Purpose: In the present study, to achieve high paclitaxel (PTX) loading in a conjugated drug delivery system with minimal long-term side effects, we formulated a novel degradable stereocomplexed micelle-like particle with a core-shell structure. Materials and methods: In this system, methoxy polyethylene glycol (MPEG) acted as the hydrophilic shell, and the stereocomplex of polylactic acid with PTX (SCPLA-PTX) acted as the hydrophobic core. The MPEG-SCPLA-PTX micelle-like particles were synthesized via the self-assembly of a MPEG-poly L-lactic acid (PLLA) copolymer with a PTX-poly D-lactic acid-PTX copolymer. The resultant copolymers and their intermediates were characterized using 1H nuclear magnetic resonance and GPC. Micelle-like particles with different molecular weight ratios of MPEG and PLLA were synthesized to demonstrate the functions of both components. Results: PTX loading into MPEG2000Da-PLLA6000Da particles reached as high as 20.11%. At 216 h, the cumulative release from MPEG5000Da-PLLA6000Da, MPEG2000Da-PLLA6000Da, and MPEG5000Da-PLLA22000Da particles were 51.5%, 37.7%, and 52.0%, respectively. Conclusions: According to the cell uptake experiments, inhibition of tumor cell growth was satisfactory, indicating that the stereocomplexed particles developed in the present study can be employed as a promising nanocarrier for PTX delivery.
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DSC curves of (a) MPEG????-PLLA???? and 5-6 particles; (b) MPEG????-PLLA???? and 2-6 particles; (c) MPEG????-PLLA???? and 5-2 particles; (d) MPEG????-PLLA???? and 5-6 blank particles. Abbreviation: DSC, differential scanning calorimetry.
TEM a-d and SEM e-h images of particles. (a,e) 5-6 particles; (b,f) 2-6 particles; (c,g) 5-2 particles; (d,h) 5-6 blank particles. Abbreviation: TEM, transition electron microscopy; SEM, scanning electron microscopy.
Curves of maximum excitation peak intensity ratio I335 nm/I333 nm of micellar aqueous solution on the logarithm of concentration. (a) 5-6 particles. (b) 2-6 particles. (c) 5-2 particles. (d) 5-6 blank particles.
(a) Cell viability, (b) normalized DCF fluorescence values, (c) mitochondrial membrane potential, and (d) normalized LysoTracker fluorescence values after 24 h exposure to PTX, 5-6 particles, 2-6 particles, and 5-2 particles.
All siRNAs were designed and synthesized by GenePharma (Suzhou, China) or RiboBio (Guangzhou, China) (Table S2). sh-circEXOC6B lentivirus vector was constructed and packaged into lentivirus particles by Genechem (Shanghai, China). All vectors used in the study were constructed by Ruibiotech (Guangzhou, China). The plasmid pCD5-ciR (Geneseed Biotech, Guangzhou, China) was used to construct circEXOC6B overexpression vector. CRC cells were transfected with siRNAs or vectors using lipofectamine3000 (#L3000015, Invitrogen, USA) according to the instruction.
Oxidative stress is associated with many acute and chronic inflammatory diseases, yet limited treatment is currently available clinically. The development of enzyme-mimicking nanomaterials (nanozymes) with good reactive oxygen species (ROS) scavenging ability and biocompatibility is a promising way for the treatment of ROS-related inflammation. Herein we report a simple and efficient one-step development of ultrasmall Cu5.4O nanoparticles (Cu5.4O USNPs) with multiple enzyme-mimicking and broad-spectrum ROS scavenging ability for the treatment of ROS-related diseases. Cu5.4O USNPs simultaneously possessing catalase-, superoxide dismutase-, and glutathione peroxidase-mimicking enzyme properties exhibit cytoprotective effects against ROS-mediated damage at extremely low dosage and significantly improve treatment outcomes in acute kidney injury, acute liver injury and wound healing. Meanwhile, the ultrasmall size of Cu5.4O USNPs enables rapid renal clearance of the nanomaterial, guaranteeing the biocompatibility. The protective effect and good biocompatibility of Cu5.4O USNPs will facilitate clinical treatment of ROS-related diseases and enable the development of next-generation nanozymes.
Advances in nanomedicine have enabled new ways of ROS clearance and thus treatment of ROS-related diseases using various functional nanomaterials13, such as carbon14, ceria15, platinum16, redox polymer17, and polyphenol nanoparticles (NPs)18. Among them, one promising strategy is to develop nanozymes to maintain natural redox balance in biological system, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)19. Such nanozymes shall have high ROS scavenging ability comparable to native enzymes, broad-spectrum ROS scavenging activities against various toxic ROS species, high stability in harsh disease environment, and rapid clearance from the body to guarantee excellent biocompatibility. Therefore we believe nanomaterials with ultrasmall size (hydrodynamic diameter
Cu5.4O ultrasmall nanoparticles with multiple enzyme-mimicking and broad-spectrum ROS scavenging ability are synthesized by a simple and green method. Due to the robust ROS scavenging ability in vivo, Cu5.4O ultrasmall nanoparticles exhibit therapeutic effect against broad ROS-related diseases, including acute kidney injury, acute liver injury and diabetic wound healing.
a Schematic preparation of Cu5.4O USNPs. b TEM image of Cu5.4O USNPs. Inset is the statistical chart of particle size distribution. The cross-sectional area of each particle was measured by using ImageJ Software from the TEM images, with at least 500 particles counted per sample. c Hydrodynamic diameter distribution of the Cu5.4O USNPs. d X-ray diffraction (XRD) pattern of the Cu5.4O USNPs, the rhombus, and star symbols represent the characteristic peaks of Cu2O and Cu, respectively. e XAES spectra of the Cu5.4O USNPs. Source data are provided as a Source Data file.
Recently, a multitude of nanomaterials have been designed as they exhibit promising potential to overcome the limitations of chemotherapy drugs for cancer therapy applications, such as liposomes [8], carbon nanomaterials [9], silica nanoparticles [10], metal-based nanoparticles [11], polymeric nanoparticles [12,13,14] and quantum dots [15, 16] have been used in biomedical applications. Compared to these nanomaterials, two-dimensional (2D) nanomaterials possess exceptional chemical, optical, and electronic properties and are thus, being considered as novel therapeutic agents for biomedicine, especially for cancer treatment. There have been some particularly interesting reports that demonstrate encouraging potential of 2D nanomaterial theranostics in the pre-clinical area and targeted delivery of cancer therapeutics [12,13,14,15,16,17]. Since graphene oxide was applied, single layer 2D nanomaterials has drawn much attention in a wide range of areas because of their unique physical and chemical properties. Owing to these excellent properties, more effort has been paid to search for other similar 2D materials [17, 18]. MoS2 nanosheets, as a kind of transition metal dichalcogenides (TMDCs), displayed huge potential applications for nanoelectronic [19,20,21], transistors [22,23,24], energy storage devices [25, 26] and catalysis [27,28,29]. Past several years, a few groups have explored the promising application of single-layer MoS2 sheets in the biomedical field [30, 31]. Photothermal therapy (PTT) as a non-invasive therapeutic approach triggered by light, can transfer optical energy into heat, resulting in the thermal ablation of cancer cells [32, 33]. As a new type of 2D TMDCs, MoS2 has exhibited its intrinsic high NIR absorbance as well as outstanding photothermal conversion efficiency, which indicated that MoS2 could be used as a photothermal agent (PTA) for PTT [31, 34,35,36]. Besides, as a NIR photothermal delivery system, MoS2 has been reported that could stimulate the drug release triggered by NIR irradiation [37, 38]. Hence, the MoS2-nanosheets could be used to form a NIR-triggered drug delivery system because of the larger surface area and amazing photothermic. However, MoS2 nanosheets rapidly aggregate in physiological solution, which hampers the application of MoS2 nanosheets in the medical field. Therefore, the surface modification of single-layer MoS2 nanosheet remains a tremendous challenge for the application of the MoS2 nanosheets in biomedicine. Chou et al. showed that the thiolated molecules could be attached to the MoS2 nanosheets at the defect sites resulted from chemical exfoliation process and reported that the modified single-layer MoS2 sheets show outstanding biocompatibility and high absorbance when under the irradiation of NIR laser [34, 39]. The novel approach for the surface modification of single-layer MoS2 nanosheet is urgently needed.
Methods: The platform was prepared by loading functional protein on pure drug nanoparticles (PNPs) followed by hyaluronic acid coating and was characterized by dynamic light scattering, transmission electron microscopy, and gel electrophoresis. In vitro, cellular uptake, trafficking, and cytotoxicity were evaluated by flow cytometry and confocal laser microscopy. Protein expression was assayed by western blot. In vivo, blood circulation and biodistribution were studied using a fluorescence imaging system, antitumor efficacy was assessed in a caspase 3-deficient tumor model, and biocompatibility was determined by comparison of hemolytic activity and proinflammatory cytokines and tissue histology.
Since insulin was commercially marketed in 1982, an increasing number of proteins and peptides, with greater than 200 products [1] in the past 3 decades, have been approved for treatment of diverse diseases including cancer, infection, diabetes, and inflammatory disease [2, 3]. Undoubtedly, protein therapeutics, such as protein replacement therapies and human antibodies [4, 5], play an essential role in treatment of human diseases. Moreover, protein-based therapy is considered safer than gene therapy due to the absence of random or permanent genetic alterations. Nonetheless, protein delivery is extremely difficult because proteins are susceptible to enzymatic degradation, have large size, short circulation half-lives and poor-membrane permeability [6, 7]. Nanomaterials, such as nanogels [8], cationic lipid particles [9], nanocapsules [10, 11], and virus-like particles [12], have been reported to improve protein delivery. Several vectors, such as PULsin (PUL) and BioPORTER, have been marketed for protein delivery [13, 14]. Indeed, these conventional nanoparticles enhance the therapy outcomes of proteins. However, intracellular protein delivery has remained a challenge. To obtain intracellular targeting by proteins, delivery into the cytoplasm is a prerequisite. Unfortunately, during internalization, these nanoparticles will be captured by the endo-lysosomal system where numerous digestive enzymes inhabit acidic conditions at pH of less than 4.5 [15-17]; therefore, dramatic degradation of proteins occurs, which results in 2ff7e9595c
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