinetic performance and serious off-target toxicity of most chemotherapeutics, the combination of prodrugs with nanotechnology could be used to overcome the shortcomings of conventional prodrug strategies and facilitate more efficient drug delivery and accumulation of anticancer prodrugs at specific sites/tissues. Phototherapy is a method that uses near-infrared (NIR) light to achieve local and non-invasive tumor therapy. The combination of chemotherapy and phototherapy has shown many therapeutic advantages, including synergistic therapeutic effects and the reduction of toxic and side effects of drugs through dose reduction. In this work, a hydrazone linkage was reported to conjugate Ti 3 C 2 T x MXene nanosheets with doxorubicin hydrochloride (DOX) and methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) through a chemical surface modification to form a two-dimensional (2D) nano-prodrug Ti 3 C 2 T x -DOX/PEG (TDP) for synergistic chemo-photothermal therapy. First, hydrazide functionalized Ti 3 C 2 T x was obtained. Then, the carbonyl group of DOX and the aldehyde group of mPEG-CHO can form a pH-responsive hydrazone bond with hydrazide-functionalized Ti 3 C 2 T x . The high surface area of Ti 3 C 2 T x could overcome the reduced drug loading caused by conjugation. Aqueous stability and biocompatibility were enhanced by the introduction of PEG, making the material capable of prolonged circulation in the body's bloodstream. By achieving excellent antitumor results with this nano-prodrug, we have added another brick to the edifice of Ti 3 C 2 T x MXene as an anticancer drug carrier, and given new vitality to the study of anticancer prodrugs combined with nanotechnology.
研究领域:
肿瘤学
·
纳米医学
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
·
IF 3.862
Tao Zhang,Meng Li,Ruyi Yang,Dong Zhang,Jibin Guan,Jiang Yu,Bin Yang,Huicong Zhang,Shenwu Zhang,Dan Liu,Yongjun Wang
Docetaxel (DTX) solution is among the most widely-used parenteral formulations used in advanced breast cancer therapy. However, severe side effects have been observed due to the use of ethanol and polysorbate 80 . Herein, a novel DTX-based prodrug , docetaxel-linoleic acid conjugate (DTX-LA) was successfully synthesized. The high lipid solubility of DTX and DTX-LA resulted in a tendency for them to become entrapped in the oil core of the emulsions. As anticipated, nano-sized, sterically stabilized oil-in-water lipid emulsions (LMs) of DTX-LA LMs and DTX LMs were successfully constructed. Unlike DTX solution, LMs exhibited high colloidal stability and sustained-release behavior, having a narrow size distribution that was ∼220 nm in diameter. Compared with DTX LMs, DTX-LA LMs had a greater drug-loading capacity. Although the cytotoxicity of DTX-LA LMs was reduced in comparison with DTX solution, the pharmacokinetic study demonstrated increased bioavailability (p < 0.001) and half-life (p < 0.01). Finally, DTX-LA LMs displayed significant antitumor efficacy with reduced side effects in a 4T1 breast cancer xenograft model. Thus, the novel lipid emulsion-based docetaxel prodrug delivery system may be a promising strategy for improving intravenous administration for breast cancer treatment.
研究领域:
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2022
·Vol. 38
·期 4
·949-956
·
IF 2.726
Ruan Yawen,Huang Peiling,Yan Jiangyu,Li Guorui,Huang Jing
Targeted prodrug strategy, which utilizes the endogenous biomarkers in cancer cells as activators to release the active drug, has been well established either in the fundamental research or the clinical treatment. However, many prodrugs suffer from safety concern due to “off-target activation”. Dual or multiple biomarkers triggered prodrug may provide an effective strategy to overcoming the “off-target effect”. Melanoma cells have both high levels of reactive oxygen species(ROS) and tyrosinase(TYR), which makes them significantly different from other tumor cells and normal cells. Here we reported a series of quinazolinone-aryl boronic acid/ester-based prodrugs, which can be activated by the cascade of ROS and TYR and selectively kill melanoma cells. The structure-activity relationship(SAR) analysis revealed that mitochondria-targeting property was vital for their cytotoxicity and the dual activated effector played a significant role in their selectivity towards melanoma cells. Among these candidates, compound 4 b showed the highest toxicity to B16, leading to an imbalance of the redox system in melanoma cells, causing mitochondrial DNA damage, and then promoting melanoma cells death.
研究领域:
肿瘤学
·
药物化学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2015
·
IF 4.384
Tingjie Yin,Qu Wu,Lei Wang,Lifang Yin,Jianping Zhou,Meirong Huo
A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer–drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer–PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23 000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer–PTX prodrug system is promising in tumor therapy.
研究领域:
药学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）