Pharmaceutics
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2023
·Vol. 15
·期 2
·668
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IF 5.4
Jie Zhu,Rui Gao,Zhongshi Wang,Zhiming Cheng,Zhonghua Xu,Zaiyang Liu,Yiqun Wu,Min Wang,Yuan Zhang
While chemotherapeutic agents have particularly potent effects in many types of cancer, their clinical applications are still far from satisfactory due to off-target drug exposure, chemotherapy resistance, and adverse effects, especially in osteosarcoma. Therefore, it is clinically promising to construct a novel tumor-targeted drug delivery system to control drug release and alleviate side effects. In this study, a pH-responsive nonapeptide hydrogel was designed and fabricated for the tumor-targeted drug delivery of doxorubicin (DOX). Using a solid-phase synthesis method, a nonapeptide named P1 peptide that is structurally akin to surfactant-like peptides (SLPs) due to its hydrophobic tail and hydrophilic head was synthesized. The physicochemical properties of the P1 hydrogel were characterized via encapsulation capacity, transmission electron microscopy (TEM), circular dichroism (CD), zeta potential, rheological analysis, and drug release studies. We also used in vitro and in vivo experiments to investigate the cytocompatibility and tumor inhibitory efficacy of the drug-loaded peptide hydrogel. The P1 peptide could self-assemble into biodegradable hydrogels under neutral conditions, and the prepared drug-loaded hydrogels exhibited good injectability and biocompatibility. The in vitro drug release studies showed that DOX-P1 hydrogels had high sensitivity to acidic conditions (pH 5.8 versus 7.4, up to 3.6-fold). Furthermore, the in vivo experiments demonstrated that the DOX-P1 hydrogel could not only amplify the therapeutic effect but also increase DOX accumulation at the tumor site. Our study proposes a promising approach to designing a pH-responsive hydrogel with controlled doxorubicin-release action based on self-assembled nonapeptides for targeted chemotherapy.Keywords:peptide hydrogel;pH responsive;tumor targeted;drug delivery;doxorubicin;osteosarcoma
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CARBOHYDRATE POLYMERS
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2022
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IF 10.723
Yuhan Yang,Yangyi Chen,Dianpeng Li,Shiyuan Lin,Hui Chen,Wei Wu,Wei Zhang
A novel delivery system based on linolenic acid (LA) conjugated chitosan (CS) polymeric micelles were proposed for improving the oral absorption of doxorubicin (DOX) through targeting intestinal fatty acid transporter. LA, as a ligand of the transporter, was grafted into CS to construct CS-LA micelles, and DOX was encapsulated into the micelles. The synthesized micelle material was identified by 1 H NMR and FT-IR. The micelles showed regular spherical shapes with a particle size of 117.1 ± 1.6 nm, drug loading of 8.77 ± 0.02 %, and critical micelle concentration (CMC) of 23.6 μg/ml. The pharmacokinetics studies showed the relative bioavailability of 166 % versus DOX·HCl. The fatty acid transport protein 4-mediated intestinal uptake process of micelles was confirmed by the intracellular uptake, immunofluorescent imaging and permeation test. These findings confirmed the potential of CS-LA micelles as an effective oral delivery vehicle, and fatty acid transporter as a target spot for enhancing intestinal drug absorption.
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Acta Biomaterialia
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2022
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IF 10.633
Xinyao Feng,Fangshen Li,Liangliang Zhang,Wenmo Liu,Xupu Wang,Rui Zhu,Zhen-An Qiao,Bin Yu,Xianghui Yu
Traditional anticancer treatments directly target tumor cells. In contrast, cancer immunotherapy fortifies host immunity. Nanoparticles that incorporate both immunomodulatory and chemotherapeutic agents regulate the tumor microenvironment by activating immune cells and enhancing antitumor immunity. Nanoparticle-based cancer immunotherapy has received considerable attention and has been extensively studied in recent years. In this study, we developed a targeted drug delivery system to enhance immunotherapeutic efficacy and overcome drug resistance by inducing tumor apoptosis and immunogenic cell death (ICD), and activating immune cells. Periodic mesoporous organosilica nanoparticles (PMOs) bore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on their surfaces, and their inner cores were loaded with doxorubicin (DOX). TRAIL enhanced the nanoparticle-targeting capacity and worked synergistically with DOX against breast cancer cells in vitro and in vivo . Furthermore, we revealed for the first time the ability of PMOs to activate dendritic cells (DCs) and elevate ICD levels of DOX in vitro , and TRAIL further enhances the immunomodulatory function of PMOs. Systemic exposure to [email protected] induced an immune response, activated DCs and CD4 + and CD8 + T cells , and significantly suppressed tumor growth in a 4T1-bearing immunocompetent mouse model. Overall, our study demonstrates that TRAIL-modified, DOX-embedded PMO nanoparticles represent a good candidate for tumor-targeted immunotherapy, which has relatively superior therapeutic efficacy and highly promising future application prospects. Statement of significance This study revealed for the first time the ability of PMOs to elevate ICD levels and activate DCs in vitro . The results explained the immunomodulatory function of PMOs and demonstrated the synergistic effects of TRAIL and DOX in triple-negative breast cancer. In addition, immunomodulatory effects of the drug delivery vectors constructed in this study were verified in vivo .
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Cells
·
2022
·Vol. 11
·期 17
·2642
·
IF 7.666
Chunyan Yang,Zixuan Guan,Xincheng Pang,Zengqi Tan,Xiaomin Yang,Xiang Li,Feng Guan
Hepatocellular carcinoma (HCC) is one of the dominating causes of cancer-related death throughout the world. Treatment options for patients with HCC vary, however, the lack of effective targeted drugs is the major reason for death in advanced HCC patients. In this study, a delivery system based on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) loaded with doxorubicin (Dox) was developed. In this system, we initially erased terminal linked α2–3 and α2–6 sialic acids on the surface of EVs by neuraminidase. The exhibition of galactose (Gal) and N-acetylgalactosamine (GalNAc) residues in treated MSC-EVs can specifically be recognized by asialoglycoprotein receptor (ASGPR) of hepatoma cells. Compared to free Dox and Dox-loaded EVs, desialylated EVs loaded with Dox significantly presented the improved cellular uptake, prioritized targeting efficacy, and had a better inhibiting effect in vitro and in vivo. Overall, the results of the present study of the demonstrated delivery system using desialylated MSC-EVs suggest its therapeutic potential for HCC.Keywords:extracellular vesicles;drug delivery;desialylation;ASGPR;liver targeting
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2022
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IF 5.999
Guolian Ren,Danyu Duan,Geng Wang,Rongrong Wang,Yujie Li,Hengtong Zuo,Qichao Zhang,Guoshun Zhang,Yongdan Zhao,Ruili Wang,Shuqiu Zhang
Doxorubicin (DOX) is used as a first-line chemotherapeutic drug , whereas dihydroartemisinin (DHA) also shows a certain degree of antitumor activity . Disulfide bonds (-SS-) in prodrug molecules can be degraded in highly reducing environments. Thus, heterodimer prodrugs of DOX and DHA linked by a disulfide bond was designed and subsequently prepared as reduction-responsive self-assembled nanoparticles (DOX-SS-DHA NPs). In an in vitro release study, DOX-SS-DHA NPs exhibited reduction-responsive activity. Upon cellular evaluation, DOX-SS-DHA NPs were found to have better selectivity toward tumor cells and less cytotoxicity to normal cells. Compared to free DiR, DOX-SS-DHA NPs showed improved accumulation at the tumor site and even had a longer clearance half-life. More importantly, DOX-SS-DHA NPs possessed a much higher tumor inhibition efficacy than DOX-sol and MIX-sol in 4T1 tumor-bearing mice. Our results suggested the superior antitumor efficacy of DOX-SS-DHA NPs with less cytotoxicity.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2021
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IF 6.514
Jiaqi Lu,Ru Li,Binsong Mu,Yao Peng,Yi Zhao,Yuesen Shi,Li Guo,Li Hai,Yong Wu
A type of pH-sensitive multi-targeted brain tumor site-specific liposomes (Lip-CTPP) co-modified with p -hydroxybenzoic acid (p-HA) and triphenylphosphonium (TPP) were designed and prepared to co-load doxorubicin (DOX) and lonidamine (LND). Lip-CTPP are promising potential carriers to exert the anti-glioma effect of DOX and LND collaboratively given the following features: 1) Lip-CTPP have a good pharmacokinetic behavior; 2) Lip-CTPP can cross the blood-brain barrier (BBB) and recognize tumor cells through the affinity of p-HA and dopamine/sigma receptors; 3) Lip-CTPP are highly positive charged once the acid-sensitive amide bonds are cleaved in endo/lysosomes to expose TPP and protonate amine groups; 4) the positive charged Lip-CTPP escape from endo/lysosomes and accumulate in mitochondria through electrostatic adsorption; 5) DOX and LND are released and synergistically increase anti-tumor efficacy. Our in vitro and in vivo results confirmed that Lip-CTPP could greatly elevate the inhibition rate of tumor cell proliferation , migration and invasion, promote apoptosis and necrosis, and interfere with mitochondrial function. In addition, Lip-CTPP could significantly prolong the survival time of glioma bearing mice, narrow the tumor region and inhibit the infiltration and metastasis capability of glioma cells. Collectively, Lip-CTPP are promising nano formulations to enhance the synergistic effect of DOX and LND in glioma treatment.
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MOLECULAR PHARMACEUTICS
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2021
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IF 4.939
Li Wu,Yan Shi,Zihui Ni,Tao Yu,Zhipeng Chen
Mitochondria are involved in the regulation of apoptosis, making them a promising target for the development of new anticancer drugs. Doxorubicin (DOX), a chemotherapeutic drug, can induce reactive oxygen species (ROS)-mediated apoptosis, improving its anticancer effects. Herein, Rhein, an active ingredient in rhubarb, with the capability of self-assembly and mitochondrial targeting, was used in conjunction with DOX to form efficient nanomaterials (Rhein–DOX nanogel) capable of sustained drug release. It was self-assembled with a hydrogen bond, π–π stacking interactions, and hydrophobic interactions as the main driving force, and its loading efficiency was up to 100%. Based on its self-assembly characteristics, we evaluated the mechanism of this material to target mitochondria, induce ROS production, and promote apoptosis. The IC50 of the Rhein–DOX nanogel (3.74 μM) was only 46.3% of that of DOX (11.89 μM), and the tumor inhibition rate of the Rhein–DOX nanogel was 79.4% in vivo, 2.3 times that of DOX. This study not only addresses the disadvantages of high toxicity of DOX and low bioavailability of Rhein, when DOX and Rhein are combined for the treatment of hepatoma, but it also significantly improved the synergistic antihepatoma efficacy of Rhein and DOX, which provides a new idea for the development of long-term antihepatoma agents with low toxicity.
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ACS Applied Materials & Interfaces
·
2021
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IF 9.229
Wenxia Dong,Zhongping Li,Wen Wen,Bin Liu,Guangming Wen
Nanomaterial selection is critical for photoelectrochemical (PEC) sensing. In this report, a novel cathodic photoelectrochemical (PEC) strategy was proposed for the detection of doxorubicin hydrochloride (Dox) and gentamicin sulfate (CN). The photocathode was synthesized by noncovalently coupling cadmium sulfide (CdS) to the porphyrin-derived metal–organic framework (CdS@PCN-224). This type of assembly created a pleasant interface for the combination of doxorubicin hydrochloride and gentamicin sulfate, resulting in a good CdS@PCN-224 donor–acceptor system. When compared to a single optoelectronic material, its photocurrent is enhanced by unprecedented nine times. This research could pave the way for the realization of PCN-224’s enormous potential in PEC sensing.
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CHINESE JOURNAL OF CHEMICAL ENGINEERING
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2021
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IF 3.171
Dong Wan,Sunfan Li,Jianxin Zhang,Guilei Ma,Jie Pan
Compared with physical drug-loaded nanocarriers, polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood, so they have great potential in cancer therapy. However, these micelles have a big disadvantage, which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously, resulting in low administration efficiency and poor therapeutic effect on cancer. To solve problems of traditional polymeric prodrug micelles, novel polymeric micelles with tumor microenvironment response were designed in this work. The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate (TPGS 3350 ), peptide (Pep), and doxorubicin (DOX) (TPGS 3350 -Pep-DOX) was self-assembled into micelles by encapsulating DOX physically. When the micelles entered the tumor tissue, the long-chain polyethylene glycol (PEG) was sensitively cut by the matrix metalloproteinase 2/9 (MMP2/9) enzyme, exposing the targeting molecule folate, then it entered the cell through the endocytic pathway mediated by the folate receptor. The drug loading content, encapsulation efficiency, critical micelle concentration , and invitro release of the micelles invented in this study were measured to characterize their properties. The particle size and zeta potential of micelles were characterized by dynamic light scattering. Images were scanned by transmission electron microscopes. In vitro cytotoxicity, cellular uptake, and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery, making it possible to apply a stimulus–response carrier drug delivery system in clinical application.
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ACS Applied Materials & Interfaces
·
2021
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IF 9.229
Yao Peng,Jiaqi Lu,Ru Li,Yi Zhao,Li Hai,Li Guo,Yong Wu
Glioma is one of the most lethal and complex tumors, and thus, an effective drug delivery system must selectively target the tumor sites and release its cargos in a controlled manner. For the first time, we combined chemotherapeutic agent doxorubicin (DOX) and chemosensitizer lonidamine (LND) to synergistically treat glioma. We also designed and prepared multitargeted redox-sensitive liposomes (Lip-SPG) co-modified with glucose and triphenylphosphonium (TPP) to effectively deliver DOX and LND for anti-glioma therapy. The anti-glioma evaluation shows that DOX and LND have a synergistic effect and Lip-SPG could further enhance their cooperation. In vitro, Lip-SPG could increase the cellular uptake and mitochondrial uptake on bEnd.3 cells and C6 cells with multitargeting ability on the brain, tumor, and mitochondria mediated by glucose and TPP. Lip-SPG can also escape from lysosomes before entering the mitochondria. The anti-glioma efficacy in vitro shows that Lip-SPG can inhibit tumor cell proliferation and induce apoptosis. In addition, Lip-SPG have a remarkable interference to mitochondria, such as reducing intracellular ATP production, inducing ROS generation, and promoting mitochondrial membrane potential depolarization. Furthermore, in vivo, the introduction of PEGylation via glutathione-sensitive disulfide bonds endows Lip-SPG with favorable pharmacokinetic properties, brain targeting ability, low toxicity to normal tissues, and great anti-glioma efficacy with the survival time extended from 19 to 39 days. In conclusion, Lip-SPG are an effective delivery system for synergistically treating glioma with DOX and LND.
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ACS Omega
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2021
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IF 3.512
Yinghua Tao,Dan Zheng,Jingyang Zhao,Kefeng Liu,Jing Liu,Jiandu Lei,Luying Wang
Pharmaceutical science based on biological nanotechnology is developing rapidly in parallel with the development of nanomaterials and nanotechnology in general. Pectin is a natural polysaccharide obtainable from a wide range of sources. Here, we show that doxorubicin (DOX)-conjugated hydrophilic pectin (PET) comprising an amphiphilic polymer loaded with hydrophobic dihydroartemisinin (DHA) self-assemble into nanoparticles. Importantly, conjugated DOX and DHA could be released quickly in a weakly acidic environment by cleavage of the acid-sensitive acyl hydrazone bond. Confocal microscopy and flow cytometry confirmed that these PET-DOX/DHA nanoparticles efficiently delivered DOX into the nuclei of MCF-7 cells. Significant tumor growth reduction was monitored in a female C57BL/6 mouse model, showing that the PET-DOX/DHA nanoparticle-mediated drug delivery system inhibited tumor growth and may improve therapy. Thus, we have demonstrated that pectin may be useful in the design of materials for biomedical applications.
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Translational Oncology
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2021
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IF 4.243
Qiuli Wang,Dong Liang,Peng Shen,Yang Yu,Yuan Yan,Wei You
Previous study has confirmed that hsa_circ_0092276 is highly expressed in doxorubicin (DOX)-resistant breast cancer cells, indicating that hsa_circ_0092276 may be involved in regulating the chemotherapy resistance of breast cancer. Here we attempted to investigate the biological role of hsa_circ_0092276 in breast cancer. We first constructed DOX-resistant breast cancer cells (MCF-7/DOX and MDA-MB-468/DOX). The 50% inhibiting concentration of MCF-7/DOX and MDA-MB-468/DOX cells was significantly higher than that of their parental breast cancer cells, MCF-7 and MDA-MB-46. MCF-7/DOX and MDA-MB-468/DOX cells also exhibited an up-regulation of drug resistance-related protein MDR1. Compared with MCF-7 and MDA-MB-46 cells, hsa_circ_0092276 was highly expressed in MCF-7/DOX and MDA-MB-468/DOX cells. Hsa_circ_0092276 overexpression enhanced proliferation and the expression of LC3-II/LC3-I and Beclin-1, and repressed apoptosis of breast cancer cells. The effect of hsa_circ_0092276 up-regulation on breast cancer cells was abolished by 3-methyladenine (autophagy inhibitor). Hsa_circ_0092276 modulated autophagy-related gene 7 (ATG7) expression via sponging miR-384. Hsa_circ_0092276 up-regulation promoted autophagy and proliferation, and repressed apoptosis of breast cancer cells, which was abolished by miR-384 overexpression or ATG7 knockdown. In addition, LV-circ_0092276 transfected MCF-7 cell transplantation promoted autophagy and tumor growth of breast cancer in mice. In conclusion, our data demonstrate that hsa_circ_0092276 promotes autophagy and DOX resistance in breast cancer by regulating miR-348/ATG7 axis. Thus, this article highlights a novel competing endogenous RNA circuitry involved in DOX resistance in breast cancer.
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