Recently, dendrimers have been widely used in medical applications such as drug delivery and gene transfection. In this study, a pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and polyethylene glycol (PEG) modified by lactose (LA-PEG-b-PSD) was synthesized. The pK(a) value of the LA-PEG-b-PSD was also measured. Then, polyamidoamine (PAMAM) complexes were prepared with PAMAM (G4.0) and LA-PEG-b-PSD by electrostatic interaction. To investigate drug pH-sensitive release in vitro, doxorubicin (DOX) was loaded in PAMAM. A higher drug cumulative release from LA-PEG-b-PSD/PAMAM complexes in phosphate buffered saline (PBS) was found at pH 6.5 than at pH 7.4. The cytotoxicity and cellular uptake of PAMAM complexes were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy. LA-PEG-b-PSD/PAMAM/DOX complexes were able to enhance the cytotoxicity of DOX against HepG2 cells at pH 7.4. Confocal microscopy showed a higher cellular uptake of PEG-b-PSD/PAMAM complexes at pH 6.5. PAMAM complexes modified by lactose showed a higher affinity for hepatic cancer cells than those without lactose at pH 7.4. These results suggest that LA-PEG-b-PSD/PAMAM complexes exhibit selective targeting and cytotoxicity against HepG2 cells. In vivo antitumor studies showed that the LA-PEG-b-PSD/PAMAM/DOX complexes displayed higher antitumor efficacy compared with non-targeted PAMAM/DOX and DOX solution. These results indicate that this strategy should be applicable to the treatment of liver cancers. 相似文献
In order to overcome the limitation of traditional active nano-therapeutic drugs on tumor targeting efficiency which cannot reach the receptor/target in sufficient amount in the body, in this work, we developed a monoclonal antibody(mAb) and a polymer-hyd-doxorubicin prodrug conjugate, which enables the self-assembled nanoparticles to have precise targeting, tumor tissue aggregation and pH-sensitive drug release. We first prepared an amphiphilic polymer prodrug, abbreviated as H2N-PEE... 相似文献
Recent researches to develop nano-carrier systems in anti-cancer drug delivery have focused on more complicated design to improve therapeutic efficacy and to reduce side effects. Although such efforts have great impact to biomedical science and engineering, the complexity has been a huddle because of clinical and economic problems. In order to overcome the problems, a simplest strategy to fabricate nano-carriers to deliver doxorubicin (DOX) was proposed in the present study. Two significant subjects (i) formation of nanoparticles loading and releasing DOX and (ii) binding specificity of them to cells, were examined. Folic acid (FA) was directly coupled with pullulan (Pul) backbone by ester linkage (FA/Pul conjugate) and the degree of substitution (DS) was varied, which were confirmed by 1H NMR and UV spectrophotometry. Light scattering results revealed that the nanogels possessed two major size distributions around 70 and 270 nm in an aqueous solution. Their critical aggregation concentrations (CACs) were less than 10 microg/mL, which are lower than general critical micelle concentrations (CMCs) of low-molecular-weight surfactants. Transmission electron microscopy (TEM) images showed well-dispersed nanogel morphology in a dried state. Depending on the DS, the nanogels showed different DOX-loading and releasing profiles. The DOX release rate from FA8/Pul (with the highest DS) for 24h was slower than that from FA4/or FA6/Pul, indicating that the FA worked as a hydrophobic moiety for drug holding. Cellular uptake of the nanogels (KB cells) was also monitored by confocal microscopy. All nanogels were internalized regardless of the DS of FA. Based on the results, the objectives of this study, to suggest a new method overcoming the complications in the drug carrier design, were successfully verified. 相似文献
A kind of pH‐responsive carbon quantum dots?doxorubicin nanoparticles drug delivery platform (D‐Biotin/DOX‐loaded mPEG‐OAL/N‐CQDs) was designed and synthesized. The system consists of fluorescent carbon dots as cross‐linkers, and D‐Biotin worked as targeting groups, which made the system have a pH correspondence, doxorubicin hydrochloride (DOX) as the target drug, oxidized sodium alginate (OAL) as carrier materials. Ultraviolet (UV)‐Vis spectrum showed that the drug‐loading rate of DOX is 10.5%, and the drug release in vitro suggested that the system had a pH response and tumor cellular targeted, the drug release rate is 65.6% at the value of pH is 5.0, which is much higher than that at the value of pH is 7.4. The cytotoxicity test and laser confocal fluorescence imaging showed that the synthesized drug delivery system has high cytotoxicity to cancer cells, and the drug‐loaded nanoparticles could enter the cells through endocytosis. 相似文献
Metal–organic framework (MOF) nano particles are a class of promising porous nano materials for biomedical applications. Owing to its high loading potential and pH-sensitive degradation, most promising of the MOFs is the zeolitic imidazolate crystal framework (ZIF-8), a progressive useful material for small molecule distribution. Doxorubicin (DOX), designated as a classical drug, was jobwise entrapped in ZIF-8 nano particles. ZIF-8 nano particles, as a novel carrier, were used to monitor the release of the anticancer drug DOX and prevent it from dissipating before reaching its goal. ZIF-8 nano particles with encapsulated DOX (DOX@ZIF-8) can be synthesized in a single pot by incorporation of DOX into the reaction mixture. MOFs and the designed drug delivery (DOX@ZIF-8) system were characterized by Fourier transfer infrared, scanning electron microscopy, N2 sorption isotherm and X-ray diffraction. The impact of MOFs and the engineered drug delivery system on the viability of human breast and liver cancer cell lines was evaluated. The loaded drug was released at pH 5 faster than at pH 7.4. The nano particles of ZIF-8 showed low cytotoxicity, while DOX@ZIF-8 showed high cytotoxicity to HepG-2 and MCF-7 cells compared with free DOX at the equivalent concentration of DOX of >12.5 μg/ml. These findings indicate that DOX@ZIF-8 nano particles are a promising method for the delivery of cancer cells to drugs. Furthermore, ZIF-8, DOX and encapsulated DOX@ZIF-8 compounds were screened for their potential antibacterial activities against pathogenic bacteria compared with standard antibiotics by the agar well diffusion technique. The results demonstrate that the DOX@ZIF-8 exhibits a strong inhibition zone against Gram-negative strains (Escherichia coli) in comparison with the reference drug gentamycin. The docking active site interactions were evaluated to predict the binding between DOX with the receptor of breast cancer 3hb5-oxidoreductase and liver cancer 2h80-lipid binding protein for anticancer activity. 相似文献
Herein, new poly(ortho ester disulfide urethanes) (POEDU) and poly(ortho ester urethanes) (POEU) were successfully synthesized via polycondensation between active esters of 1,6-hexandiol (HD) and dual-stimuli-sensitive ortho ester disulfide diamine or pH-senstive ortho ester diamine. The corresponding POEDU and POEU nanospheres were easily fabricated using an oil-in-water emulsion technique. In vitro degradation experiments indicated that POEDU nanospheres degraded faster than POEU nanospheres in mildly acidic and reductive environments. Doxorubicin (DOX) as a model antitumor drug was successfully incorporated into these nanospheres to give DOX-loaded nanoparticles (POEDU-DOX and POEU-DOX). In vitro drug release studies showed that release of DOX from dual-stimuli-sensitive POEDU-DOX was accelerated compared with release from the pH-sensitive POEU-DOX under DL-dithiothreitol (DTT) and mildly acidic conditions. In addition, in vitro uptake and cytotoxicity assays revealed that POEDU-DOX exhibited more efficient antitumor effect than POEU-DOX did against both two-dimensional (2D) cells and three-dimensional (3D) multicellular tumor spheroids (MCTS). Finally, in a mice H22 tumor model, POEDU-DOX exhibited preferable antitumor capability. In conclusion, the pH and redox dual-stimuli-sensitive POEDU nanospheres can be superior drug carriers for cancer treatment. 相似文献
Amphiphilic macromolecules (AMs) have unique branched hydrophobic domains attached to linear PEG chains. AMs self‐assemble in aqueous solution to form micelles that are hydrolytically stable in physiological conditions (37 °C, pH 7.4) over 4 weeks. Evidence of AM biodegradability was demonstrated by complete AM degradation after 6 d in the presence of lipase. Doxorubicin (DOX) was chemically conjugated to AMs via a hydrazone linker to form DOX–AM conjugates that self‐assembled into micelles in aqueous solution. The conjugates were compared with DOX‐loaded AM micelles (i.e., physically loaded DOX) on DOX content, micellar sizes and in vitro cytotoxicity. Physically encapsulated DOX loading was higher (12 wt.‐%) than chemically bound DOX (6 wt.‐%), and micellar sizes of DOX‐loaded AMs (≈16 nm) were smaller than DOX–AMs (≈30 nm). In vitro DOX release from DOX–AM conjugates was faster at pH 5.0 (100%) compared to pH 7.4 (78%) after 48 h, 37 °C. Compared to free DOX and physically encapsulated DOX, chemically bound DOX had significantly higher cytotoxicity at 10?7 M DOX dose against human hepatocellular carcinoma cells after 72 h. Overall, DOX–AM micelles showed promising characteristics as stable, biodegradable DOX nanocarriers.
Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, we have designed a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system to overcome the challenges. The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (~6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (~5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy. 相似文献
The poly(lactide-co-glycolide)-coated magnetic nanoparticles (PLGA MNPs) were prepared as carriers of doxorubicin (PLGA-DOX MNPs) through water-in-oil-in-water (W/O/W) emulsification method. The characteristics of PLGA-DOX MNPs were measured by using transmission electron microscopy (TEM) and vibrating-sampling magnetometry (VSM). It was found that the synthesized nanoparticles were spherical in shape with an average size of 100 ± 20 nm, low aggregation and good magnetic responsivity. Meanwhile, the drug content and encapsulation efficiency of nanoparticles can be achieved by varying the feed weight ratios of PLGA and DOX particles. These PLGA-DOX MNPs also demonstrated sustained release of DOX at 37 °C in buffer solution. Besides, influence of drug-loaded nanoparticles on in vitro cytotoxicity was determined by MTT assay, while cellular apoptosis was detected by Annexin V-FITC apoptosis detection kit. The results showed that PLGA-DOX MNPs retained significant antitumor activities. Therefore, PLGA-DOX MNPs might be considered a promising drug delivery system for cancer chemotherapy. 相似文献
A series of drug delivery systems based on a sodium alginate derivative were prepared by mixing glycyrrhetinic acid(GA) and doxorubicin(DOX) conjugates at different ratios. GA(a liver-targeting ligand) and DOX(an antitumor drug) were both conjugated to oligomeric glycol monomethyl ether-modified sodium alginate(ALG-mOEG) for prolonged duration of action. These NP-based delivery systems exhibited active cell uptake and cytotoxicity in vitro and liver-targeted distribution and anti-tumor activity in vivo. In addition, nanoparticles with a 1:1(W:W) ratio of GA-ALG-mOEG and DOXALG-mOEG(NPs-3) showed the highest cellular uptake and cytotoxicity in vitro and liver-targeted distribution and antitumor activity in vivo. Specifically, when mixed nanoparticles defined as NPs-3 were injected in mice, liver DOX concentration reached 61.9 μg/g 3 h after injection, and AUC0-∞ and t1/2 of DOX in liver reached 4744.9 μg·h/g and 49.5 h, respectively. In addition, mice receiving a single injection of NPs-3 exhibited much slower tumor growth(88.37% reduction in tumor weight) 16 days after injection compared with placebo. These results indicate that effective cancer treatment may be developed using mixed NP delivery systems with appropriate ratio of targeted ligand and drug. 相似文献
The use of nanoparticles as chemotherapeutic carriers has been suggested as a way to overcome a range of side effects associated with classical cancer treatment such as poor selectivity and tumor resurgence. Obtaining precise control of the size and shape of therapeutic nanoparticles is crucial to optimize the targeting of tumor sites. In this work, it is shown that a previously developed system of polypeptide encapsulating individual DNA molecules, that forms rod-shaped nanoparticles of precisely controlled aspect ratio, can be loaded with the DNA-intercalating chemotherapeutic drug doxorubicin (DOX). It is characterized the size and shape of the DOX loaded-Virus-Like DNA Particles (DOX-VLDP) and shown that in this system the DOX payload does not leak out. Through in vitro cell studies, it is shown that DOX-VLDP is internalized by melanoma tumor cells (B16F10 cells) in a delayed and endocytosis-dependent way culminating in increased cytotoxicity and selectivity to tumor cells in comparison with free DOX. In addition, it is found that DOX-VLDP trigger apoptosis and autophagy pathways in treated cells. Taken together, the data on the DOX-VLDP nanoparticles shows that they kill cancer cells differently from free DOX. 相似文献
The authors describe new bifunctional mesoporous silica nanoparticles (NPs) for specific targeting of tumor cells and for intracellular delivery of the cancer drug doxorubicin (DOX). Mesoporous silica nanoparticles (MSNPs) were coated with blue fluorescent N-graphene quantum dots, loaded with the drug DOX, and finally coated with hyaluronic acid (HA). Cellular uptake of the NPs with an architecture of the type HA-DOX-GQD@MSNPs enabled imaging of human cervical carcinoma (HeLa) cells via fluorescence microscopy. The cytotoxicity of the nanoparticles on HeLa cells was also assessed. The results suggest that the NPs are higher cytotoxicity effect and exert in living cell imaging ability. Compared to the majority of other drug nanocarrier systems, the one described here enables simultaneous DOX release and fluorescent monitoring.
Graphical abstract Schematic of the bifunctional mesoporous silica nanoparticles were obtained via the Stöber method, along with the doxorubicin loaded and the hyaluronic acid capped. The sensor shows good specificity and significant cytotoxicity effect on Hela cells. (TEOS: tetraethyl orthosilicate; GQDs: graphene quantum dots; DOX: doxorubicin; HA: Hyaluronic acid).
This study reports the therapeutic effectiveness of doxorubicin-conjugated zinc oxide nanoparticles against lung cancer cell line. The zinc oxide nanoparticles (ZnONPs) were first synthesised using a fungus, isolated from air with an extraordinary capability to survive in very high concentrations of zinc salt. Molecular analysis based on 18S rRNA gene sequencing led to its identification as Aspergillus niger with the NCBI accession no. {"type":"entrez-nucleotide","attrs":{"text":"OL636020","term_id":"2155690654"}}OL636020. The fungus was found to produce ZnONPs via the reduction of zinc ions from zinc sulphate. The ZnONPs were characterised by various biophysical techniques. ZnONPs were further bioconjugated with the anti-cancer drug doxorubicin (DOX), which was further confirmed by different physical techniques. Furthermore, we examined the cytotoxic efficacy of Doxorubicin-bioconjugated-ZnONPs (DOX-ZnONPs) against lung cancer A549 cells in comparison to ZnONPs and DOX alone. The cytotoxicity caused due to ZnONPs, DOX and DOX-ZnONPs in lung cancer A549 cells was assessed by MTT assay. DOX-ZnONPs strongly inhibited the proliferation of A549 with IC50 value of 0.34 μg/mL, which is lower than IC50 of DOX alone (0.56 μg/mL). Moreover, DOX-ZnONPs treated cells also showed increased nuclear condensation, enhanced ROS generation in cytosol and reduced mitochondrial membrane potential. To investigate the induction of apoptosis, caspase-3 activity was measured in all the treated groups. Conclusively, results of our study have established that DOX-ZnONPs have strong therapeutic efficacy to inhibit the growth of lung cancer cells in comparison to DOX alone. Our study also offers substantial evidence for the biogenically synthesised zinc oxide nanoparticle as a promising candidate for a drug delivery system. 相似文献
Novel amphiphilic copolymers based on poly(ε-caprolactone) (PCL) and hyperbranched poly (amine-ester) (HPAE) with various compositions were synthesized. The amphiphilic copolymers can self-assemble into nanoscopic micelles and their hydrophobic cores can encapsulate doxorubicin (DOX) in aqueous solutions. The DOX-loaded HPAE-co-PCL nanoparticles diameter increased from 121 to 184 nm with the increasing PCL segment in the copolymer composition. An in vitro study at 37°C demonstrated that DOX-release from nanoparticles at pH 5.0 was much faster than that at pH 7.4. The cytotoxicity for HeLa cells study demonstrated that DOX-loaded HPAE-co-PCL nanoparticles exhibited the anti-tumor effect was enhanced significantly, suggesting that the DOX-loaded HPAE-co-PCL nanoparticles have great potential as a tumor drug carrier. 相似文献