PHARMACEUTICAL RESEARCH
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2017
·Vol. 34
·期 12
·2829-2841
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IF 3.002
Li Zhengxiong,Zhang Linlin,Tang Cui,Yin Chunhua
Purpose The present study is aimed at designing an appropriate co-delivery system for chemotherapeutic drugs and gene drugs with high loading capacity, on-demand release behaviors, efficient endosomal escape, and enhanced nucleic localization, thereby providing efficacious antitumor activity. Methods Schiff-base linked imidazole dendritic mesoporous silica nanoparticles (SL-IDMSN) were developed and employed to load doxorubicin (DOX) and survivin shRNA-expressing plasmid (iSur-pDNA) to form nanocomplexes. The nanoparticles were assessed by structural characterization, drug loading and release, cellular uptake, intracellular distribution, gene transfection, in vitro anti-proliferation of hepatoma cells, and in vivo tumor growth inhibition in H-22 tumor bearing mice. Results SL-IDMSN showed high loading capacity for both DOX and iSur-pDNA due to their hierarchical mesostructures. The cleavage of Schiff-base linkage on SL-IDMSN in the weakly acidic endosomes/lysosomes led to microenvironment-specific release of both DOX and iSur-pDNA. Meanwhile, the imidazole modification could trigger the efficient endosomal escape via proton sponge effect, thereby enhancing nuclear accumulation of iSur-pDNA and gene silencing efficiency. More importantly, these superior performances of SL-IDMSN resulted in their improved inhibitory effects on in vitro cancer cell proliferation and in vivo tumor growth. Conclusions SL-IDMSN is a microenvironment-sensitive and biocompatible nanocarrier for the co-delivery of DOX and iSur-pDNA, which might be a promising carrier for co-delivery of chemotherapeutic drugs and gene drugs for synergistic cancer therapy.
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Materials Science & Engineering C-Materials for Biological Applications
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2016
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IF 3.42
Yang Qiu,Chao Wu,Jie Jiang,Yanna Hao,Ying Zhao,Jie Xu,Tong Yu,Peng Ji
A carrier consisting of lipid-coated hollow mesoporous silica nanospheres (L-HMSN) was produced for the combination of the water-insoluble drug (paclitaxel, PTX) and the water-soluble drug (doxorubicin, DOX). DOX was adsorbed into the nanoscale hollow structure of the hollow mesoporous silica nanospheres (HMSN) by adsorption and PTX was wrapped in the phospholipid layer of the HMSN surface by lipid film hydration method. The characterization results showed that DOX and PTX were present in the nanopheres in an amorphous state. The loaded L-HMSN (DOX/PTX@L-HMSN) in vitro drug release showed a sustained release in phosphate buffered solution (PBS) at pH 6.8 and 0.001%SDS. The cellular uptake experiment indicated that L-HMSN was successfully taken up by A549 cells. In addition, the combination of DOX and PTX in L-HMSN exhibited a marked synergistic effect in inhibiting the proliferation of A549 cells. The pharmacokinetic study demonstrated that L-HMSN could significantly improve the relative bioavailability of DOX and PTX. These results confirm that L-HMSN is a promising carrier for successful drug combination.
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Nanoscale Research Letters
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2019
·Vol. 14
·期 1
·1-10
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IF 3.159
He Jinyuan,Gong Chulian,Qin Jie,Li Mingan,Huang Shaohong
Current cancer therapy usually succumbs to many extracellular and intracellular barriers, among which untargeted distribution and multidrug resistance (MDR) are two important difficulties responsible for poor outcome of many drug delivery systems (DDS). Here, in our study, the dilemma was addressed by developing a cancer cell membrane (CCM)-coated silica (SLI) nanoparticles to co-deliver miR495 with doxorubicin (DOX) for effective therapy of lung cancer (CCM/SLI/R-D). The homologous CCM from MDR lung cancer cells (A549/DOX) was supposed to increase the tumor-homing property of the DDS to bypass the extracellular barriers. Moreover, the MDR of cancer cells were conquered through downregulation of P-glycoprotein (P-gp) expression using miR495. It was proved that miR495 could significantly decrease the expression of P-gp which elevated intracellular drug accumulation in A549/DOX. The in vitro and in vivo results exhibited that CCM/SLI/R-D showed a greatly enhanced therapeutic effect on A549/DOX, which was superior than applying miR495 or DOX alone. The preferable effect of CCM/SLI/R-D on conquering the MDR in lung cancer provides a novel alternative for effective chemotherapy of MDR cancers.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2018
·
IF 3.862
Yan Chen,Yao Cheng,Pengxuan Zhao,Shasha Zhang,Minsi Li,Chuanchuan He,Xiaojuan Zhang,Tan Yang,Ruicong Yan,Peng Ye,Xiang Ma,Guangya Xiang
Multidrug resistance to chemotherapeutic drugs is a major obstacle to breast cancer treatment. In this study, doxorubicin (DOX) and imatinib (IM) were co-loaded into folate receptor targeted (FR-targeted) pH-sensitive liposomes (denoted as FPL-DOX/IM) to fulfill intracellular acid-sensitive release and reverse drug resistance. FPL-DOX/IM could maintain stability in blood circulation with approximate diameters of 100 nm and rapidly release encapsulated drugs in tumor acidic microenvironment. Moreover, the IM in combination therapy could overcome chemoresistance associated with DOX effectively by inhibiting ABC transporter function and improving chemotherapy sensitivity. The designed liposomes co-loaded with DOX and IM significantly enhanced anti-tumor effects both in vitro and in vivo . These findings suggest that FPL-DOX/IM provides a novel strategy to improve chemotherapeutic efficacy against MDR tumors.
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Nanoscience and Nanotechnology Letters
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2019
·Vol. 11
·期 6
·749-759
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IF 0
Wang Zhi,Du Yawei,He Wei,Zhou Wenya,Xia Qing,Li Xinsong
Drug resistance is one of the major reasons for chemotherapy failure in breast cancer clinical therapy. In this study, a novel liposomal two-drug co-delivery delivery system was assembled from all-trans retinoic acid (ATRA) dimer phospholipid conjugate (diATRA-PC) and developed as a
doxorubicin (DOX) carrier to overcome drug resistance in breast cancer. The DOX encapsulated diATRA-PC liposomes (diATRA-PC/DOX liposomes) were prepared by classic method, with a uniform size distribution between 50–100 nm. The free ATRA and DOX were released from liposomes simultaneously
under simulated tumor intracellular environment. Moreover, the diATRA-PC liposomes exhibited enhanced cellular uptake, cytotoxicity and migration, inhibiting capacity against DOX-resistant human breast cancer cell line (MCF-7/ADR) when compared with controls. Reverse transcription-polymerase
chain reaction (RT-PCR) analysis demonstrated that the diATRA-PC/DOX liposomes had an effective promotion of apoptosis in DOX-resistant cells, with up-regulation of Caspase-3 and down-regulation of Bcl-2 mRNA expression. One could speculate that the reversed drug resistance in MCF-7/ADR cells
was attributed to the enhanced cellular uptake of DOX by cancer cells in overcoming the drug efflux. In addition, pharmacokinetics studies showed that diATRAPC/DOX liposomes had a longer circulating time in comparison with free drug. In summary, the diATRA-PC liposomes can be regarded as a
potential multi-drug combination therapeutic system for reversing drug resistance in breast cancer.
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Pharmaceutics
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2020
·Vol. 12
·期 7
·680
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IF 4.421
Jin Zhang,Xiaoyue Tang,Chuanqing Huang,Zeyu Liu,Yong Ye
Oleic acid (OA) as main component of plant oil is an important solvent but seldom used in the nanocarrier of anticancer drugs because of strong hydrophobicity and little drug release. In order to develop a new type of OA nanomaterial with dual responses to pH and near infrared light (NIR) to achieve the intelligent delivery of anticancer drugs. The novel OA copolymer (mPEG-PEI-(NBS, OA)) was synthesized by grafting OA ando-nitrobenzyl succinate (NBS) onto mPEGylated polyethyleneimine (mPEG-PEI) by amidation reaction. It was further conjugated with NaYF4:Yb3+/Er3+nanoparticles, and encapsulated doxorubicin (DOX) through self-assembly to make upconversion nanomicelles with dual response to pH and NIR. Drug release behavior of DOX, physicochemical characteristics of the nanomicelles were evaluated, along with its cytotoxic profile, as well as the degree of cellular uptake in A549 cells. The encapsulation efficiency and drug loading capacity of DOX in the nanomicelles were 73.84% ± 0.58% and 4.62% ± 0.28%, respectively, and the encapsulated DOX was quickly released in an acidic environment exposed to irradiation at 980 nm. The blank nanomicelles exhibited low cytotoxicity and excellent biocompatibility by MTT assay against A549 cells. The DOX-loaded nanomicelles showed remarkable cytotoxicity to A549 cells under NIR, and promoted the cellular uptake of DOX into the cytoplasm and nucleus of cancer cells. OA copolymer can effectively deliver DOX to cancer cells and achieve tumor targeting through a dual response to pH and NIR.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
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IF 4.152
Xiaole Qi,Yao Rui,Yuchao Fan,Haiyan Chen,Ning Ma,Zhenghong Wu
Carbon nanotubes (CNTs) are well known for their distinctive drug-loading ability that is mainly due to their large surface area, which permits covalent attachment of various target ligands or drug molecules by π–π stacking, allowing them to act as potential tumor-targeting carriers. Herein, we describe the development of galactosylated chitosan-graftedoxidized CNTs (O-CNTs-LCH) for pH-dependent sustained release and hepatic tumor-targeted delivery of doxorubicin (DOX). The in vitro release behavior in aqueous release media of different pH values (5.5, 6.5 and 7.4) verified the pH-dependent sustained release of DOX from O-CNTs-LCH-DOX. Moreover, these nanocarriers exhibited significant in vitro tumor-targeting properties, with a higher cellular uptake efficiency than that of free DOX in HepG2 cells. In addition, the good biocompatibility and low toxicity of O-CNTs-LCH-DOX was demonstrated by evaluating HepG2 cytotoxicity, vascular irritation and the maximum tolerated dose. Moreover, after intravenous administration in mice bearing the H22 tumor, O-CNTs-LCH-DOX showed higher antitumor activity and stronger fluorescent intensity in tumor tissue compared to free DOX. These results indicated the selective hepatic tumor targeting and the therapeutic effect of those nanocarriers.
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RSC Advances
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2019
·Vol. 9
·期 54
·31264-31273
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IF 3.049
Wei Li,Cheng Tao,Jiexin Wang,Yuan Le,Jianjun Zhang
The complex construction within the oral cavity causes incomplete surgical resection of oral squamous cell carcinoma (OSCC) that may enhance the risk of recurrence and metastasis in the treatment. In situ forming injectable hydrogels with minimally invasive procedures, encapsulation stability and stimuli-responsive degradation have emerged as promising carriers for local drug delivery. In this study, doxorubicin (DOX) was first encapsulated in biodegradable poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PDLLA-PEG-PDLLA) micelles and then loaded into an in situ injectable hyaluronic acid (HA) hydrogel, which was cross-linked by a matrix metalloproteinase-2 (MMP-2)-responsive peptide (GCRDGPQGIWGQDRCG) through a Michael addition reaction. In vitro studies demonstrated that the HA hydrogel had a sensitive MMP-2-responsive drug release profile. Investigations including MTT, live-dead, apoptosis, and wound healing assays illustrated that DOX micelle-loaded HA hydrogels exhibited outstanding cytotoxicity against squamous carcinoma cells (SCC-15). Furthermore, by in vivo studies, we also proved that HA hydrogels degraded faster in the tumor site than in normal tissue, which led to a local sustained release of DOX-loaded micelles and tumor growth inhibition of oral squamous cell carcinoma (OSCC) without any damage to the organs. Therefore, this work provides a remarkable drug delivery platform for local chemotherapy and other applications.
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International Journal of Nanomedicine
·
2021
·
IF 6.4
Jialang Zhuang,Siqi Chen,Ye Hu,Fan Yang,Qin Huo,Ni Xie
Introduction Metastatic breast cancer seriously harms women’s health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.
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International Journal of Nanomedicine
·
2025
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IF 6.5
Lulu Zhang,Haiyang Liu,Jin Ren,Junyi Shao,Yanrong Cao,Shuangshuang Wang,Changchun Peng,Shengwen Shao,Haixia Ge,Jingmou Yu
Background Stimuli-responsive polymer-drug nanoparticles have emerged as a versatile and effective platform for delivering drugs in the treatment of malignant tumors. The integration of chemo-phototherapy has gained increasing prominence due to its remarkable synergistic antitumor effects.Methods Hydrophilic sericin (Ser) was linked to antitumor drug doxorubicin (DOX) via a disulfide bond. The obtained Ser-ss-DOX conjugate was characterized by Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). The near-infrared (NIR) fluorescent dye IR780 was encapsulated into Ser-ss-DOX by a dialysis method. The physical state of IR780 within Ser-ss-DOX/IR780 nanoparticles was analyzed by differential scanning calorimetry (DSC). The photothermal properties and drug release behavior of IR780-loaded nanoparticles were systematically investigated. Cellular uptake and reactive oxygen species (ROS) generation capacity and in vitro cytotoxicity of IR780-containing nanoparticles were studied in 4T1 breast cancer cells. In addition, 3D multicellular tumor spheroid model was conducted to investigate the antitumor activity of the nanoparticles.Results The Ser-ss-DOX conjugate was successfully synthesized. Ser-ss-DOX and Ser-ss-DOX/IR780 nanoparticles were spherical in shape, and their particle sizes measured by DLS were 326 and 190 nm, respectively. IR780 was in an amorphous state within the Ser-ss-DOX/IR780 nanoparticles. The loading contents of DOX and IR780 were 8.26% and 2.78%, respectively. Ser-ss-DOX/IR780 exhibited ideal photothermal properties in vitro and reduction-sensitive drug release in a high glutathione (GSH) environment. Ser-ss-DOX/IR780 displayed higher cellular uptake in 4T1 cells than Ser-ss-DOX and free DOX. Under 808 nm laser irradiation, Ser-ss-DOX/IR780 showed a strong capacity to generate ROS. Importantly, Ser-ss-DOX/IR780 with laser irradiation effectively inhibited the growth of 4T1 cells and 3D multicellular tumor spheroids.Conclusion This work demonstrated that Ser-ss-DOX/IR780 integrated dual functionalities of chemotherapy and phototherapy, thereby enabling substantial potential for application in tumor treatment.
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International Journal of Nanomedicine
·
2023
·
IF 8
Jijun Fu,Qianni Wu,Yuanye Dang,Xueping Lei,Guining Feng,Mingyue Chen,Xi-Yong Yu
Introduction Traditional antitumor chemotherapy faces great challenges, such as multi-drug resistance (MDR) and poor penetration into tumor tissues. The newly emerging nitric oxide (NO)-based gas therapy has been recognized to reduce MDR and has improved permeation into tumor tissue.Methods In this study, NO-generating prodrug sodium nitroprusside (SNP) was doped to hollow mesoporous Prussian blue (PB) nanoparticles to fabricate NO-generating nanoparticles (NO-PB), which was further loaded with doxorubicin (DOX).Results DOX loaded NO-PB (DOX-NO-PB) was released quicker at pH 6 compared with neutral pH, suggesting NO-PB may facilitate the release of loaded drug in acidic tumor tissue. The capacity of NO production by NO-PB was measured, and the results showed the presence of NO in the culture medium from 4T1 cells incubated with NO-PB and inside the cells. NP-PB could be detected by photoacoustic imaging (PAI) in tumor tissue in 4T1 tumor bearing mice, suggesting this nanoparticle may serve as contrast agent for the noninvasive diagnosis of tumor tissues. NO-PB suppressed the growth of tissues in 4T1 tumor bearing mice. DOX-NO-PB showed more potent anti-tumor effects in 4T1 cells and tumor bearing mice compared with free DOX and NO-PB alone, indicating that the combination of DOX and NO-PB exhibited synergistic effects on tumor suppression.Conclusion This study provides a novel nanocarrier for gas therapy with additional PAI imaging capacity. This nanocarrier can be utilized for combination therapy of NO and chemotherapeutics which may serve as theranostic agents.
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Nature Biomedical Engineering
·
2020
·Vol. 4
·期 7
·732-742
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IF 18.952
Li Suping,Zhang Yinlong,Ho Shih-Hsin,Li Bozhao,Wang Meifang,Deng Xiongwei,Yang Na,Liu Guangna,Lu Zefang,Xu Junchao,Shi Quanwei,Han Jing-Yan,Zhang Lirong,Wu Yan,Zhao Yuliang,Nie Guangjun
Drugs that induce thrombosis in the tumour vasculature have not resulted in long-term tumour eradication owing to tumour regrowth from tissue in the surviving rim of the tumour, where tumour cells can derive nutrients from adjacent non-tumoral blood vessels and tissues. Here, we report the performance of a combination of tumour-infarction therapy and chemotherapy, delivered via chitosan-based nanoparticles decorated with a tumour-homing peptide targeting fibrin–fibronectin complexes overexpressed on tumour-vessel walls and in tumour stroma, and encapsulating the coagulation-inducing protease thrombin and the chemotherapeutic doxorubicin. Systemic administration of the nanoparticles into mice and rabbits bearing subcutaneous or orthotopic tumours resulted in higher tumour growth suppression and decreased tumour recurrence than nanoparticles delivering only thrombin or doxorubicin, with histological and haematological analyses indicating an absence of detectable toxicity. The co-administration of a cytotoxic payload and a protease to elicit vascular infarction in tumours with biodegradable tumour-targeted nanoparticles represents a promising strategy for improving the therapeutic index of coagulation-based tumour therapy.
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