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1.
J Agric Food Chem ; 72(22): 12516-12528, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38491972

ABSTRACT

Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3ß (GSK3ß) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.


Subject(s)
Cognitive Dysfunction , Diabetes Mellitus, Type 2 , Saponins , Signal Transduction , Triterpenes , Animals , Humans , Male , Mice , Blood Glucose/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/genetics , Hippocampus/drug effects , Hippocampus/metabolism , Mice, Inbred C57BL , Neurons/drug effects , Neurons/metabolism , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Saponins/pharmacology , Saponins/administration & dosage , Signal Transduction/drug effects , Triterpenes/pharmacology , Triterpenes/administration & dosage
2.
J Ethnopharmacol ; 308: 116294, 2023 May 23.
Article in English | MEDLINE | ID: mdl-36804201

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) was considered to be a neurodegenerative disease that caused cognitive impairment. Reactive Oxidative stress (ROS) was considered to be one of a major cause of the onset and progression of AD. Platycodin D (PD), a representative saponin from Platycodon grandiflorum, has conspicuous antioxidant activity. However, whether PD could protect nerve cell against oxidative injury remains unknown. AIM OF STUDY: This study investigated the regulatory effects of PD on neurodegeneration caused by ROS. To determine whether PD could play its own antioxidant role in neuronal protection. MATERIALS AND METHODS: First, PD(2.5, 5 mg/kg) ameliorated the memory impairment induced by AlCl3 (100 mg/kg) combined with D-galactose (D-Gal) (200 mg/kg) in mice, using the radial arm maze (RAM) test, and neuronal apoptosis in the hippocampus was evaluated by hematoxylin and eosin staining (HE). Next, the effects of PD (0.5, 1, and 2 µM) on okadaic-acid (OA) (40 nM) -induced apoptosis and inflammation of HT22 cells were investigated. Mitochondrial ROS production was measured by fluorescence staining. The potential signaling pathways were identified through Gene Ontology enrichment analysis. The role of PD in regulating AMP-activated protein kinase (AMPK) was assessed using siRNA silencing of genes and an ROS inhibitor. RESULTS: In vivo, PD improved memory in mice, and recovered the morphological changes of brain tissue and nissl bodies. In vitro experiment, PD increased cell viability (p < 0.01; p < 0.05;p < 0.001), decreased apoptosis (p < 0.01), reduced excessive ROS and MDA, rised SOD and CAT content(p < 0.01; p < 0.05). Morover, it can block the inflammatory response caused by ROS. Be important, PD strengthen antioxidant ability by elevating AMPK activation both in vivo and in vitro. Furthermore, molecular docking suggested a good likelihood of PD-AMPK binding. CONCLUSION: AMPK activity is vital for the neuroprotective effect of PD, suggesting that PD may be a potential pharmaceutical agent to treat ROS-induced neurodegeneration.


Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Saponins , Mice , Animals , Reactive Oxygen Species/metabolism , Antioxidants/pharmacology , AMP-Activated Protein Kinases/metabolism , Molecular Docking Simulation , Oxidative Stress , Saponins/pharmacology , Alzheimer Disease/drug therapy , Apoptosis , Inflammation
3.
ACS Omega ; 7(21): 18122-18130, 2022 May 31.
Article in English | MEDLINE | ID: mdl-35664604

ABSTRACT

1-O-Acetylbritannilactone (ABL) is a marker component of Inula britannica L. and is reported to exhibit multiple pharmacological activities, including antiaging, anti-inflammatory, and antidiabetic properties. Although the protective effect of Inula britannica L. on animal models of liver injury has been widely reported, the effect of ABL on alcohol-induced liver damage has not been confirmed. The present study was designed to investigate the protective effect of ABL against alcohol-induced LO2 human normal liver cell injury and to further clarify the underlying mechanism. Our results revealed that ABL at concentrations of 0.5, 1, and 2 µM could remarkably suppress the decreased viability of LO2 cells stimulated by alcohol. In addition, ABL pretreatment improved alcohol-induced oxidative damage by decreasing the level of reactive oxygen species (ROS) and the excessive consumption of glutathione peroxidase (GSH-Px), while increasing the level of catalase (CAT) in LO2 cells. Moreover, Western blotting analysis showed that ABL pretreatment activated protein kinase B (Akt) phosphorylation, increased downstream antiapoptotic protein Bcl-2 expression, and decreased the phosphorylation level of the caspase family including caspase 9 and caspase 3 proteins, thereby attenuating LO2 cell apoptosis. Importantly, we also found that ABL significantly inhibits the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the secretion of proinflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin (IL-1ß). In conclusion, the current research clearly suggests that the protective effect of ABL on alcohol-induced hepatotoxicity may be achieved in part through regulation of the ROS/Akt/NF-κB signaling pathway to inhibit inflammation and apoptosis in LO2 cells. (The article path map has not been seen.).

4.
J Colloid Interface Sci ; 603: 70-84, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34186412

ABSTRACT

Nanotherapy based on thermochemotherapy has boomed as a promising alternative for oncotherapy due to the enhanced permeability and retention (EPR) effect. However, a lack of self-targeting capacity prevents nanotherapy from efficiently accumulating in tumor tissue and internalizing into tumor cells, resulting in a suboptimal therapeutic effect. To overcome these bottlenecks, a kind of methotrexate (MTX)-soybean phospholipid (SPC) inclusion complex (MTX-SPC)-modified graphene oxide (CGO) nanotherapy (CGO-MTX-SPC) is constructed by CGO nanosheets as a supporter for MTX-SPC, thereby realizing active-targeting and synergistic thermochemotherapy. As an FDA-approved chemotherapeutic drug, MTX can be regarded as a tumor-targeting enhancer against the folate receptor on account of its similar structure to folic acid (FA). The fabricated CGO-MTX-SPC has a sheet shape with a size of ca. 109 nm and tumor microenvironment-responsive on-demand drug release. It is worth noting that the physiological stability of CGO-MTX-SPC is better than that of CGO while displaying an improved photothermal effect. In addition, CGO-MTX-SPC can specifically recognize tumor cells and then achieve on-demand drug burst release by dual stimuli of internal lysosomal acidity and an external laser. Moreover, in vivo experimental results further demonstrate that CGO-MTX-SPC displays significant enrichment at the tumor location by active targeting mechanisms due to the introduction of MTX-SPC, endowing the synergistic thermochemotherapy effect upon 808 nm laser irradiation and almost thorough tumor elimination while significantly erasing undesirable side effects. Taken together, the design idea of our nanotherapy not only provides a potential tumor-targeting therapeutic strategy but also broadens the drug payload method of two-dimensional nanomaterials.


Subject(s)
Drug Delivery Systems , Nanoparticles , Cell Line, Tumor , Cell Survival , Graphite , Methotrexate
5.
Sci Adv ; 6(20): eaaz8411, 2020 05.
Article in English | MEDLINE | ID: mdl-32426500

ABSTRACT

Transcriptional status determines the HIV replicative state in infected patients. However, the transcriptional mechanisms for proviral replication control remain unclear. In this study, we show that, apart from its function in HIV integration, LEDGF/p75 differentially regulates HIV transcription in latency and proviral reactivation. During latency, LEDGF/p75 suppresses proviral transcription via promoter-proximal pausing of RNA polymerase II (Pol II) by recruiting PAF1 complex to the provirus. Following latency reversal, MLL1 complex competitively displaces PAF1 from the provirus through casein kinase II (CKII)-dependent association with LEDGF/p75. Depleting or pharmacologically inhibiting CKII prevents PAF1 dissociation and abrogates the recruitment of both MLL1 and Super Elongation Complex (SEC) to the provirus, thereby impairing transcriptional reactivation for latency reversal. These findings, therefore, provide a mechanistic understanding of how LEDGF/p75 coordinates its distinct regulatory functions at different stages of the post-integrated HIV life cycles. Targeting these mechanisms may have a therapeutic potential to eradicate HIV infection.


Subject(s)
HIV Infections , HIV Integrase , HIV-1 , Cell Line , HIV Infections/genetics , HIV Integrase/genetics , HIV-1/physiology , Humans , Intercellular Signaling Peptides and Proteins , Proviruses/genetics , Transcription Factors/genetics , Virus Integration
6.
J Mater Chem B ; 8(9): 1922-1934, 2020 03 04.
Article in English | MEDLINE | ID: mdl-32052817

ABSTRACT

Carrier-free nanoparticles (NPs) via chemotherapeutic drug-drug conjugate assembly are a promising alternative for tumor chemotherapy. However, these NPs are still hindered via their nonspecific internalization into certain healthy cells and tissues. Herein, dual-acting methotrexate (MTX) and mannose (MAN) were conjugated via a hydrolyzable ester bond to synthesize a MTX-MAN conjugate as one molecule, which could be directly self-assembled into stimulus-responsive carrier-free NPs (MTX-MAN NPs) in aqueous solution. Such carrier-free MTX-MAN NPs with an accurate drug to sugar ratio could achieve on-demand drug release by dual stimuli of lysosomal acidity and esterase. Besides, MTX-MAN NPs could be dual-recognized by tumor cells in vitro and specifically by tumors in vivo. Moreover, the large proportion of MAN located on the NPs' surface could exert a shielding effect to avoid phagocytosis of macrophages, leading to long blood circulation. Therefore, the MTX-MAN NPs sharply reduced the drug dosage and decreased the toxicity to normal cells and tissues. Further in vitro and in vivo studies consistently confirmed that the MTX-MAN NPs exhibited superior tumor accumulation and highly synergistic chemotherapeutic effects. Furthermore, we found for the first time that MAN could enhance the antitumor activity of MTX. Considering that bi-functional MTX and MAN are approved via the FDA, and MAN is highly biosafe, the dual-self-recognizing, stimulus-responsive, and carrier-free MTX-MAN NPs might be a simple, selective, and safe chemotherapeutic strategy.


Subject(s)
Antineoplastic Agents/pharmacology , Mannose/pharmacology , Methotrexate/pharmacology , Nanoparticles/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Delivery Systems , Drug Liberation , Drug Screening Assays, Antitumor , Humans , Mannose/chemistry , Methotrexate/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/drug therapy , Optical Imaging , Particle Size , Surface Properties
7.
Mol Pharm ; 16(7): 3133-3144, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31198046

ABSTRACT

The clinical translation of methotrexate (MTX) is limited because of low aqueous solubility, poor bioavailability, low uptake efficiency, and toxicity concerns. Herein, dual-acting MTX (not only targeting folate receptors but also killing cells via inhibition of intracellular folate metabolism) and hyaluronic acid (HA, targeting CD44 receptors) were selected to be covalently linked by the redox-responsive disulfide bond. The synthesized prodrug (HA-SS-MTX) as a molecular structural motif could self-assemble into simple yet multifunctional nanoparticles (HA-SS-MTX NPs) in aqueous solution. The HA-SS-MTX NPs displayed an average diameter of ∼110 nm with a uniformly spherical shape and maintained stability in different physiological media. Moreover, the HA-SS-MTX NPs could exhibit a sharp redox-dependent response for rapid structure disassembly and sequential MTX release compared to the redox-irresponsive group (HA-ADH-MTX NPs). Furthermore, the results of confocal microscopy and flow cytometry verified that the nanosystems were selectively uptaken by cancer cells via folate and CD44 receptor-mediated internalization through the dual-active targeting mechanism. In addition, HA-SS-MTX NPs could accumulate within tumor sites for a longer period. Notably, in vitro and in vivo antitumor results demonstrated that HA-SS-MTX NPs significantly promoted the death of cancer cells and enhanced the inhibition of tumor growth while reducing the toxicity as compared to MTX and HA-ADH-MTX NPs. Therefore, the smart HA-SS-MTX NPs as the simple and efficient platform have great potential in tumor-targeting drug delivery and therapy.


Subject(s)
Drug Delivery Systems/methods , Folic Acid Antagonists/metabolism , Hyaluronic Acid/metabolism , Methotrexate/metabolism , Nanoparticles/chemistry , Prodrugs/metabolism , Uterine Cervical Neoplasms/drug therapy , Animals , Cell Survival/drug effects , Disulfides/chemistry , Drug Liberation , Female , Folic Acid Antagonists/chemistry , Folic Acid Antagonists/pharmacology , HeLa Cells , Humans , Hyaluronan Receptors/antagonists & inhibitors , Hyaluronan Receptors/metabolism , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Methotrexate/chemistry , Methotrexate/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Oxidation-Reduction , Tissue Distribution , Treatment Outcome , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
8.
Biomater Sci ; 6(7): 1818-1833, 2018 Jun 25.
Article in English | MEDLINE | ID: mdl-29785434

ABSTRACT

Combinational cancer therapy has been considered as a promising strategy to achieve synergetic therapeutic effects and suppression of multidrug resistance. Herein, we adopted a combination of methotrexate (MTX), an antimetabolite acting on cytoplasm, and 10-hydroxycamptothecin (HCPT), an alkaloid acting on nuclei, to treat cancer. Given the different solubilities, membrane permeabilities, and anticancer mechanisms of both drugs, we developed a dual-targeting delivery system based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-hyaluronic acid (a principal ligand of CD44 receptors)-MTX (a selective ligand of folate receptors) nanoparticles, which was exploited to carry HCPT-MTX conjugate for synergistically boosting dual-drug co-delivery. The HCPT-MTX conjugate was synthesized by a blood-stable yet intracellularly hydrolysable ester bond. The core-shell-corona DSPE-HA-MTX nanoparticles encapsulating HCPT-MTX (HCPT-MTX@DHM) exhibited high drug entrapment efficiency (∼91.8%) and pH/esterase-controlled release behavior. Cellular uptake studies confirmed significant increase in the efficiency of selective internalization of HCPT-MTX@DHM via CD44/folate receptors compared with those of DSPE-HA nanoparticles encapsulating HCPT-MTX (HCPT-MTX@DH), both drugs, or each individual drug. Furthermore, in vivo near-infrared fluorescence and photoacoustic dual-modal imaging indicated that DiR-doped HCPT-MTX@DHM nanoparticles efficiently accumulated at the tumor sites through passive-plus-active targeting. Finally, the synergistic active targeting and synchronous dual-drug release at a synergistic drug-to-drug ratio resulted in highly synergetic tumor cell-killing and tumor growth inhibition in MCF-7 tumor-bearing mice. Therefore, HCPT-MTX@DHM nanoparticles can be an efficient and smart platform for tumor-targeting therapy.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Camptothecin/analogs & derivatives , Hyaluronic Acid/chemistry , Methotrexate/pharmacology , Phosphatidylethanolamines/chemistry , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Animals , Antimetabolites, Antineoplastic/chemistry , Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Camptothecin/chemistry , Camptothecin/pharmacology , Drug Carriers , Drug Compounding/methods , Drug Synergism , Female , Folate Receptors, GPI-Anchored/genetics , Folate Receptors, GPI-Anchored/metabolism , Folic Acid/metabolism , Humans , MCF-7 Cells , Methotrexate/chemistry , Mice , Mice, Nude , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Nanoparticles/metabolism , Survival Analysis , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
9.
Int J Nanomedicine ; 13: 1381-1398, 2018.
Article in English | MEDLINE | ID: mdl-29563794

ABSTRACT

AIM: We designed acid-labile methotrexate (MTX) targeting prodrug self-assembling nanoparticles loaded with curcumin (CUR) drug for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy. METHODS: A dual-acting MTX, acting as both an anticancer drug and as a tumor-targeting ligand, was coupled to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethylene glycol)-2000] via Schiff's base reaction. The synthesized prodrug conjugate (DSPE-PEG-Imine-MTX) could be self-assembled into micellar nanoparticles (MTX-Imine-M) in aqueous solution, which encapsulated CUR into their core by hydrophobic interactions (MTX-Imine-M-CUR). RESULTS: The prepared MTX-Imine-M-CUR nanoparticles were composed of an inner hydrophobic DSPE/CUR core and an outside hydrophilic bishydroxyl poly (ethyleneglycol) (PEG) shell with a self-targeting MTX prodrug corona. The imine linker between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethyleneglycol)-2000] and MTX, as a dynamic covalent bond, was strong enough to remain intact in physiological pH, even though it is rapidly cleaved in acidic pH. The MTX-Imine-M-CUR could codeliver MTX and CUR selectively and efficiently into the cancer cells via folate receptor-mediated endocytosis followed by the rapid intracellular release of CUR and the active form of MTX via the acidity of endosomes/lysosomes. Moreover, the MTX-Imine-M-CUR resulted in significantly higher in vitro and in vivo anticancer activity than pH-insensitive DSPE-PEGAmide-MTX assembling nanoparticles loaded with CUR (MTX-Amide-M-CUR), MTX unconjugated DSPE-PEG assembling micellar nanoparticles loaded with CUR (M-CUR), combination of both free drugs, and individual free drugs. CONCLUSION: The smart system provided a simple, yet feasible, drug delivery strategy for targeted combination chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Curcumin/therapeutic use , Drug Delivery Systems/methods , Methotrexate/therapeutic use , Nanoparticles/chemistry , Neoplasms/drug therapy , Neoplasms/pathology , Prodrugs/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Death/drug effects , Colloids , Curcumin/chemistry , Curcumin/pharmacology , Drug Carriers/chemistry , Drug Liberation , Endocytosis/drug effects , HeLa Cells , Humans , Hydrodynamics , Hydrogen-Ion Concentration , MCF-7 Cells , Methotrexate/pharmacology , Mice, Inbred BALB C , Mice, Nude , Micelles , Particle Size , Phosphatidylethanolamines/chemical synthesis , Phosphatidylethanolamines/chemistry , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/chemistry , Prodrugs/pharmacology
10.
J Mater Chem B ; 5(33): 6835-6846, 2017 Sep 07.
Article in English | MEDLINE | ID: mdl-32264333

ABSTRACT

Nanoparticles (NPs) functionalized with targeting ligands have shown promise, but are still limited by their nonspecific uptake by certain healthy tissues and cells that express low or even comparable levels of receptors. To increase their accumulation at tumor sites while decreasing the unintended toxicity, a possible solution is the involvement of two separate tumor-specific ligands in the localization. In this study, a dual tumor-targeting drug-loaded NP system was self-assembled by the amphiphilic conjugate of methotrexate-hyaluronic acid-octadecylamine (MTX-HA-OCA) with curcumin (CUR) encapsulated within the hydrophobic core (designated as MTX-HA-OCA/CUR NPs). The advantages of this nanosystem are that the anticancer drug MTX can be utilized as a tumor-targeting ligand toward folate receptors due to its structural similarity to folic acid (FA), and HA can serve as another tumor-targeting ligand toward CD44 receptors. The MTX-HA-OCA/CUR NPs are ∼70 nm in diameter and have sustained/controlled drug release behavior. An in vitro cellular uptake and competition inhibition study exhibited that MTX-HA-OCA/CUR NPs could significantly enhance the internalization efficiency in HeLa cells via folate/CD44 receptor-mediated endocytosis as compared to HA-OCA/CUR NPs. More importantly, the in vitro cytotoxicity of MTX-HA-OCA/CUR NPs was significantly enhanced as compared to those of the HA-OCA/CUR NPs, both free drugs, and individual free drug. Furthermore, the real-time in vivo and ex vivo fluorescence imaging of HeLa tumor-bearing mice showed that MTX-HA-OCA/CUR NPs could more efficiently enhance their accumulation and improve the penetration at the tumor site as compared to HA-OCA/CUR NPs. Therefore, these dually folate/CD44 receptor-targeted self-assembled HA NPs for the co-delivery of both anticancer drugs might provide a promising strategy for dual-targeted combination cancer therapy.

11.
Nanoscale Res Lett ; 11(1): 384, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27581601

ABSTRACT

We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells.

12.
Int J Pharm ; 512(1): 194-203, 2016 Oct 15.
Article in English | MEDLINE | ID: mdl-27566011

ABSTRACT

Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with specific targeting and synergistic therapeutic functions for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. We hypothesize that using a macromolecular prodrug with a dual role will be conductive to integrating its dual function into self-targeted multidrug co-delivery and combination cancer therapy. In this paper, the on-off switching function-responsive, macromolecular methotrexate (MTX) prodrug-self-targeted, controlled-/sustained-release, and high drug-loading hydroxylcamptothecin (HCPT) drug nanospheres were prepared and characterized. The self-targeting system can co-deliver multi-drug to different action sites with distinct anticancer mechanisms to specifically target folate receptors-overexpressing cancer cells with synergistic therapeutic efficiency.


Subject(s)
Camptothecin/administration & dosage , Camptothecin/pharmacology , Drug Carriers/administration & dosage , Methotrexate/administration & dosage , Methotrexate/pharmacology , Nanospheres/administration & dosage , Nanospheres/chemistry , Animals , Camptothecin/chemistry , Camptothecin/pharmacokinetics , Cell Line, Tumor , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Drug Liberation , Drug Stability , Inhibitory Concentration 50 , Methotrexate/chemistry , Methotrexate/pharmacokinetics , Mice , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemistry , Prodrugs/administration & dosage , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Xenograft Model Antitumor Assays
13.
Nanoscale Res Lett ; 11(1): 294, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27299649

ABSTRACT

The high-aspect-ratio nanoparticles were proved to be internalized much more rapidly and efficiently by cancer cells than the nanoparticles with an equal aspect ratio. Herein, a kind of high-aspect ratio, pointed-end nanoneedles (NDs) with a high drug loading (15.04 %) and the prolonged drug release profile were fabricated with an anti-tumor drug-10-hydroxycamptothecin (HCPT)-via an ultrasound-assisted emulsion crystallization technique. It is surprising to see that the cellular internalization of NDs with an average length of 5 µm and an aspect ratio of about 12:1 was even much faster and higher than that of nanorods with the same size and the nanospheres with a much smaller size of 150 nm. The results further validated that cellular internalization of the nanoparticles exhibited a strong shape-dependent effect, and cellular uptake may favor the particles with sharp ends as well as a high-aspect ratio instead of particle size. The NDs with enhanced cytotoxicity would lead to a promising sustained local drug delivery system for highly efficient anticancer therapy. More importantly, the fabrication of NDs opens a door to design new formulations of nanoneedle drug delivery systems for highly efficient cancer.

14.
Yao Xue Xue Bao ; 51(8): 1309-15, 2016 08.
Article in Chinese | MEDLINE | ID: mdl-29906035

ABSTRACT

In this study, we used Shirasu porous glass membrane(SPG) as a template and hydroxy camptothecin (HCPT) as a model drug to prepare the comet-shaped Me PEG [methoxyl poly(ethylene glycol)]- PLGA [poly(lactic-co-glycolic acid)-HCPT amphiphilic block copolymer. Our method was optimized by the orthogonal design method. The partical size, zeta potential, drug-loaded content, yield, shape and status of the obtained comet-shaped Me PEG-PLGA-HCPT particles were further characterized by dynamic light scattering(DLS), scanning electron microscopy(SEM)/transmission electron microscopy (TEM), X-ray diffraction(XRD) and differential scanning calorimetry (DSC) et al, respectively. In vitro release was preliminary evaluated. MTT assay to preliminary evaluate the cytotoxicity of particles against human liver BEL-7402 cells. Based on these experimental results, the optimal preparation conditions contain: weight ratio of HCPT to Me PEG-PLGA was 1:1, nitrogen pressure was 100 k Pa and SPG membrane pore size was 1.1 µm. The particles exhibited a comet-shaped shape, fairly uniform size and were well dispersed. The drug-loading content was 46.2%, with yield of 96.4%, and zeta-31.4 m V. The distribution of HCPT in particles was very uniform, and HCPT showed a amorphous state existed in particles. The release behavior in vitro showed sustained releasing, and with the drug loading content in proportion to the release of the drug. MTT test indicated that the HCPT-loaded comet-shaped particles had enhanced the cytotoxicity against human liver BEL-7402 cells relatively to the HCPT-loaded spherical particles in vitro. The results showed a promising potential application of the preparation in clinical treatment of tumor.


Subject(s)
Camptothecin/administration & dosage , Drug Carriers/chemistry , Lactic Acid/chemistry , Polyglycolic Acid/chemistry , Calorimetry, Differential Scanning , Cell Line , Humans , Nanoparticles , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer , X-Ray Diffraction
15.
ACS Appl Mater Interfaces ; 7(46): 25553-9, 2015 Nov 25.
Article in English | MEDLINE | ID: mdl-26529185

ABSTRACT

We constructed 10-hydroxycamptothecin (CPT) "nanodrugs" with functionalization of lipid-PEG-methotrexate (MTX) to prepare high-drug-loaded, and sustained/controlled-release MTX-PEG-CPT nanorods (NRs), in which MTX drug itself can serve as a specific "targeting ligand". The self-targeted nanodrug can codeliver both CPT and MTX drugs with distinct anticancer mechanisms. Furthermore, MTX-PEG-CPT NRs significantly reduced burst release, improved blood circulation and tumor accumulation, enhanced cellular uptake, and synergistically increased anticancer effect against tumor cells compared with MTX-PEG-CPT nanospheres (NSs) and either both free drugs or individual free drug. Therefore, the synergistic targeting/therapeuticy nano-multi-drug codelivery assisted by shape design may advantageously offer a promising new strategy for nanomedicine.


Subject(s)
Antineoplastic Agents/pharmacology , Camptothecin/analogs & derivatives , Cell Nucleus/metabolism , Methotrexate/pharmacology , Nanotubes/chemistry , Animals , Camptothecin/pharmacology , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Survival/drug effects , Delayed-Action Preparations , Drug Synergism , Endocytosis/drug effects , Fluorescence , Mice, Inbred BALB C , Mice, Nude , Nanospheres/chemistry , Nanospheres/ultrastructure , Nanotubes/ultrastructure , Particle Size , Rats, Sprague-Dawley
16.
ACS Appl Mater Interfaces ; 7(32): 17573-81, 2015 Aug 19.
Article in English | MEDLINE | ID: mdl-26234408

ABSTRACT

Integrating advantages of mitomycin C (MMC)-phospholipid complex for increased drug encapsulation efficiency and reduced premature drug release, DSPE-PEG-folate (DSPE-PEG-FA) for specific tumor targeting, we reported a simple one-pot self-assembly route to prepare the MMC-phospholipid complex-loaded DSPE-PEG-based nanoparticles (MP-PEG-FA NPs). Both confocal imaging and flow cytometry demonstrated that MMC was distributed into nuclei after cellular uptake and intracellular drug delivery. More importantly, the systemically administered MP-PEG-FA NPs led to increased blood persistence and enhanced tumor accumulation in HeLa tumor-bearing nude mice. This study introduces a simple and effective strategy to design the anticancer drug-phospholipid complex-based targeted drug delivery system for sustained/controlled drug release.


Subject(s)
Antineoplastic Agents/chemistry , Drug Carriers/chemistry , Nanoparticles/chemistry , Phospholipids/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Survival/drug effects , Drug Carriers/metabolism , Drug Carriers/toxicity , Drug Liberation , Female , Folic Acid/analogs & derivatives , Folic Acid/chemistry , Half-Life , HeLa Cells , Humans , Mice , Mice, Nude , Microscopy, Confocal , Mitomycin/administration & dosage , Mitomycin/chemistry , Mitomycin/pharmacokinetics , Polyethylene Glycols/chemistry , Rats , Tissue Distribution , Transplantation, Heterologous , Uterine Cervical Neoplasms/drug therapy
17.
ACS Appl Mater Interfaces ; 7(22): 11908-20, 2015 Jun 10.
Article in English | MEDLINE | ID: mdl-25978458

ABSTRACT

Multifunctional nanocomposites hold great potential to integrate therapeutic and diagnostic functions into a single nanoscale structure. In this paper, we prepared the MTX-PEG-CS-IONPs-Cy5.5 nanocomposites by functionalizing the surface of chitosan-decorated iron oxide nanoparticles (CS-IONPs) with polyethylene glycolated methotraxate (MTX-PEG) and near-infrared fluorescent cyanin dye (Cy5.5). A clinically useful PEGylated anticancer prodrug, MTX-PEG, was also developed as a tumor cell-specific targeting ligand for self-targeted cancer treatment. In such nanocomposites, the advantage was that the orthogonally functionalized, self-targeted MTX-PEG-CS-IONPs-Cy5.5 can synergistically combine an early phase selective tumor-targeting efficacy with a late-phase cancer-killing effect, which was also confirmed by dual model (magnetic resonance and fluorescence) imaging. Furthermore, with the aids of the folate (FA) receptor-mediated endocytosis (able to turn cellular uptake "off" in normal cells and "on" in cancer cells) and pH/intracellular protease-mediated hydrolyzing peptide bonds (able to turn drug release "off" in systemic circulation and "on" inside endo/lysosomes), the MTX-PEG-CS-IONPs-Cy5.5 could deliver MTX to FA receptors-overexpressed cancer cells, showing the improved anticancer activity with the reduced side effects. Together, the MTX-PEG-CS-IONPs-Cy5.5 could act as a highly convergent, flexible, and simplified system for dual model imaging and synergistically self-targeted cancer therapy, holding great promise for versatile biomedical applications in future.


Subject(s)
Diagnostic Imaging , Drug Delivery Systems , Nanocomposites/chemistry , Neoplasms/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Chitosan/chemistry , Chitosan/therapeutic use , Ferric Compounds/chemistry , Ferric Compounds/therapeutic use , Humans , Methotrexate/chemistry , Methotrexate/therapeutic use , Nanocomposites/therapeutic use , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Neoplasms/diagnosis , Neoplasms/pathology , Polyethylene Glycols/chemistry
18.
Mol Pharm ; 12(4): 1318-27, 2015 Apr 06.
Article in English | MEDLINE | ID: mdl-25710590

ABSTRACT

The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy.


Subject(s)
Bacillus , Drug Delivery Systems , Neoplasms/drug therapy , Polymers/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Drug Carriers/chemistry , Flow Cytometry , HeLa Cells , Humans , Lactic Acid/chemistry , Methotrexate/administration & dosage , Mice , Nanoparticles/chemistry , Particle Size , Polyesters/chemistry , Polyethylene Glycols/chemistry
19.
Chem Sci ; 6(3): 1650-1654, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-28694944

ABSTRACT

Delicate mesoscopic architectures, bearing complex forms with multiple hierarchy levels, lead to significant functions in biogenic minerals. Herein, a bio-inspired approach was developed to fabricate comet-shaped assemblies of an anti-tumor drug - 10-hydroxycamptothecin (HCPT). The anti-solvent co-precipitation of HCPT and the excipient - PEG-b-PLGA - within the emulsifier leads to the immediate nucleation of comet bundles, followed by a secondary nucleation to generate the comet head, which is an assembly of nanofibers aligned almost in parallel. The continuous manufacturing furnishes drug-excipient hybrid particles with high drug-loading and a sustained drug release profile. This simple and efficient bio-inspired approach led to a promising sustained local drug delivery system, and could be extended to the fabrication of other functional organic materials bearing mesoscopic structural units.

20.
J Mater Chem B ; 3(39): 7707-7717, 2015 Oct 21.
Article in English | MEDLINE | ID: mdl-32264580

ABSTRACT

Poor drug distribution and inefficient drug concentrations within the tumor intracellular environment still limit the therapeutic efficacy of drugs for cancer chemotherapy. Local drug delivery (physical targeting) combined with receptor-mediated drug delivery (chemical targeting) and assistance by a novel shape design is a promising strategy to treat the infiltrating tumor (even those that persist post surgery). In this paper, we prepared dye and methotrexate (MTX) functionalized nanobacilli (MPEG-PLA-MTX-Cy5.5 NB) by a self-assembly technique combined with extrusion through a SPG membrane for intratumoral administration, in which the bacillus-shaped MPEG-PLA-MTX-Cy5.5 NB were armed with a dual-acting MTX that can specifically and efficiently enhance their cellular uptake, while avoiding their dispersion from tumor sites. After intratumoral administration to a H22 xenograft mouse model, the MPEG-PLA-MTX-Cy5.5 NB delivered the drug more effectively to the tumor compared to the MPEG-PLA-Cy5.5 nanospheres (MPEG-PLA-Cy5.5 NSs) and MPEG-PLA-MTX-Cy5.5 nanospheres (MPEG-PLA-MTX-Cy5.5 NSs). Compared to the free MTX and MPEG-PLA-MTX-Cy5.5 NSs, the controlled-release MPEG-PLA-MTX-Cy5.5 NB also significantly inhibited the tumor growth and improved therapeutic efficacy. The platforms are highly convergent, flexible and simplified systems that may serve as guides in the further design of nanoparticles with a revolutionary new shape and function for clinical applications.

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