Dendritic Mesoporous Silica Nanoparticles for pH‐Stimuli‐Responsive Drug Delivery of TNF‐Alpha

Abstract

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-α is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF-α and deliver it into various cancer cell lines and dendritic cells. Half-maximal effective concentration (EC ) for loaded TNF-α is reduced by more than two orders of magnitude. Particle stability and premature cargo release are assessed with enzyme-linked immunosorbent assay. TNF-α-loaded particles are stable for up to 5 d in medium. Tumor cells are grown in vitro as 3D fluorescent ubiquitination-based cell cycle indicator spheroids that mimic in vivo tumor architecture and microenvironment, allowing real-time cell cycle imaging. DMSN penetrate these spheroids, release TNF-α from its pores, preferentially affect cells in S/G2/M phase, and induce cell death in a time- and dose-dependent manner. In conclusion, DMSN encapsulation is demonstrated, which is a promising approach to enhance delivery and efficacy of antitumor drugs, while minimizing adverse side effects.

High Rates of Aseptic Loosening After Revision Total Knee Arthroplasty for Periprosthetic Joint Infection

“…However, it has yet to be debated whether the absence of antibiotic-loaded cement may increase the risk of recurrent PJI. Antimicrobial nanoparticle prosthetic coatings might offer a suitable alternative 38 - 41 . Furthermore, because longer stems are needed for cementless prostheses, the intraoperative risk of periprosthetic fractures and the rates of perforation of the tibia or femur are increased 42 , 43 .…”

Lectin-conjugated pH-responsive mesoporous silica nanoparticles for targeted bone cancer treatment

“…The performance of these smart nanosystems relies on triggering drug release at the target site by using moieties that are sensitive to external stimuli (light, magnetic fields, electric fields, ultrasounds, etc.) [22][23][24][25][26][27][28][29][30], internal stimuli (variations in pH, redox potential, or the concentrations of enzymes or specific analytes) [31][32][33][34][35][36], or combination of both [37]. However, the side effects in most of these nanosystems cannot be disregarded in practice because these particles frequently lack of specific cancer cell targeting capability and can be also internalized by normal cells.…”

Comprehensive high-throughput image analysis for therapeutic efficacy of architecturally complex heterotypic organoids

“…g ., tetrazolium and trypan blue assays) that are not optimized for 3D culture models 13 , and which simplify treatment responses by reporting a single metric that may not accurately reflect the full scope of effects 14 . For 3D cultures, live/dead staining utilizing calcein AM and propidium iodide (PI)/ethidium bromide/DRAQ7/DAPI are widely used for qualitative purpose 15 – 17 but are not frequently used as a quantitative readout. To address this scarcity in information-rich treatment response assays for organotypic cultures, several groups have developed useful imaging-based platforms to investigate tumor architecture and viability 14 , 18 .…”