Biomaterials Science最新文献

Fluorescent therapeutic molecules offer a unique platform to study cellular uptake and biological pathways of drug candidates. Inhibition of the p53-HDM2 protein complex with the reactivation of the p53 pathway leading to apoptosis is a promising way to overcome the barriers and challenges in cancer therapeutic design. Although p53 helix mimetics based on the 'hotspots' design using either helical or non-helical backbones are known, cell-permeable and biocompatible inherently fluorescent helix mimetics have not yet been described. We report theragnostic helix mimetics featuring both therapeutic and bioimaging properties in a cancer cell model for the first time. The solvatochromic phthalimide unit in the scaffold functions as a site to append the hotspot mimicking residues, helps in the intramolecular hydrogen bonding mediated pre-organization of side chains on one face, and importantly, exhibits intrinsic fluorescence. The design of the mimetics, synthesis, conformational studies, and molecular docking results are discussed. In vitro cytotoxicity studies were carried out on four cell lines: U87MG (human glioblastoma), A549 (human non-small cell lung cancer), MDA-MB-231 (human triple-negative breast cancer) and HEK293 (non-cancerous cell line). The molecules showed anticancer activity in the micromolar range. The fluorescence properties provided valuable insights into their cellular permeability, distribution, and selectivity towards cancer cells and can shed light on their mechanisms of action.

The design of biodegradable and thermoresponsive polymeric hydrogels with tuneable properties holds immense promise for localised and sustained drug delivery. In this study, we designed and synthesised a library of novel pentablock copolymers, incorporating poly(D,L-lactide) (PLA) into methoxypoly(ethylene glycol)-poly(ε-caprolactone)-methoxypoly(ethylene glycol) (mPEG-PCL-mPEG, or PECE) hydrogels to enhance the hydrolytic degradation and drug release profiles. A pentablock copolymer, methoxypoly(ethylene glycol)-b-poly(D,L lactide)-b-poly(ε-caprolactone)-b-poly(D,L lactide)-b-methoxypoly(ethylene glycol) (mPEG-PLA-PCL-PLA-mPEG, or PELCLE), was selected based on its thermoresponsive sol-gel transition behaviour at a physiologically relevant temperature (37 °C). Physicochemical characterisation revealed that both PECE and PELCLE hydrogels self-assembled into micellar structures, with PELCLE exhibiting smaller micellar sizes compared to PECE. The incorporation of PLA led to reduced hydrogel stiffness, enhanced degradability, and decreased swelling compared to PECE. In vitro drug release studies demonstrated that both hydrogels exhibited sustained release of various anti-cancer drugs, with PELCLE generally showing slower release kinetics, highlighting its potential for prolonged drug delivery. For potential pancreatic cancer applications, we evaluated the biocompatibility and therapeutic efficacy of PELCLE hydrogels loaded with gemcitabine and oxaliplatin (GEMOX). In vitro and in vivo studies demonstrated safety and some anti-tumour efficacy of GEMOX-loaded PELCLE compared to free drug administration, attributed to enhanced tumour retention and sustained drug release. These findings highlight the potential of the PELCLE hydrogel as a versatile and effective local drug delivery platform for the treatment of pancreatic cancer and other solid tumours, warranting further investigation towards its clinical translation.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon part of the large intestine. Since there is no cure for this disease, conventional therapies only provide symptomatic relief. Recently, phytomolecules have shown promising treatment results in various diseases. However, short half-life, hydrophobicity, and poor bioavailability limit their therapeutic potential. To overcome all these challenges, we have earlier conjugated a phytomolecule (gallic acid) (GA) with the FDA-approved generally recognized as safe (GRAS) material that is glycerol monostearate (GMS). This GA-GMS conjugate self-assembles as a hydrogel via the heating-cooling method and acts as a pro-drug of GA. The in vivo imaging results suggest that the GA-GMS hydrogel more efficiently adheres to the inflamed colon than a therapeutic enema. Additionally, it is known that the gut microbiota exaggerates UC by creating a hypoxic environment in the colon. This hypoxia is linked with NLRP3 inflammasome activation that triggers the release of IL-1β and IL-18 that downregulates MUC2 protein expression in the colon, responsible for mucin secretion in the colon. Therefore, chrysin (CR) (HIF-1α inhibitor) is encapsulated into the GA-GMS hydrogel to target hypoxia. The CR@GA-GMS hydrogel follows the enzyme-responsive release of the CR and restores DSS-induced damage to colonic tissue. Furthermore, the CR@GA-GMS hydrogel downregulates HIF-1α mediated NLRP3 inflammasome signalling while upregulating MUC2 production.

Nanomedicine-based photothermal therapy (PTT) has been considered as an excellent alternative for treatment of tumor tissue due to its high therapeutic efficiency and controllable range. However, the overexpression of heat shock proteins (HSPs) during PTT and the hypoxic properties of the tumor microenvironment can lead to intracellular thermal resistance and reduce its effectiveness. Reactive oxygen species (ROS), followed by the application of chemodynamic therapy (CDT) and photodynamic therapy (PDT), can eliminate HSPs and overcome thermal resistance. High concentration H₂O₂ was used to catalyze oxygen production in the tumor microenvironment to improve the anaerobic state. Therefore, we present a multifunctional nanocarrier system driving chemodynamic-photodynamic-photothermal synergistic therapy via self-supplied hydrogen peroxide and relieved hypoxia for prostate tumor treatment.

Various cell sheets have been used as effective and useful cellular tissues in tissue engineering and regenerative therapy. Poly(N-isopropylacrylamide) (PNIPAAm)-modified surfaces have been investigated for effective cell sheet preparation. In this study, the effective PNIPAAm graft density and chain length of PNIPAAm brushes for various cell types were investigated. The PNIPAAm brush-grafted glass was prepared via silanization and subsequent atom transfer radical polymerization (ATRP). The density of the PNIPAAm brushes was modulated by changing the ATRP initiator and co-adsorber composition, while the PNIPAAm brush length was modulated by changing the monomer concentration in the ATRP. The hydrophilicity of the PNIPAAm brushes increased with increasing PNIPAAm brush length because long PNIPAAm brushes tended to hydrate. Fibronectin adsorption increased with decreasing PNIPAAm brush concentration because the exposed hydrophobic co-adsorber in the dilute PNIPAAm brush enhanced the adsorption of fibronectin. The cell-sheet fabrication ability was investigated using six types of PNIPAAm brushes. An endothelial cell sheet was fabricated using a dense, short PNIPAAm brush. NIH/3T3 sheets can be fabricated using three types of PNIPAAm brushes: dense-long PNIPAAm brushes, moderately dense-short PNIPAAm brushes, and dilute-long PNIPAAm brushes. MDCK cell sheets could not be prepared using the PNIPAAm brushes. A549 cell sheets were prepared using a dense-short PNIPAAm brush and moderately dense-short PNIPAAm brushes. These results indicate that the optimal PNIPAAm brush conditions for cell sheet preparation vary depending on cell type. Thus, modulation of PNIPAAm brush density and length is an effective approach for preparing target cell sheets.

The practical benefits and therapeutic potential of tumor vaccines in immunotherapy have drawn significant attention in the field of cancer treatment. Among the available vaccines, nanovaccines that utilize nanoparticles as carriers or adjuvants have demonstrated considerable effectiveness in combating cancer. Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN), a common adjuvant in tumor nanovaccines, activates both humoral and cellular immunity by recognizing toll-like receptor 9 (TLR9), thereby aiding in the prevention and treatment of cancer. Metal nanoparticles hold great promise in tumor immunotherapy due to their adjustable size, surface functionalization, ability to regulate innate immunity, and capacity for controlled delivery of antigens or immunomodulators. Consequently, composite nanoadjuvants, formed by combining metal nanoparticles with CpG ODNs, can be customized to meet the specific performance requirements of different application scenarios, effectively overcoming the limitations of conventional immunotherapy approaches. This review provides a comprehensive analysis of the critical role of metal-CpG composite nanoadjuvants in advancing vaccine adjuvants for cancer therapy and prevention, highlighting their efficacy in preclinical settings.

In the pursuit of more effective cancer therapies, phototherapy has emerged as a promising approach due to its non-invasive nature and high precision. This study presents the development of a near-infrared (NIR) light-responsive phenothiazine (PTZ) based phototherapeutic system designed for targeted cancer treatment. This phototherapeutic system integrates four crucial elements for enhanced therapeutic efficacy: cancer cell-specific activity, mitochondrial targeting, photothermal conversion, and controlled drug release. The PTZ system utilizes the acidochromic 1,3-oxazine ring, which opens in the acidic tumor microenvironment, forming a positive iminium ion (CN⁺). This ionic species targets cancer cell mitochondria, ensuring precise localization. Under NIR light irradiation (640 nm), the phototherapeutic system undergoes a red shift in the absorption and reduction in the fluorescence intensity, demonstrating a significant photothermal effect that converts light to heat, thereby inducing tumor cell apoptosis. Furthermore, NIR light triggers the controlled release of the anticancer drug chlorambucil, enabling precise spatiotemporal drug delivery. The closed form of the phototherapeutic system also facilitates drug release upon visible light irradiation (≥410 nm) with high photochemical efficiency. This dual-mode photothermal and photocontrolled drug delivery offers a synergistic approach to cancer therapy, maximizing therapeutic outcomes while minimizing side effects. Our findings underscore the potential of this innovative phototherapeutic system to advance cancer treatment through targeted, controlled, and effective drug delivery.

Chronic infections involving bacterial biofilms pose significant treatment challenges due to the resilience of biofilms against existing antimicrobials. Here, we introduce a nanomaterial-based platform for treating Staphylococcus epidermidis biofilms, both in isolation and within a biofilm-infected burn skin model. Our approach leverages biocompatible and photothermal polydopamine nanoparticles (PDNP), functionalized with branched polyethyleneimine (PEI) and loaded with the antibiotic rifampicin, to target bacteria dwelling within biofilms. A key innovation of our method is its ability to not only target planktonic S. epidermidis but also effectively tackle biofilm-embedded bacteria. We demonstrated that PDNP-PEI interacts effectively with the bacterial surface, facilitating laser-activated photothermal eradication of planktonic S. epidermidis. In a 3D skin burn injury model, PDNP-PEI demonstrates anti-inflammatory and reactive oxygen species (ROS)-scavenging effects, reducing inflammatory cytokine levels and promoting healing. The rifampicin-loaded PDNP-PEI (PDNP-PEI-Rif) platform further shows significant efficacy against bacteria inside biofilms. The PDNP-PEI-Rif retained its immunomodulatory activity and efficiently eradicated biofilms grown on our burn-injured 3D skin model, effectively addressing the challenges of biofilm-related infections. This achievement marks a significant advancement in infection management, with the potential for a transformative impact on clinical practice.

Despite advances in cardiovascular technology, treating stenosis in tortuous arteries with balloon-expandable stents, typically deployed in a straight orientation, remains a challenge. This study developed novel balloon-expandable "hot-dog-string" (HDS) drug-eluting poly(ε-caprolactone) (PCL) nanofibrous stents using solvent casting and coaxial electrospinning techniques. A unique HDS geometry was designed for the PCL stent backbone, while aspirin and sirolimus were loaded into the core-sheath structured poly(lactic-co-glycolic acid) (PLGA) nanofibers, which were then wrapped around the degradable stent. In vitro characterization of the biodegradable HDS stent and drug-eluting nanofibers was conducted. The results indicate that the biodegradable HDS stents exhibited excellent mechanical properties and superior flexibility, allowing them to navigate curved sections of a simulated in vitro vessel model more effectively than metallic stents. The core-sheath structure of the nanofibers enabled sustained release of high concentrations of aspirin and sirolimus over 14 and 23 days, respectively, with sirolimus effectively inhibiting smooth muscle cell proliferation. Moreover, in vivo animal tests showed that the rabbits remained in good health with excellent vessel patency following stent placement. By implementing the innovative design and techniques proposed in this study, we anticipate fabricating biodegradable drug-eluting HDS stents of various sizes for diverse cardiovascular applications at curved lesions.

We investigated the role of dichloro-squaraine (SQ) dye aggregates in facilitating thymine-thymine interstrand photo-crosslinking within double crossover (DX) tiles, to develop thermally stable and structurally uniform two-dimensional (2D) DNA-based nanostructures. By strategically incorporating SQ modified thymine pairs, we enabled site-selective [2 + 2] photocycloaddition under 310 nm UV light. Strong dye-dye interactions, particularly through the formation of aggregates, facilitated covalent bond formation between proximal thymines. To evaluate the impact of dye aggregation on crosslinking efficiency, ten DX tile variants with varying SQ-modified thymine positions were tested. Our results demonstrated that SQ dye aggregates significantly enhanced crosslinking, driven by precise SQ-modified thymine dimer placement within the DNA tiles. Analytical techniques, including denaturing PAGE and UV-visible spectroscopy, validated successful crosslinking in DNA tiles with multiple SQ-modified thymine pairs. This non-phototoxic method offers a potential route for creating thermally stable, homogeneous higher-order DNA-dye assemblies with potential applications in photoactive and exciton-based fields such as optoelectronics, nanoscale computing, and quantum computing. The insights from this study establish a foundation for further exploration of advanced DNA-dye systems, enabling the design of next-generation DNA nanostructures with enhanced functional properties.