JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2018
·
IF 1.911
Caochuan Feng,Xiaoxiong Han,Lili Chi,Jing Sun,Feirong Gong,Yaling Shen
Combination therapy of two or more drugs has gradually become of outmost importance in cancer treatment. Cabazitaxel (CTX) is a taxoid drug and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of TNF superfamily. In this study, we prepared TRAIL-modified and CTX-loaded polymer micelle (TRAIL-M-CTX). This nanoparticle was self-assembled from biodegradable amphiphilic copolymers, monomethoxyl poly(ethylene glycol)–b-poly(DL-lactide) (mPEG-PLA) and COOH-PEG-PLA, via a nanoprecipitation method and were modified with the TRAIL protein, resulting in a particle size of 39.75 ± 0.17 nm in diameter and a drug encapsulation efficiency of 95.52 ± 1.69%. The successful coupling was confirmed by 1H NMR, FTIR spectroscopy, and DLS article size measurement. Pharmacodynamic analysis in two human cancer cell lines with different TRAIL sensitivities showed that TRAIL-M-CTX has a significantly better anticancer efficacy than the individual CTX and TRAIL protein. Importantly, TRAIL-M-CTX showed synergistic effects against TRAIL-insensitive cells (MCF-7). A study of cellular uptake implied that the modified micelles were internalized into MCF-7 cells more effectively than unmodified micelles, owing to the coupled TRAIL protein. A cell cycle assay of MCF-7 cells revealed that TRAIL-M-CTX significantly increased the sub-G1 population compared with CTX or TRIAL, thus, facilitating cancer cell apoptosis. These results suggest that TRAIL-M-CTX micelles have potential as a cancer chemotherapy formulation.
研究领域:
药学
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纳米技术
·
癌症研究
·
生物医学工程
·
细胞生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Hongshuai Lv,Weiping Jia,Li Yang,Peng Dong,Jiaojiao Liu,Si Wang,Xiaohai Li,Jinghua Hu,Ling Zhao,Yikang Shi
Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.
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PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2026
·
IF 4.9
Wei Mingli,Chu Chenxiao,Ding Huaiwei,Zhao Jiansong,Ji Muse,Liang Xinxin,Bi Xiaoshuang,Zhao Jiaqi,Gou Jingxin,Yin Tian,He Haibing,Tang Xing,Zhang Yan,Zhang Yu
Cabazitaxel (CTX) exhibits potent antineoplastic activity
and is
demonstrated to promote antitumor immunity by triggering immunogenic
cell death (ICD). This is commonly used in the clinical treatment
of advanced and metastatic triple-negative breast cancer (TNBC). However,
the therapeutic index of commercial CTX injections is severely restricted
by their definite systemic toxicity and low tolerability. Herein,
we developed biomimetic low-density lipoprotein nanoparticles (CTX 2 TK&VP@LDL NPs) by integrating ROS-responsive CTX dimeric
prodrugs (CTX 2 TK) and the photosensitizer verteporfin (VP)
into LDL NPs to selectively target tumors and achieve synergistic
chemophotodynamic therapy and immunotherapy for TNBC with improved
biosafety. CTX 2 TK&VP@LDL NPs were able to enhance the
accumulation and cellular uptake in 4T1 tumors overexpressing LDL
receptor, improving the targeted codelivery efficiency. When CTX 2 TK&VP@LDL NPs were deposited at the tumor sites, localized 1 O 2 was generated upon irradiation for triggering
ultrafast CTX release with low premature CTX leakage in the off-target
tissue. Additionally, the generated 1 O 2 can
further synergistically reinforce ICD and elicit robust antitumor
immune activation. The combination treatment with CTX 2 TK&VP@LDL
NPs and PD-L1 blockade notably inhibited abscopal tumor growth and
lung metastasis. Taken together, the biomimetic CTX 2 TK&VP@LDL
NPs exploit endogenous LDL functionality to enable receptor-mediated
tumor targeting and synergistic chemophotodynamic immune activation,
providing an effective and safe therapeutic strategy for TNBC.
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DOI
高影响因子
BMEMat
·
2026
·
IF 17.2
Shengyao Xu,Danping Wang,Si Zheng,Zhiyu Kuang,Ya Gao,Haiyu Zhao,Lurong Zhang,Jiayu Guo,Jingyi Zhang,Weiyao Li,Anhua Wang,Hongrui Lei,Zhonggui He,Ken-ichiro Kamei,Jianzhao Niu,Lingyun Ma,Bingjun Sun
Liposomes represent one of the most extensively investigated nanocarriers in drug delivery. However, the efficient encapsulation of highly hydrophobic drugs like cabazitaxel (CTX) remains challenging due to their limited affinity with phospholipid bilayers. Herein, a lipid-mimetic modification strategy was applied to improve the affinity between CTX and phospholipids. Briefly, octyldodecanol (ODA) which possessed a similar structure with the phospholipids' tail group was connected to CTX via disulfide bond to design a lipid-mimetic CTX prodrug (CTX-SS-ODA). Thereafter, CTX prodrug-loaded liposomes (CPLs) with varying drug-to-lipid ratios (1:10, 1:20, and 1:30) were successfully prepared and systematically evaluated. Compared with CTX liposomes, the CPLs had higher encapsulation efficiency, drug loading capacity and stability. More notably, a high drug-to-lipid ratio could reduce the particle concentration, thereby improving cell uptake and pharmacokinetic behavior. CPLs@D/L 1:10 with the highest drug-to-lipid ratio demonstrated remarkable pharmacokinetic improvements, exhibiting a 402-fold increase in AUC 0-72h compared to free CTX. This optimized formulation not only displayed potent antitumor activity but also maintained an excellent safety profile. Our findings underscore the effectiveness of lipid-mimetic prodrug modification for liposome and emphasize the crucial role of drug-to-lipid ratio in developing high-performance nanomedicines.
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高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Mingyang Zhang,Yifan Miao,Can Zhao,Tong Liu,Xiyan Wang,Zixuan Wang,Wenxin Zhong,Zhonggui He,Chutong Tian,Jin Sun
The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances ( e.g. , ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.
研究领域:
药理学
·
肿瘤学
·
药物化学
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DOI
PubMed
高影响因子
American Journal of Translational Research
·
2022
·
IF 3.94
Zheng Xu,Luwei Xu,Yuzheng Ge,Hongbin Sun,Jiageng Zhu,Quanliang Dou,Ruipeng Jia
Background: Cabazitaxel has been applied to the treatment of castration-resistant prostate cancer (CRPC), but the molecular mechanism remained to be fully understood. Methods: After treatment with Cabazitaxel alone or in combination with ionizing radiation (IR), CRPC cell viability, proliferation and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assay, colony formation, and flow cytometry, respectively. Tumor volume was measured after the establishment of animal xenograft model. Relative expressions of proteins related to apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase 3) and phosphoinositide 3-kinase (PI3K)/AKT pathway were measured by Western blot, and the phosphorylated-PI3K/PI3K and p-AKT/AKT ratios were determined as well. Results: Cell viability and proliferation were suppressed, and apoptosis was promoted in CRPC cells after Cabazitaxel treatment alone, accompanied with upregulated expressions of Bax and cleaved caspase 3 and downregulated Bcl-2 expression. Also, a single treatment with Cabazitaxel resulted in suppression of PI3K/AKT pathway activation, along with downregulated expressions of p-PI3K and p-AKT and a reduced ratio of p-PI3K/PI3K to p-AKT/AKT. Meanwhile, Cabazitaxel enhanced the effects of IR on suppressing survival and promoting apoptosis in CRPC cells through downregulating Bcl-2 and upregulating Bax and cleaved caspase 3. However, Cabazitaxel suppressed IR-induced PI3K/AKT pathway activation via downregulating p-PI3K and p-AKT, leading to a reduced ratio of p-PI3K/PI3K to p-AKT/AKT. Furthermore, Cabazitaxel further promoted the effects of IR on suppressing tumor growth in vivo . Conclusion: Cabazitaxel inhibited the proliferation and promoted the apoptosis and radiosensitivity of CRPC cells, which is related to the suppression of PI3K/AKT pathway, providing a therapeutic method for CRPC in clinical practice.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2024
·
IF 3.6
Jianming Gong,Renqian Feng,Xiaoqing Fu,Qi Lin,Bicheng Wu
Ovarian cancer is the primary cause of death from cancer in female patients. The existing treatments for ovarian cancer are restricted and ineffective in achieving a cure for the disease. To address this issue, we provide a novel approach to treating ovarian cancer by utilizing a liposomal carrier that effectively delivers the chemotherapeutic drugs carmustine (BCNU) and cabazitaxel (CTX). Initially, the combined impact of BCNU and CTX was confirmed, revealing that this impact reaches its maximum at a ratio of 1:2 mol/mol (BCNU/CTX). After that, the BC-Lipo co-delivery system was developed, which has a high capability for loading drugs (97.48% ± 1.14 for BCNU, 86.29% ± 3.03 for CTX). This system also has a sustained release profile and a beneficial long-circulating feature. The accumulation of BC-Lipo in tumors was dramatically enhanced compared to the accumulation of the free drug. Furthermore, BC-Lipo demonstrated similar levels of cytotoxicity to free BCNU and CTX (BCNU/CTX) when tested on HeLa cells in an in vitro model. Biochemical staining methods investigated the cancer cell’s morphological examination. The apoptosis was confirmed by FITC-Annexin-V/PI staining by flow cytometry analysis. In addition, the investigation of fluorescence and protein markers examined the apoptosis mechanistic pathway, and the results indicated that BC-Lipo induced apoptosis due to mitochondrial membrane potential variation. This proof-of-concept study has established the probability of these BCNU-CTX combined treatments as active drug delivery nanocarriers for poorly soluble BCNU and CTX.
研究领域:
肿瘤学
·
药剂学
·
纳米技术
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cancer Nanotechnology
·
2023
·Vol. 14
·期 1
·1-34
·
IF 5.7
Tan Tiantian,Feng Yuxin,Wang Weimin,Wang Rongrong,Yin Liyan,Zeng Yiying,Zeng Zhaowu,Xie Tian
Background In the current treatment of non-small cell lung cancer (NSCLC), traditional chemotherapy causes high toxicity, so it is necessary to develop safe chemical drug delivery vehicles clinically. Chemotherapy monotherapy is prone to drug resistance. Chemotherapy combined with other therapies such as nucleic acid drugs is an effective way to avoid drug resistance and the toxicity of continuous chemotherapy. In this study, chemotherapy and siRNA therapy were combined to treat paclitaxel-resistant NSCLC in order to increase efficacy and reduce toxicity. This study aims to develop a cabazitaxel-loaded human serum albumin nanoparticles (CTX-HSA-NPs) to improve the toxicity of traditional CTX-Tween 80 and increase targeting, and to develop a TGFβ-1 siRNA lipid Nanoparticles (TGFβ-1 siRNA LNP) combined with chemotherapy in the treatment of paclitaxel-resistant NSCLC. Results This study prepared CTX-HSA-NPs and TGFβ-1 siRNA LNP had small particle size, high encapsulation efficiency (EE). CTX-HSA-NPs lyophilized powder has high stability after dissolved. The antitumor effect of CTX-HSA-NPs on paclitaxel-resistant NSCLC was higher than that of CTX-Tween, and the toxicity was 1.8 times lower than that of CTX-Tween. More importantly, the combined treatment of TGFβ-1 siRNA LNP and CTX-HSA-NPs could effectively improve the antitumor efficacy of paclitaxel-resistant NSCLC in vivo and in vitro. The results of tumor immunohistochemistry showed that TGFβ-1 siRNA LNP significantly inhibited the expression of TGFβ-1, and compared with other groups, the expression of P-gp after low-dose CTX-HSA-NPs treatment was lower, which did not cause obvious drug resistance. Conclusions The antitumor effect of CTX-HSA-NPs on paclitaxel-resistant NSCLC was higher than that of CTX-Tween, and the toxicity was lower than that of CTX-Tween. TGFβ-1 siRNA LNP can treat paclitaxel-resistant NSCLC by inhibiting the express of TGFβ-1 mRNA. The combined treatment of TGFβ-1 siRNA LNP and CTX-HSA-NPs could effectively improve the antitumor efficacy of paclitaxel-resistant NSCLC. A combination therapy of chemotherapy and nucleic acid drugs could be an effective approach for treating paclitaxel-resistant NSCLC.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
纳米技术
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产品关联
DOI
高影响因子
JOURNAL OF MATERIALS SCIENCE
·
2023
·Vol. 58
·期 25
·10441-10456
·
IF 4.5
Xia Qing,Shen Jia,Li Xiang
Clinical chemotherapy is hindered due to its poor therapeutic impact and severe adverse effects. To work within the challenges of poor circulation stability and unexpected drug leakage in blood circulation, we developed pH-responsive nanoplatforms based on silk sericin-coated zeolitic imidazolate framework-8 to deliver the chemotherapeutic cabazitaxel (designated ZIF-8@CTX@SS, ZCS). ZIF-8's improved stability and biocompatibility can be attributed to the shielding of the naturally occurring and non-toxic sericin protein. ZIF-8's coordinating action triggers the release of CTX drugs in a low pH environment, like that observed in the microenvironment of tumor cells. Newly fabricated nanoparticles showed improved anticancer potential in liver cancer cells (HepG2 and Bel7402). According to the fluorescence-based mechanism of anticancer activity, ZIF-8@CTX@SS enhanced reactive oxygen species (ROS) levels and caused DNA fragmentation, which resulted in apoptosis. The study's findings indicate that ZIF-8@CTX@SS is a potentially biocompatible nanomaterial for drug delivery systems for treating liver cancer applications. Taken together with all the advantages in this investigation, this silk sericin-based nanoframework represents a promising approach for developing stimuli-responsive by employing natural polymers to enhance the chemotherapy effects.
研究领域:
生物材料学
·
肿瘤学
·
药剂学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）