Amylase-Sensitive Polymeric Nanoparticles Based on Dextran Sulfate and Doxorubicin with Anticoagulant Activity.
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ABSTRACT:
SUBMITTER: Pyataev NA
PROVIDER: S-EPMC6571953 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To overcome the toxicity, pharmacokinetics and drug resistance associated with doxorubicin (DOX), a strategy was developed by encapsulating DOX- loaded-PLGA-PVA- nanoparticles within chitosan-dextran sulfate nanoparticles (CS-DS) [CS-DS-coated-DOX-loaded -PLGA-PVA-NP] and study the sensitivity against DOX- resistance- breast cancer cells (MCF-7-DOX-R). These CS-DS and PLGA-PVA double coated DOX are spherical, stable, polydispersed and have zeta potential +2.89?mV. MCF-7- DOX-R cells were derived by exposing increasing doses of DOX in MCF-7 cells. These cells were resistance to 500?nM of DOX while parental cells were susceptible at 150?nM. The double coated NP caused more cytotoxicity in cancer and MCF-7-DOX-R cells without affecting the normal cells in comparison to DOX-loaded-PLGA-PVA-NP. These NP enhances the uptake of DOX in MCF-7-DOX-R cells and caused apoptosis by increasing apoptotic nuclei, Bax/Bcl-xL ratio, cleaved product PARP-1, tumor suppressor gene p21, p53, topoisomerase inhibition activity, DNA damage and decreasing the migratory potential of cells. An increased S phase arrest was noted in DOX and DOX- loaded- PLGA-PVA-NP treated cells but reduction of S phase and simultaneous increase of Sub-G1 was observed in double coated-NP. Thus, data revealed that CS-DS- DOX- loaded PLGA-PVA- NP caused DOX-resistance cell death by inducing inhibition of topoisomerase activity followed by DNA damage.
| S-EPMC5438340 | biostudies-literature
Project description:Background:Doxorubicin (DOX) is one of the most effective treatments for hepatocellular carcinoma (HCC), but is restricted by its poor pharmacokinetics. Herein, we exploited efficient targeted drug delivery systems and they have been found to be a worthy strategy for liver cancer therapy. Materials and methods:We investigated polymeric nanoparticles which were synthesized based on host-guest interaction between β-cyclodextrin and benzimidazole. The properties of nanoparticles with regard to size/shape, encapsulation efficiency, and drug release were investigated using conventional experiments. Cell proliferation assay in vitro, cell uptake assay, and cell apoptosis analysis were used to investigate cytotoxicity, uptake, and mechanism of targeted supramolecular prodrug complexes (TSPCs)-based self-assemblies and supramolecular prodrug complexes (SPCs)-based self-assemblies. Results:The pH-sensitive lactobionic acid (LA)-modified pH-sensitive self-assemblies were synthesized successfully. The results of in vitro released assay showed that the accelerated released of DOX from TSPCs-based self-assemblies with the decrease of pH value. When TSPCs-based self-assemblies were taken up by HepG2 cells, they demonstrated a faster release rate under acidic conditions and proved to have higher cytotoxicity than in the presence of LA. A mechanistic study revealed that TSPCs-based self-assemblies inhibited liver cell proliferation by inducing cell apoptosis. Conclusion:The pH-sensitive nanocomplex, as liver-targeted nanoparticles, facilitated the efficacy of DOX in HepG2 cells, offering an appealing strategy for the treatment of HCC.
| S-EPMC6433111 | biostudies-other
Project description:Tumor cells show acidic conditions compared with normal cells, which further inspires scientist to build nanocarrier responsive to tumor microenvironment (TME) for enhancing tumor therapeutic efficacy. Here, we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin (DOX) prodrug (DOXDT) for enhanced chemotherapy. High-density DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells, improving chemotherapy efficacy. Specifically, a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization (ATRP); then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond. The structure of DOXDT can be well-controlled. The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4 nm, which presented excellent micellar stability. Compared to lipid-based drug delivery system, the DOXDT prodrug showed higher drug load capacity up to 23.6%. In addition, excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo. Hence, this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations, which would be widely applied in cancer therapy.
| S-EPMC7610203 | biostudies-literature
Project description:The fruition, commercialisation and clinical application combining nano-engineering, nanomedicine and material science for utilisation in drug delivery is becoming a reality. The successful integration of nanomaterial in nanotherapeutics requires their critical development to ensure physiological and biological compatibility. Mesoporous silica nanoparticles (MSNs) are attractive nanocarriers due to their biodegradable, biocompatible, and relative malleable porous frameworks that can be functionalized for enhanced targeting and delivery in a variety of disease models. The optimal formulation of an MSN with polyethylene glycol (2% and 5%) and chitosan was undertaken, to produce sterically stabilized, hydrophilic MSNs, capable of efficient loading and delivery of the hydrophobic anti-neoplastic drug, doxorubicin (DOX). The pH-sensitive release kinetics of DOX, together with the anticancer, apoptosis and cell-cycle activities of DOX-loaded MSNs in selected cancer cell lines were evaluated. MSNs of 36-60 nm in size, with a pore diameter of 9.8 nm, and a cumulative surface area of 710.36 m²/g were produced. The 2% pegylated MSN formulation (PCMSN) had the highest DOX loading capacity (0.98 mgdox/mgmsn), and a sustained release profile over 72 h. Pegylated-drug nanoconjugates were effective at a concentration range between 20-50 μg/mL, inducing apoptosis in cancer cells, and affirming their potential as effective drug delivery vehicles.
| S-EPMC7037074 | biostudies-literature
Project description:Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options for us to explore safer agents. The swim bladder is a tonic food and folk medicine, and its GAGs show good anticoagulant activity. In this study, two GAGs, CMG-1.0 and GMG-1.0, were extracted and isolated from the swim bladder of Cynoscion microlepidotus and Gadus morhua. The physicochemical properties, precise structural characteristics, and anticoagulant activities of these GAGs were determined for the first time. The analysis results of the CMG-1.0 and GMG-1.0 showed that they were chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains with molecular weights of 109.3 kDa and 123.1 kDa, respectively. They were mainly composed of the repeating disaccharide unit of -{IdoA-α1,3-GalNAc4S-β1,4-}- (DS-A). The DS-B disaccharide unit of -{IdoA2S-α1,3-GalNAc4S-β1,4-}- also existed in both CMG-1.0 and GMG-1.0. CMG-1.0 had a higher proportion of CS-O disaccharide unit -{-GlcA-β1,3-GalNAc-β1,4-}- but a lower proportion of CS-E disaccharide unit -{-GlcA-β1,3-GalNAc4S6S-β1,4-}- than GMG-1.0. The disaccharide compositions of the GAGs varied in a species-specific manner. Anticoagulant activity assay revealed that both CMG-1.0 and GMG-1.0 had potent anticoagulant activity, which can significantly prolong activated partial thromboplastin time. GMG-1.0 also can prolong the thrombin time. CMG-1.0 showed no intrinsic tenase inhibition activity, while GMG-1.0 can obviously inhibit intrinsic tenase with EC50 of 58 nM. Their significantly different anticoagulant activities may be due to their different disaccharide structural units and proportions. These findings suggested that swim bladder by-products of fish processing of these two marine organisms may be used as a source of anticoagulants.
| S-EPMC10817686 | biostudies-literature
Project description:In this study, we analyzed the antimicrobial activities of poly-N-isopropylacrylamide (pNIPAM)-based polymeric nanoparticles encapsulating silver nanoparticles (AgNPs). Three sizes of AgNP-encapsulating pNIPAM- and pNIPAM-NH2-based polymeric nanoparticles were fabricated. Highly stable and uniformly distributed AgNPs were encapsulated within polymeric nanoparticles via in situ reduction of AgNO3 using NaBH4 as the reducing agent. The formation and distribution of AgNPs was confirmed by UV-visible spectroscopy, transmission electron microscopy, and inductively coupled plasma optical emission spectrometry, respectively. Both polymeric nanoparticles showed significant bacteriostatic activities against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria depending on the nanoparticle size and amount of AgNO3 used during fabrication.
| S-EPMC5757205 | biostudies-literature
Project description:A novel amphiphilic cholesterol-based block copolymer comprised of a polymethacrylate bearing cholesterol block and a polyethylene glycol block with reducible disulfide bonds (PC5MA-SS-PEO) was synthesized and evaluated as a redox-sensitive nanoparticulate delivery system. The self-assembled PC5MA-SS-PEO nanoparticles (SS-NPs) encapsulated the anticancer drug doxorubicin (DOX) with high drug loading (18.2% w/w) and high encapsulation efficiency (94.9%). DOX-encapsulated PC5MA-SS-PEO self-assembled nanoparticles (DOX-encapsulated SS-NPs) showed excellent stability and exhibited a rapid DOX release in response to dithiothreitol reductive condition. Importantly, following internalization by lung cancer cells, the reducible DOX-encapsulated SS-NPs achieved higher cytotoxicity than the non-reducible thioester NPs whereas blank nanoparticles were non-cytotoxic. Furthermore, in vivo imaging studies in tumor-bearing severe combined immunodeficiency (SCID) mice showed that the nanoparticles preferentially accumulated in tumor tissue with remarkably reduced accumulation in the healthy non-target organs. The results indicated that the SS-NPs may be a promising platform for cancer-cell specific delivery of hydrophobic anticancer drugs.The use of nanocarriers for drug delivery against tumors has been under intense research. One problem of using carrier system is the drug release kinetics at tumor site. In this article, the authors continued their previous study in the development of an amphiphilic cholesterol-based block copolymer with redox-sensitive modification, so that the payload drug could be released in response to the microenvironment. The interesting results should provide a new direction for designing future novel nanocarrier systems.
| S-EPMC4628861 | biostudies-literature
Project description:Lymph node (LN) dissection followed by histological analysis is the current standard for diagnosis of LN metastasis but the method suffers from patient morbidity and low sensitivity of detection. Ultra-pH sensitive (UPS) nanoparticles show remarkable accuracy in the delineation of primary tumor margins for precision cancer surgery. Herein we investigate the effectiveness of UPS nanoparticles to detect cancer-involved LNs. Methods: We synthesized a series of indocyanine green (ICG) conjugated UPS nanoparticles with distinct pKa (UPS5.3, UPS6.1, and UPS6.9). Systemically administered UPS-ICG nanoparticles in the 4T1.2-BALB/cj mouse model were imaged with real-time, near-infrared fluorescence (NIRF) to guide removal of LNs. Ex vivo imaging of gross tissue enabled quantification of fluorescence intensity. Histological analysis was used as the gold standard diagnostic test. Results: Macrophage uptake of UPS nanoparticles elevates the background signal in benign LNs. However, cancer foci within LNs show distinctive clustering of UPS-ICG fluorescence. UPS5.3 achieves accurate detection of metastatic LNs as shown by a receiver operating characteristic (ROC) area under the curve (AUC) of 0.96 ± 0.03. UPS6.1 and UPS6.9 offer decreased discriminatory power at ROC AUC of 0.73 ± 0.1 and 0.88 ± 0.07, respectively. Conclusions: All UPS compositions show cancer-specific discrimination of metastatic LNs over benign LNs with the best outcomes from UPS5.3. Detection of micro-metastatic LNs (cancer foci < 2 mm) remains a challenge. This study provides information on the detection of LN status for image-guided resection of metastatic LNs.
| S-EPMC7053196 | biostudies-literature
Project description:One major challenge of current surface modification of nanoparticles is the demand for chemical reactive polymeric layers, such modification is always complicated, inefficient, and may lead the polymer lose the ability to encapsulate drug. To overcome this limitation, we adopted a pH-sensitive platform using polydopamine (PDA) as a way of functionalizing nanoparticles (NPs) surfaces. All this method needed to be just a brief incubation in weak alkaline solution of dopamine, which was simple and applicable to a variety of polymer carriers regardless of their chemical reactivity. We successfully conjugated the doxorubicin (DOX)-PDA-poly (lactic-co-glycolic acid) (PLGA) NPs with two typical surface modifiers: folate (FA) and a peptide (Arg-Gly-Asp, RGD). The DOX-PDA-FA-NPs and DOX-PDA-RGD-NPs (targeting nanoparticles) were characterized by particle size, zeta potential, and surface morphology. They were quite stable in various physiological solutions and exhibited pH-sensitive property in drug release. Compared to DOX-NPs, the targeting nanoparticles possessed an excellent targeting ability against HeLa cells. In addition, the in vivo study demonstrated that targeting nanoparticles achieved a tumor inhibition rate over 70%, meanwhile prominently decreased the side effects of DOX and improve drug distribution in tumors. Our studies indicated that the DOX-PLGA-NPs modified with PDA and various functional ligands are promising nanocarriers for targeting tumor therapy.
| S-EPMC6058689 | biostudies-literature
Project description:IntroductionDespite significant progress in the field of oncology, cancer remains one of the leading causes of death. Chemotherapy is one of the most common treatment options for cancer patients but is well known to result in off-target toxicity. Theranostic nanomedicines that integrate diagnostic and therapeutic functions within an all-in-one platform can increase tumor selectivity for more effective chemotherapy and aid in diagnosis and monitoring of therapeutic responses.Material and methodsIn this work, theranostic nanoparticles were synthesized with commonly used biocompatible and biodegradable polymers and used as cancer contrast and therapeutic agents for optical imaging and treatment of breast cancer. These core-shell nanoparticles were prepared by nanoprecipitation of blends of the biodegradable and biocompatible amphiphilic copolymers poly(lactic-co-glycolic acid)-b-poly-l-lysine and poly(lactic acid)-b-poly(ethylene glycol). Poly-l-lysine in the first copolymer was covalently decorated with near-infrared fluorescent Alexa Fluor 750 molecules.ResultsThe spherical nanoparticles had an average size of 60-80 nm. The chemotherapeutic drug doxorubicin was encapsulated in the core of nanoparticles at a loading of 3% (w:w) and controllably released over a period of 30 days. A 33-fold increase in near-infrared fluorescence, mediated by protease-mediated cleavage of the Alexa Fluor 750-labeled poly-l-lysine on the surface of the nanoparticles, was observed upon interaction with the model protease trypsin. The cytocompatibility of drug-free nanoparticles and growth inhibition of drug-loaded nanoparticles on MDA-MB-231 breast cancer cells were investigated with a luminescence cell-viability assay. Drug-free nanoparticles were found to cause minimal toxicity, even at high concentrations (0.2-2,000 µg/mL), while doxorubicin-loaded nanoparticles significantly reduced cell viability at drug concentrations >10 µM. Finally, the interaction of the nanoparticles with breast cancer cells was studied utilizing fluorescence microscopy, demonstrating the potential of the nanoparticles to act as near-infrared fluorescence optical imaging agents and drug-delivery carriers.ConclusionDoxorubicin-loaded, enzymatically activatable nanoparticles of less than 100 nm were prepared successfully by nanoprecipitation of copolymer blends. These nanoparticles were found to be suitable as controlled drug delivery systems and contrast agents for imaging of cancer cells.
| S-EPMC6217908 | biostudies-literature