Journal of materials chemistry. B最新文献

Although natural killer (NK) cell-based adoptive cell transfer (ACT) has shown promise in cancer immunotherapy, its efficacy against solid tumors is limited in the immunosuppressive tumor microenvironment (TME). Combinatorial therapies involving chemotherapeutic drugs such as gemcitabine (Gem) and NK cells have been developed to modulate the TME; however, their clinical application is constrained by low drug delivery efficiency and significant off-target toxicity. In this study, we developed cell membrane-immobilized Gem conjugates (i.e., lipid-Gem conjugates), designed to anchor seamlessly onto NK cell surfaces. Our modular-designed ex vivo cell surface engineeringmaterials comprise a lipid anchor for membrane immobilization, poly(ethylene glycol) to inhibit endocytosis, a disulfide bond as cleavable linker by glutathione (GSH) released during cancer cell lysis, and Gem for targeted sensitization. We demonstrated that the intrinsic properties of NK cells, such as proliferation and surface ligand availability, were preserved despite coating with lipid-Gem conjugates. Moreover, delivery of Gem prodrugs by lipid-Gem coated NK (GCNK) cells was shown to enhance antitumor efficacy against pancreatic cancer cells (PANC-1) through the following mechanisms: (1) NK cells recognized and attacked cancer cells, (2) intracellular GSH was leaked out from the lysed cancer cells, enabling cleavage of disulfide bond, (3) released Gem from the GCNK cells delivered to the target cells, (4) Gem upregulated MHC class I-related chain A and B on cancer cells, and (5) thereby activating NK cells led to enhance antitumor efficacy. The simultaneous co-delivery of membrane-immobilized Gem with NK cells could potentially facilitate both immune synapse-mediated cancer recognition and chemotherapeutic effects, offering a promising approach to enhance the anticancer efficacy of conventional ACTs.

Highly branched poly(N-isopropyl acrylamide) additives chain end functionalised with vancomycin have been designed to agglutinate and report on targetted Gram-positive strains of bacteria (S. aureus). These branched systems selectively desolvate with temperature or binding interactions depending on their chain architecture. We have prepared samples with three different degrees of branching which have incorporated Nile red acrylate as a low concentration of co-monomer to report upon their solution properties. A linear analogue polymer functionalised with vancomycin along the chain instead of the termini is presented as a control which does not bind to targeted bacteria. These samples were analysed by diffusion NMR spectrometry (DOSY), calorimetry, fluorescence lifetime measurements, optical microscopy and scanning electron microscopy to gain a full understanding of their solution properties. The branched polymers are shown conclusively to have a core-shell structure, where the chain ends are expressed from the desolvated globule even above the lower critical solution temperature - as demonstrated by NMR measurements. The level of desolvation is critically dependent on the degree of branching, and as a result we have found intermediate structures provide optimal body temperature bacterial sensing as a consequence of the Nile red reporting dye.

Rhodium nanoparticles have been recently discovered as good photosensitizers with great potential in cancer photodynamic therapy by effectively inducing cytotoxicity in cancer cells under near-infrared laser. This study evaluates the molecular mechanisms underlying such antitumoral effect through quantitative proteomics. The results revealed that rhodium nanoparticle-based photodynamic therapy disrupts tumor metabolism by downregulating key proteins involved in ATP synthesis and mitochondrial function, leading to compromised energy production. The treatment also induces oxidative stress and apoptosis while targeting the invasion capacity of cancer cells. Additionally, key proteins involved in drug resistance are also affected, demonstrating the efficacy of the treatment in a multi-drug resistant cell line. In vivo evaluation using a chicken embryo model also confirmed the effectiveness of the proposed therapy in reducing tumor growth without affecting embryo viability.

Self-assembled lipid nanoparticles containing Gd-chelating lipids are a new type of positive magnetic resonance imaging contrast agents (MRI CAs). High molecular weight imposes reduced molecular reorientation (τ_r) and corresponding longer reorientation correlation times (τ_c), finally resulting in overall high relaxivity (r₁) of such contrast agents. Therefore, we report nanoassemblies based on two types of amphiphile molecules: glyceryl monooleate (GMO) as a matrix embedded with DTPA-bis(stearylamide) and its gadolinium salt (DTPA-BSA-Gd) as a Gd-chelating lipid, stabilized by surfactant Pluronic F127 molecules. The loading of DTPA-BSA-Gd into the GMO matrix was investigated at low (5% w/w) and high (30, 40, 50% w/w) contents. Small angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS) results show that although the nanoassembly of both amphiphile molecules within the nanoparticle is disturbed in terms of the formed phases, this composition ensures their colloidal stability. In nanoparticles with low DTPA-BSA-Gd contents, the assembly results in a cubic diamond phase that is co-existing with a fraction of liposomes. For high DTPA-BSA-Gd contents, swelling of the structure occurs such that the initially formed primitive cubic phase transforms toward a lamellar phase in the nanoassemblies. Results from inductively coupled plasma mass spectrometry (ICP-MS) indicate that for almost all systems, the loading efficiency (LE) of DTPA-BSA-Gd is high (reaching up to approx. 85%), and the nanoassembly provides strong entrapment of Gd³⁺ ions, which are then efficiently uptaken by cells. Moreover, the higher the surfactant content, the higher the LE. The viability studies demonstrate that the prepared nanoassemblies preserve high biocompatibility towards both cancer (HeLa) and normal cells (MSU 1.1). Nuclear magnetic resonance relaxometry studies (NMR relaxometry) followed by MRI on the prepared nanoassembly dispersions proved that the formation of GMO@DTPA-BSA-Gd nanoassemblies, considered as high molecular weight CAs, results in high relaxivity parameters (e.g., r₁ = 19.72 mM^-1 s^-1 for 2GMO-40DTPA-10F127) that are superior to commercially developed ones (e.g., Magnevist or Gadovist). These comprehensive studies imply that a high degree of internal ordering of nanoassemblies with a higher content of Gd-chelating lipid is not a decisive factor in determining the increase in relaxivity, thus confirming their potential as positive MRI CAs.

Self-assembling peptide hydrogels (SAPHs) are increasingly being used as two-dimensional (2D) cell culture substrates and three-dimensional (3D) matrices due to their tunable properties and biomimicry of native tissues. Despite these advantages, SAPHs often represent an end-point in cell culture, as isolating cells from them leads to low yields and disruption of cells, limiting their use and post-culture analyses. Here, we report on a protocol designed to easily and effectively disassemble peptide amphiphile (PA) SAPHs to retrieve 3D encapsulated cells with high viability and minimal disruption. Due to the pivotal role played by salt ions in SAPH gelation, tetrasodium ethylenediaminetetraacetic acid (Na₄EDTA) was used as metal chelator to sequester ions participating in PA self-assembly and induce a rapid, efficient, clean, and gentle gel-to-sol transition. We characterise PA disassembly from the nano- to the macro-scale, provide mechanistic and practical insights into the PA disassembly mechanism, and assess the potential use of the process. As proof-of-concept, we isolated different cell types from cell-laden PA hydrogels and demonstrated the possibility to perform downstream biological analyses including cell re-plating, gene analysis, and flow cytometry with high reproducibility and no material interference. Our work offers new opportunities for the use of SAPHs in cell culture and the potential use of cells cultured on SAPHs, in applications such as cell expansion, analysis of in vitro models, cell therapies, and regenerative medicine.

There is an increasing understanding that condensation is a crucial intermediate step in the assembly of biological materials and for a multitude of cellular processes. To apply and to understand these mechanisms, in vitro biophysical characterisation techniques are central. The formation and biophysical properties of protein condensates depend on a multitude of factors, such as protein concentration, pH, temperature, salt concentration, and presence of other biomolecules as well as protein purification and storage conditions. Here we show how critical the procedures for preparing protein samples for in vitro studies are. We compare two purification methods of the recombinant spider silk protein CBM-AQ12-CBM and study the effect of background molecules, such as DNA, on the formation and properties of the condensates. We characterize the condensates using aggregation induced emitters (AIEs), coalescence studies, and micropipette aspiration. The condensated sample containing background molecules exhibit a lower threshold concentration for condensate formation accompanied by a lower surface tension and longer coalescence time when compared to the pure protein condensates. Furthermore, the partitioning of small AIEs is enhanced in the presence of background molecules. Our results highlight that the purification method and remaining background molecules strongly affect the biophysical properties of spider silk condensates. Using the acquired knowledge about spider silk protein purification we derive guidelines for reproducible condensate formation that will foster the use of spider silk proteins as adhesives or carriers for biomedical applications.

Owing to their inherent flexibility and excellent biocompatibility, liquid metals (LMs) have been explored at the frontiers of clinical therapy. Herein, a LM and tanshinone IIA (TA) drugs were dispersed into sodium alginate (SA) solution by ultrasonication to prepare SA/LM/TA, which is an injectable biomaterial for stable drug release and intrapericardial injection for the treatment of myocardial infarction (MI). The SA/LM/TA has a low viscosity and can be injected smoothly using a syringe. In rat models of MI, we demonstrated that SA/LM/TA injection in the pericardial cavity is a biosafe and effective method to deliver a carrier containing LM particles and TA drugs for MI treatment. After injection, the drug release is slow and stable in the pericardial cavity, increasing the cardiac retention of drugs. After surgery and treatment for 7 days, the cardiac function of rats improved compared with the control group and the TA direct injection group. The intrapericardial injection of SA/LM/TA improves cardiac functions and mitigates cardiac remodeling post myocardial infarction of rats. Overall, the present study establishes a therapeutic strategy for treatment of myocardial infarction by intrapericardial injection of SA/LM/TA and expands the application categories of LM biomaterials in disease treatments.

Chemodynamic therapy (CDT) has been recognized as an emerging therapeutic strategy. It has attracted considerable attention in recent years as it can generate the most harmful reactive oxygen species (ROS)-hydroxyl radicals (•OH) through the Fenton reaction or a Fenton-like reaction under the catalysis of versatile metal cations, such as, Fe(II), Fe(III), Cu(I), Mn(II), and Mn(III). However, a large number of reducing species (e.g., GSH) in tumors inhibit the therapeutic effects of CDT. This study proposes a nanocarrier strategy that can release versatile metal cations in the initial stage to consume the reducing substances, which can be convenient for subsequent CDT treatment. A novel nano-delivery system based on H-MnO₂@PDA/Cu-CD@Ad-TK-Ad@Ploy-CD (abbreviated as MNZ) was proposed to resolve the above problems. Herein, hollow mesoporous manganese dioxide nanoparticles (H-MnO₂) were coated with PDA and modified with copper ions on the surface of PDA. The PDA was then functionalized with β-cyclodextrin (β-CD) substitutions that were further assembled with N-((1S,3R,5S)-adamantan-1-yl)-3-((2-((3-(((3s,5s,7s)-adamantan-1-yl)amino)-3-oxopropyl)thio)propan-2-yl)thio)propenamide (Ad-TK-Ad). Poly-CD was assembled with CD to improve the stability of the reactor. The MNZ nanotheranostic platform can release Cu(II) and Mn(II), which could react with intracellular GSH to consume the reducing substances in tumors. Subsequently, H₂O₂ can be converted into •OH, and the effect is improved with increasing temperatures. Cytotoxicity of MNZ (200 μg mL^-1) was studied by cell counting kit-8 (CCK-8) assay using HeLa cells as the models. Results indicated that cell viability was clearly reduced to 22% by the nanoparticles alone, to 18% by the nanoparticles with H₂O₂, and to 9% by the nanoparticles with H₂O₂ and NIR, under weak acidic condition (pH 6.8). This work provides a beneficial exploration for the application of nano-delivery strategies for combined photothermal and chemodynamic therapy agents.

The quest for effective cancer treatment methodologies underpins numerous research endeavors. Despite the therapeutic efficacy of conventional chemotherapy against malignant tumors, tumor recurrence post-therapy remains a formidable challenge. Addressing this, we developed a dual drug delivery system, rooted in a modified metal-organic framework (MOF), specifically by substituting the metal nodes of Uio-66 with cerium to augment its anti-oxidative potential. This engineered system, pyrene-modified hyaluronic acid, functions as a linker, enabling the self-assembly and encapsulation of both the material and the therapeutic agents, and encompasses both doxorubicin and curcumin, aimed at targeting cancer cell eradication and tumorigenesis inhibition. This system demonstrated significant antioxidant capacity through free radical scavenging assays, positioning it as a potential agent in mitigating tumor recurrence. Enhanced anti-tumor activity was distinctly evidenced in human colon cancer cell lines. Additionally, in vitro drug release assessments revealed slow-release kinetics and acid-responsive traits, attributed to the incorporation of pyrenylated hyaluronic acid. Within the xenograft nude mouse model, this system contained a lower amount of doxorubicin, yet, exhibited tumor inhibition capability comparable to the free doxorubicin group. Moreover, it delivered anticancer efficiency under conditions of enhanced antioxidative capacity, underscoring its prospective utility in clinical cancer therapeutics. This dual drug delivery platform not only advances cancer treatment and prophylaxis but also extends novel insights into the therapeutic implications of simultaneous dual drug delivery systems.

Nanobubbles are designed to increase structural stability and enhance the distribution of the transported drug to the targeted site. They can efficiently penetrate the desired area from the bloodstream due to the small size of nanobubbles. In general, the structure of the bubbles contains a gas inside, surrounded by an outer polymeric shell. In this study, perfluoropentane was utilized as a gaseous core whereas collagen was used to form shells because of its biodegradability and excellent biocompatibility. The release studies of collagen nanobubbles prepared at several drug doses were carried out in a Franz cell using a dialysis membrane at different pH (5.5-7.4) and temperature (4.0-40.0 °C) ranges. In the release experiments with collagen nanobubbles, it was observed that approximately 70% of the drug was released within 6 days at pH 7.4 whereas the same releasing rate was achieved within only 24 h after exploding by ultrasound treatment. At the same time, a cytotoxicity study was carried out to demonstrate the effectiveness of the synthesized nanobubbles. With increasing drug loading concentration and ultrasound treatment, the cytotoxic activities of nanobubbles became similar to those of the free drug (ibrutinib). Furthermore, cell culture studies were performed to assess in vitro drug-releasing efficiencies of nanobubbles by using the HeLa cell line as a model of soft cancer tissue. In conclusion, these nanobubbles could be classified as an efficient alternative to carrying active agents for treating soft tissue tumors.