DRUG DELIVERY
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2023
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IF 6
Wen Zhang,Peng Zhang,Xiaopeng Xu,Minghui Li,Shasha Wang,Hongjie Mu,Kaoxiang Sun
Doxorubicin (DOX) is a commonly studied chemotherapeutic agent for the treatment of solid tumors, but the severe side effects limit its clinical application. It is shown that DOX-metal chelate has lower in vitro cytotoxicity compared with DOX, as the anthracyclines of DOX can form coordinative interaction with transition metal ions. In addition, the transition metal ions could catalyze the production of hydroxyl radicals (·OH) via Fenton/Fenton-like reactions to achieve antitumor chemodynamic therapy (CDT). In this study, copper ions (Cu2+) were applied to obtain DOX/Cu(II) prodrug, and a liposomal formulation was used to avoid the rapid blood clearance and optimize the biodistribution of this prodrug. In vitro and in vivo antitumor results demonstrated that this pH sensitive Cu-chelating prodrug can reduce adverse effects of DOX but improve the antitumor efficiency due to the combination of chemotherapy and chemodynamic therapy. Our study provided a facile and effective approach of metal-chelating prodrug strategy for combination cancer therapy strategy.
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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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JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Lei Zhao,Siyuan Han,Chengzhi Chai
Ethnopharmacological relevance Huangkui capsule (HKC), a Chinese patent medicine, has been widely used in China as adjuvant therapy for chronic kidney disease (CKD). It displays superior anti-proteinuria efficacy than losartan in patients with CKD at stages 1–2, however, the mechanism of HKC alleviating proteinuria has not been well elucidated. Aim of the study This study aims to confirm the therapeutic effect and investigate associated underlying mechanism of HKC against proteinuria by in vivo and in vitro experiments. Materials and methods We established a doxorubicin (DOX) induced proteinuria mouse model to evaluate kidney function by biochemical markers measurement and to observe histopathological alterations by hematoxylin and eosin (H&E), Masson's trichrome and Periodic Acid-Schiff (PAS)-stained sections of renal, respectively. Moreover, the expressions of Nephrin and Podocin were measured by immunohistochemistry (IHC) and western blotting analysis to investigate podocyte damage. Furthermore, we established Mouse Podocyte Clone-5 (MPC-5) injury model to identify the active components of HKC against podocyte damage by detecting the expressions of Nephrin, Podocin, and ZO-1 proteins. At last, the key protein levels of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were assessed by western blotting analysis to explore the underlying mechanism of HKC against proteinuria. Results Our results showed that HKC administration for three consecutive weeks dose-dependently ameliorated both renal function and histopathological damages, elevated the expressions of Nephrin and Podocin, the pivotal molecules maintaining filtration function of the podocyte, indicating the promising protective effect against podocyte injury under DOX exposure. Consistently, in vitro experiments showed HKC administration effectively reversed the abnormal expressions of Nephrin and Podocin in MPC-5 cells treated with DOX, suggesting its protective effect against podocyte injury to maintain filtration barrier integrity. In addition, Hibifolin was identified as the most active ingredients in HKC, which suppressed upstream JAK2/STAT3 and PI3K/Akt pathway phosphorylation to maintain the structural and functional integrity of podocyte filtration barrier. Of note, AG490 , a selective JAK2 inhibitor , was used to further affirm the role of Hibifolin involving in regulation JAK2/STAT3. Conclusions Our study suggested that HKC may protect podocytes via JAK2/STAT3 and PI3K/Akt pathway to display its effects of ameliorating proteinuria.
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COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2023
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IF 5.2
Hailiang Chen,Chenyu Liu,Simiao Yu,Hengjun Zhou,Farishta Shafiq,Weihong Qiao
The emergence of liposomes has provided a breakthrough for the clinical use of highly toxic chemotherapeutic drugs . However, the clinical effects of conventional drug-loaded liposomes are unsatisfactory due to the lack of specific targeting of cancer cells and the inability to achieve endosome escape and controllable release in vivo. In this paper, a cRGD-PEOz-Hz-DOB (cPzD) molecule with specific targeting, endosomal escape, and endogenous acid-sensitive controlled release ability was creatively designed and synthesized to prepare drug-loaded liposomes cPzDGX encapsulating the anticancer drug Doxorubicin (DOX) in order to enhance the anticancer performance of DOX. The study found that the hydrazone bond in cPzD reached a breakage rate of 42% within 48 h at pH 5.0, so the cumulative release rate of cPzDGX at pH 5.0 for 48 h was as high as 82.9%, which was 22.5% higher than that at pH 7.4. Moreover, the uptake of cPzDGX in A549/ADR cells was increased by 62% at 2 h, and the expression of the green fluorescent protein gene EGFP was also increased by 36% relative to the targeting control group, indicating that cRGD modification could effectively improve the targeting ability of liposomes to cancer cells. In addition, it was demonstrated that PEOz modification could help drug carriers achieve endosome escape because the green fluorescent protein expression in the PEOz-modified liposome group was 60.5% higher than that in the PEG-modified group. Finally, the cell viability of the cPzDGX group decreased by 17.2% relative to the free DOX group when the DOX concentration was 1 μg/mL in the cytotoxicity assay, and the diameter reduction of 3D tumor MCs increased by 34.4%. And cPzDGX could effectively enhance the permeability of free DOX to solid tumors. The above results indicate that the DOX-loaded liposomes cPzDGX we designed have great prospects for the accurate and efficient treatment of cancer.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Mengli Lu,Li Ma,Juncan Li,Jie Li,Miao Tong,Fuli Dai,Feiyu Song,Xueqiong Zhang,Tong Qiu
As a first-line drug for breast cancer chemotherapy, the effectiveness of doxorubicin (DOX) is challenged by high doses and high toxicity. Studies showed the combination of Tanshinone IIA (TSIIA) and DOX could enhance the efficacy of DOX for cancer and reduce the toxic effects to normal tissues. Unfortunately, free drugs are easily metabolized in the systemic circulation, which are less prone to aggregation at the tumor site to exert anticancer efficacy. In present study, we prepared a carboxymethyl chitosan-based hypoxia-responsive nanoparticles loaded with DOX and TSIIA for the treatment of breast cancer. The results demonstrated that these hypoxia-responsive nanoparticles not only improved the delivery efficiency of the drugs but also enhanced the therapeutic efficacy of DOX. The average size of nanoparticles was about 200–220 nm, the optimal drug loading and encapsulation efficiency of TSIIA in DOX/TSIIA NPs were 9.06 % and 73.59 %, respectively. Hypoxia-responsive behavior were recorded in vitro, while the synergistic efficacy is significantly exhibited in vivo and the tumor inhibitory rate was 85.87 %. Notably, TUNEL assay and immunofluorescence staining verified that the combined nanoparticles exerted a synergistic anti-tumor effect by inhibiting tumor fibrosis, decreasing the expression of HIF-1α and inducing tumor cell apoptosis. Collectively, this carboxymethyl chitosan-based hypoxia-responsive nanoparticles could have promising application prospect for effective breast cancer therapy.
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CARBOHYDRATE POLYMERS
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2022
·
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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Cells
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2022
·Vol. 11
·期 17
·2642
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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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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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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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ACS Applied Materials & Interfaces
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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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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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