ABSTRACT
Calcium overload, a notable instigator of acute pancreatitis (AP), induces oxidative stress and an inflammatory cascade, subsequently activating both endogenous and exogenous apoptotic pathways. However, there is currently lack of available pharmaceutical interventions to alleviate AP by addressing calcium overload. In the present study, the potential clinical application of liposome nanoparticles (LNs) loaded with 1,2bis(2aminophenoxy)ethaneN,N,N',N'tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTAAM), a cellpermeant calcium chelator, was investigated as a therapeutic approach for the management of AP. To establish the experimental models in vitro, AR42J cells were exposed to high glucose/sodium oleate (HGO) to induce necrosis, and in vivo, intraductal taurocholate (TC) infusion was used to induce AP. The findings of the present study indicated that the use of BAPTAAMloaded LN (BLN) effectively and rapidly eliminated excessive Ca2+ and reactive oxygen species, suppressed mononuclear macrophage activation and the release of inflammatory cytokines, and mitigated pancreatic acinar cell apoptosis and necrosis induced by HGO. Furthermore, the systemic administration of BLN demonstrated promising therapeutic potential in the rat model of AP. Notably, BLN significantly enhanced the survival rates of rats subjected to the TC challenge, increasing from 37.5 to 75%. This improvement was attributed to the restoration of pancreatic function, as indicated by improved blood biochemistry indices and alleviation of pancreatic lesions. The potential therapeutic efficacy of BLN in rescuing patients with AP is likely attributed to its capacity to inhibit oxidative stress, prevent premature activation of zymogens and downregulate the expression of TNFα, IL6 and cathepsin B. Thus, BLN demonstrated promising value as a novel therapeutic approach for promptly alleviating the burden of intracellular Ca2+ overload in patients with AP.
Subject(s)
Egtazic Acid/analogs & derivatives , Pancreatitis , Humans , Rats , Animals , Pancreatitis/metabolism , Liposomes/metabolism , Calcium/metabolism , Acute Disease , Acinar Cells/pathology , Necrosis/metabolismABSTRACT
Artemisia argyi, commonly known as wormwood, is a traditional Chinese herbal food and medicine celebrated for its notable antibacterial and anti-inflammatory properties. This study explores a novel delivery method for wormwood, aiming for more convenient and versatile applications. Specifically, we present the first investigation into combining wormwood with microstructures to create a microneedle (MN) patch for wound healing. The wormwood microneedle (WMN) patch is formulated with milled wormwood sap, calcium carbonate, and sodium hyaluronate. The addition of 0.3% (w/v) sodium hyaluronate enhances the mechanical strength of the WMN patch. Pectin, derived from wormwood, is combined with calcium carbonate to create a gelatinous and solidified substance. The WMN patch exhibits a well-defined shape and sufficient mechanical strength to penetrate the epidermis, as confirmed by our results. In vitro experiments demonstrate the biocompatibility of the WMN patch with fibroblasts and highlight its antibacterial and anti-inflammatory properties. Furthermore, the patch facilitates collagen deposition at the wound site. In an excisional rat model, the WMN patch significantly accelerates the wound closure rate compared to the control group. Our findings suggest that the WMN patch has the potential to serve as a natural treatment for wound healing. Additionally, this approach can be extended to other biologically active substances with similar physiochemical characteristics in future applications.
Subject(s)
Artemisia , Needles , Rats, Sprague-Dawley , Wound Healing , Wound Healing/drug effects , Animals , Artemisia/chemistry , Male , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Hyaluronic Acid/chemistry , Hyaluronic Acid/administration & dosage , Rats , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Fibroblasts/drug effects , Pectins/chemistry , Pectins/administration & dosage , Mice , HumansABSTRACT
Mucosal drug delivery permits direct and prompt drug absorption, which is capable of reducing undesirable decomposition that occurs before absorption. However, mucus clearance of those mucosal drug delivery systems strongly retards their actual application. Herein, we propose chromatophore nanoparticles embedded with FOF1-ATPase motors to promote mucus penetration. The FOF1-ATPase motor-embedded chromatophores were firstly extracted from Thermus thermophilus by using a gradient centrifugation method. Then, the model drug (curcumin) was loaded onto the chromatophores. The drug loading efficiency and entrapment efficiency were optimized by using different loading approaches. The activity, motility, stability and mucus permeation of the drug-loaded chromatophore nanoparticles were thoroughly investigated. Both the in vitro and in vivo studies revealed that the FOF1-ATPase motor-embedded chromatophore successfully enhanced mucus penetration glioma therapy. This study indicates that the FOF1-ATPase motor-embedded chromatophore is a promising alternative as a mucosal drug delivery system.
ABSTRACT
AIMS: To establish a FOF1-ATP synthase molecular motor biosensor to accurately identify colon cancer miRNAs. MAIN METHODS: The FOF1-ATP synthase molecular motor is extracted by fragmentation-centrifugation and connected to the colon cancer-specific miR-17 capture probe in the manner of the ε subunit-biotin-streptavidin-biotin system. Signal probes are designed for dual-signal characterization to increase detection accuracy. The FOF1-ATPase rotation rate decreases when the signaling and capture probes are combined with the target miRNA, resulting in a decrease in ATP synthesis. miR-17 concentrations are determined by changes in ATP-mediated chemiluminescence intensity and signal probe-mediated OD450nm. KEY FINDINGS: The chemiluminescence intensity and OD450nm show a good linear relationship with the miR-17 concentration in the range of 5 to 200 nmol L-1 (R2 = 0.9985, 0.9989). The colon cancer mouse model is established for the blood samples, and miR-17 in serum and RNA extracts is quantitatively determined using the constructed sensor. SIGNIFICANCE: The results are consistent with colon cancer progression, and the low concentration of miR-17 detecting accuracy is comparable to the PCR assay. In conclusion, the developed method is a direct, rapid, and promising method for miRNA detection of colon cancer.
Subject(s)
Biosensing Techniques , Colonic Neoplasms , MicroRNAs , Animals , Mice , Adenosine Triphosphate , Biotin , Colonic Neoplasms/diagnosis , Colonic Neoplasms/genetics , MicroRNAs/genetics , Nitric Oxide Synthase , Proton-Translocating ATPasesABSTRACT
Tumor microenvironment (TME) plays an important role in the growth, invasion, and metastasis of tumor cells. The pH of TME is more acidic in solid tumors than in normal tissues. Although targeted delivery in TME has progressed, the complex and expensive construction of delivery systems has limited their application. FOF1-ATP synthase (FOF1-ATPase) is a rotation molecular motor found in bacteria, chloroplasts, and mitochondria. Here, FOF1-ATPase loaded chromatophores (chroma) isolated from thermophilic bacteria were extracted and utilized as a new delivery system targeting TME for the first time. Curcumin as model drug was successfully loaded by a filming-rehydration ultrasonic dispersion method to prepare a curcumin-loaded chroma delivery system (Cur-Chroma). The mobility and propensity distributions of Cur-Chroma reveal its specific pH-sensitive targeting driven by the transmembrane proton kinetic potential, demonstrating its distinct distribution in the TME and more favorable targeting delivery. Cellular uptake experiments indicated that Cur-Chroma entered cells through grid pathway-mediated endocytosis. In vivo studies have shown that Cur-Chroma can specifically target tumor tissue and effectively inhibit tumor growth with good safety. Curcumin's bioavailability and anti-tumor effects were significantly improved. These studies demonstrate that ATPase-loaded chromatophores are potentially ideal vehicles for anti-tumor drug delivery and have promising applications.
Subject(s)
Antineoplastic Agents , Chromatophores , Curcumin , Nanoparticles , Neoplasms , Humans , Curcumin/chemistry , Drug Carriers/chemistry , Tumor Microenvironment , Antineoplastic Agents/chemistry , Neoplasms/drug therapy , Proton-Translocating ATPases , Drug Delivery Systems/methods , Nanoparticles/chemistryABSTRACT
Efficient drug loading, tumor targeting, intratumoral penetration, and cellular uptake are the main factors affecting the effectiveness of drug delivery systems in oncotherapy. Based on the tumor microenvironment, we proposed to develop Curcumin (Cur)-loaded matrix metalloproteinase (MMP)-responsive nanoparticles (Cur-P-NPs) by static electricity, to enhance tumor targeting, cellular uptake, and drug loading efficiency. These nanoparticles combine the properties of both PEG-peptides (cleaved peptide + penetrating peptide) and star-shaped polyester (DPE-PCL) nanoparticles. Cur-P-NPs displayed good entrapment efficiency, drug loading and biocompatibility. Additionally, they showed an enhanced release rate, cellular uptake, and anti-proliferative activity by activating peptides under the simulated tumor microenvironment. Furthermore, intraperitoneal injection of losartan (LST) successfully enhanced intratumoral drug penetration by collagen I degradation. In vivo studies based on the systematic administration of the synergistic LST + Cur-P-NPs combination to mice confirmed that combined antitumor therapy with LST and Cur-P-NPs could further improve intratumor distribution, enhance anticancer efficacy, and reduce the toxicity and side effects. Therefore, LST + Cur-P-NPs represent a new and efficient system for clinical oncotherapy.
Subject(s)
Curcumin , Nanoparticles , Neoplasms , Animals , Cell Line, Tumor , Collagen , Curcumin/chemistry , Drug Delivery Systems , Losartan , Matrix Metalloproteinases/metabolism , Mice , Nanoparticle Drug Delivery System , Nanoparticles/chemistry , Neoplasms/drug therapy , Particle Size , Polyesters/chemistry , Tumor MicroenvironmentABSTRACT
Chemotherapeutic treatments are indispensable in the treatment of breast cancer. However, the emergence of multidrug-resistance, strong cell toxicity, and poor targeting selection has inhibited their clinical application. In this study, two synergistic drugs, doxorubicin (DOX) and curcumin (CUR), were co-administered to overcome multidrug resistance (MDR). Based on the characteristics of the tumor microenvironment, we developed folic acid-modified nanoparticles ((DOX + CUR)-FA-NPs) based on a star-shaped polyester (FA-TRI-CL) to enhance the tumor targeting selectivity and drug loading (DL) capacity. The (DOX + CUR)-FA-NPs displayed a characteristic spheroid morphology with an ideal diameter (186.52 nm), polydispersity index (0.024), zeta potential (-18.87 mV), and good entrapment efficiency (97.64%/78.13%, DOX/CUR) and DL (20.27%/11.29%, DOX/CUR) values. In vitro pharmacokinetic and pharmacodynamic experiments demonstrated that the (DOX + CUR)-FA-NPs were gradually released, and they displayed the highest cell apoptosis and cellular uptake in MCF-7/ADR cells. Additionally, in vivo results illustrated that (DOX + CUR)-FA-NPs not only displayed significant tumor targeting and anticancer efficacy, but also induced less pathological damage to the normal tissue. In summary, co-administered DOX and CUR appeared to reverse MDR, and this targeted combinational nanoscale delivery system could thus be a promising carrier for tumor therapies in the future.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Curcumin/pharmacology , Doxorubicin/pharmacology , Nanoparticles/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Survival/drug effects , Chemistry, Pharmaceutical , Curcumin/administration & dosage , Curcumin/pharmacokinetics , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Drug Carriers/chemistry , Drug Combinations , Drug Liberation , Drug Resistance, Neoplasm/drug effects , Female , Folic Acid/chemistry , Humans , MCF-7 Cells , Mice , Mice, Inbred BALB C , Particle Size , Polyesters/chemistry , Surface Properties , Tumor MicroenvironmentABSTRACT
PURPOSE: A novel folate receptor-targeted ß-cyclodextrin (ß-CD) drug delivery vehicle was constructed to improve the bioavailability, biosafety, and drug loading capacity of curcumin. Controlled release and targeted delivery was achieved by modifying the nanoparticles with folic acid (FA). METHODS: Folate-conjugated ß-CD-polycaprolactone block copolymers were synthesized and characterized. Curcumin-loaded nanoparticles (FA-Cur-NPs) were structured by self-assembly. The physicochemical properties, stability, release behavior and tumor-targeting ability of the fabricated nanoparticles were studied. RESULTS: The average particle size and drug loading of FA-Cur-NPs was 151.8 nm and 20.27%, respectively. Moreover, the FA-Cur-NPs exhibited good stability in vitro for 72 h. The drug release profiles showed that curcumin from FA-Cur-NPs was released significantly faster in a pH 6.4 phosphate buffered solution (PBS) than in pH 7.4, indicating that curcumin can be enriched around the tumor site compared with normal cells. Additionally, the internalization of FA-Cur-NPs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. Furthermore, in vivo studies confirmed that FA-Cur-NPs exhibited marked accumulation in the tumor site and excellent antitumor activity. CONCLUSION: These findings suggest that FA-Cur-NPs are a promising approach for improving cancer therapy through active targeting and controllable release.
Subject(s)
Curcumin/administration & dosage , Drug Delivery Systems , Folic Acid/administration & dosage , Nanoparticles , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Curcumin/pharmacokinetics , Curcumin/pharmacology , Drug Carriers/chemistry , Drug Liberation , Female , Folate Receptors, GPI-Anchored/metabolism , Folic Acid/pharmacokinetics , Folic Acid/pharmacology , HeLa Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasms/drug therapy , Particle Size , Polyesters/chemistry , Tissue Distribution , Xenograft Model Antitumor Assays , beta-Cyclodextrins/chemistryABSTRACT
PURPOSE: To develop microchannel-based preparation of curcumin (Cur)-loaded hybrid nanoparticles using enzyme-targeted peptides and star-shaped polycyclic lipids as carriers, and to accomplish a desirable targeted drug delivery via these nanoparticles, which could improve the bioavailability and antitumor effects of Cur. METHODS: The amphiphilic tri-chaintricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) and the enzyme-targeted tetra-chain pentaerythritol-poly (ε-caprolactone)-polypeptide (PET-CL-P) were synthesized. The Cur-loaded enzyme-targeted hybrid nano-delivery systems (Cur-P-NPs) were prepared by using the microfluidic continuous granulation technology. The physicochemical properties, release behavior in vitro, and stability of these Cur-P-NPs were investigated. Their cytotoxicity, cellular uptake, anti-proliferative efficacy in vitro, biodistribution, and antitumor effects in vivo were also studied. RESULTS: The particle size of the prepared Cur-P-NPs was 146.1 ± 1.940 nm, polydispersity index was 0.175 ± 0.014, zeta potential was 10.1 ± 0.300 mV, encapsulation rate was 74.66 ± 0.671%, and drug loading capacity was 5.38 ± 0.316%. The stability of Cur-P-NPs was adequate, and the in vitro release rate increased with the decrease of the environmental pH. Seven days post incubation, the cumulative release values of Cur were 52.78%, 67.39%, and 98.12% at pH 7.4, pH 6.8 and pH 5.0, respectively. Cur-P-NPs exhibited better cell entry and antiproliferation efficacy against U251 cells than the Cur-solution and Cur-NPs and were safe for use. Cur-P-NPs specifically targeted tumor tissues and inhibited their growth (78.63% tumor growth inhibition rate) with low toxic effects on normal tissues. CONCLUSION: The enzyme-targeted hybrid nanoparticles prepared in the study clearly have the tumor-targeting ability. Cur-P-NPs can effectively improve the bioavailability of Cur and have potential applications in drug delivery and tumor management.
Subject(s)
Curcumin/chemistry , Curcumin/pharmacology , Lab-On-A-Chip Devices , Nanoparticles/chemistry , Nanotechnology/instrumentation , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Caproates/chemistry , Cell Line, Tumor , Curcumin/pharmacokinetics , Drug Carriers/chemistry , Humans , Lactones/chemistry , Mice , Particle Size , Polyethylene Glycols/chemistry , Tissue DistributionABSTRACT
Micro/nanomotors (MNMs), both self-propelled actuators and external fields-promoted machines, have joined forces in the past decade to accomplish versatile tasks such as precise detection and targeted cargo delivery with adequate propulsion and desirable locomotion. Amongst, enzyme-driven MNMs have been able to differentiate themselves from others owing to their distinct characteristics, such as absence of chemical fuel, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. In the present review, we aim to highlight and summarize recent advances in enzyme-driven MNMs, particularly to provide an in-depth discussion focusing on the enzyme linking approaches onto those MNMs and motion control strategies of such MNMs with advantages and limitations thereof. Conclusions and future perspectives are also provided in brief.
Subject(s)
Enzymes/metabolism , Nanostructures/chemistry , Biological Products/chemistry , Biological Products/pharmacology , Catalysis , Motion , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacologyABSTRACT
The limitations of anticancer drugs, including poor tumor targeting and weak uptake efficiency, are important factors affecting tumor therapy. According to characteristics of the tumor microenvironment, in this study, we aimed to synthesize matrix metalloproteinase (MMP)-responsive curcumin (Cur)-loaded nanoparticles (Cur-P-NPs) based on amphiphilic block copolymer (MePEG-peptide-PET-PCL) with MMP-cleavable peptide (GPLGIAGQ) and penetrating peptide (r9), modified to improve tumor targeting and cellular uptake. The average size of Cur-P-NPs was 176.9 nm, with a zeta potential of 8.1 mV, and they showed drug entrapment efficiency and a loading capacity of 87.07% ± 0.63% and 7.44% ± 0.16%, respectively. Furthermore, Cur release from Cur-P-NPs was sustained for 144 h at pH 7.4, and the release rate was accelerated under enzyme reaction condition. The MTT assay demonstrated that free P-NPs had favorable biosafety, and the anti-proliferative activity of Cur-P-NPs was positively correlated with Cur concentration in MCF-7 cells. Additionally, the results of cellular uptake, in vivo pharmacokinetics, and biodistribution showed that Cur-P-NPs had a good effect on cellular uptake and tumor targeting, resulting in the best bioavailability in tumor therapy. Therefore, Cur-P-NPs, as a promising drug delivery system, might lead to a new and efficient route for targeted therapy in clinical practice.
Subject(s)
Curcumin/pharmacology , Matrix Metalloproteinases/metabolism , Nanoparticles/chemistry , Neoplasms/drug therapy , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Curcumin/metabolism , Drug Carriers/chemistry , Drug Delivery Systems/methods , Female , Humans , MCF-7 Cells , Mice, Nude , Neoplasms/metabolism , Particle Size , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , Rats , Rats, Sprague-Dawley , Tissue Distribution , Tumor Microenvironment/drug effectsABSTRACT
Elastomers are largely developed for biomedical applications; however, little is reported on them although they are an effective and controllable delivery system for proteins. In the present study, we investigated the pharmacokinetics, biosecurity, and hypoglycemic effect of an insulin-loaded elastomer formulation in diabetic rats. Cylindrical insulin-loaded elastomers were fabricated using a UV cross-linking process based on methyl-acrylic-star-poly(ε-caprolactone-co-D,L-lactide) cyclic ester and methyl-bi-acrylic-poly(ε-caprolactone-b-polyethylene glycol-b-ε-caprolactone) (CLPEGCLMA). The encapsulated insulin was well protected during the formulation. An in vitro pharmacokinetic study revealed that the rate of insulin release from the elastomers was affected by the hydrophilicity/hydrophobicity of the system and controlled by the CLPEGCLMA (hydrophilic prepolymer) composition. It was observed that insulin release followed the Higuchi model. In addition, the more hydrophilic elastomers showed higher degradation rates in vivo. Furthermore, in the pharmacodynamic study, all the elastomers, except those that contained star-poly(ε-caprolactone-co-D,L-lactide) (number-average molecular weight, Mn), polyethylene glycol (PEG) (kMn), ε-caprolactone/PEG (mol/mol), and CLPEGCLMA (weight, %) at a ratio of 3432:10:20:30, respectively, decreased blood glucose concentration and maintained it at a stable level. It was observed that the hypoglycemic effect of the drug-loaded elastomers was directly proportional to the rate of in vitro insulin release; however, emaciation was not observed. Moreover, elastomers play a positive role in biosecurity. Therefore, the elastomers might be effective carriers for the delivery of peptide drugs in the form of implants.
Subject(s)
Biocompatible Materials/chemistry , Drug Carriers/chemistry , Elastomers/chemistry , Insulin/chemistry , Polyesters/chemistry , Animals , Biocompatible Materials/metabolism , Biocompatible Materials/pharmacology , Biocompatible Materials/therapeutic use , Blood Glucose/analysis , Cell Survival/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Drug Liberation , Elastomers/metabolism , Elastomers/pharmacology , Ethylene Glycols/chemistry , Half-Life , Hydrophobic and Hydrophilic Interactions , Insulin/pharmacology , Insulin/therapeutic use , Male , Mice , Microscopy, Electron, Scanning , Prostheses and Implants , RAW 264.7 Cells , Rats , Rats, WistarABSTRACT
Biodegradable polymeric nanoparticles (NPs) have potential therapeutic applications; however, preparing NPs of a specific diameter and uniform size distribution is a challenge. In this work, we fabricated a microchannel system for the preparation of curcumin (Cur)-loaded NPs by the interfacial precipitation method, which rapidly and consistently generated stable NPs with a relatively smaller diameter, narrow size distribution, and higher drug-loading capacity and entrapment efficiency. Poly(ε-caprolactone)-poly(ethylene glycol)-poly (ε-caprolactone) triblock copolymers(PCEC) used as the carrier material was synthesized and characterized. Cur-loaded PCEC NPs had an average size of 167.2nm with a zeta potential of -29.23mV, and showed a loading capacity and drug entrapment efficiency of 15.28%±0.23% and 96.11%±0.13%, respectively. Meanwhile, the NPs demonstrated good biocompatibility and bioavailability, efficient cellular uptake, and long circulation time and a possible liver targeting effect in vivo. These results indicate that the Cur-loaded PCEC NPs can be used as drug carriers in controlled delivery systems and other biomedical applications.