Functionalized carbon nanotubes (f-CNTs) are being produced in increased volume because of the ease of dispersion and maintenance of the pristine material physicochemical properties when used in composite materials as well as for other commercial applications. However, the potential adverse effects of f-CNTs have not been quantitatively or systematically explored, and in this study we used a library of covalently functionalized multiwall carbon nanotubes (f-MWCNTs), established from the same starting material, to assess the impact of surface charge in a predictive toxicological model that relates the tubes’ pro-inflammatory and pro-fibrogenic effects at cellular level to the development of pulmonary fibrosis. Carboxylated (COOH), polyethylene glycol (PEG), amine (NH2), sidewall amine (sw-NH2) and polyetherimide (PEI) modified MWCNTs were successfully established from raw or as-prepared (AP-) MWCNTs, and comprehensively characterized by TEM, XPS, FTIR and DLS to obtain information about morphology, length, degree of functionalization, hydrodynamic size and surface charge. Cellular screening in BEAS-2B and THP-1 cells showed that, compared to AP-MWCNTs, anionic functionalization (COOH and PEG) decreased the production of pro-fibrogenic cytokines and growth factors (including IL-1β, TGF-β1 and PDGF-AA), while neutral and weak cationic functionalization (NH2 and sw-NH2) showed intermediary effects. In contrast, the strongly cationic PEI-functionalized tubes induced robust biological effects. These differences could be attributed to differences in cellular uptake and NLRP3 inflammasome activation, which depends on the propensity towards lysosomal damage and cathepsin B release in macrophages. Moreover, the in vitro hazard ranking was validated by the pro-fibrogenic potential of the tubes in vivo. Compared to pristine MWCNTs, strong cationic PEIMWCNTs induced significant lung fibrosis, while carboxylation significantly decreased the extent of pulmonary fibrosis. These results demonstrate that surface charge plays an important role in the structure-activity relationships that determine the pro-fibrogenic potential of f-CNTs in the lung.

The exocytosis of phosphonate modified mesoporous silica nanoparticles (P‐MSNs) is demonstrated and lysosomal exocytosis is identified as the mechanism responsible for this event. Regulation of P‐MSN exocytosis can be achieved by inhibiting or accelerating lysosomal exocytosis. Slowing down P‐MSN exocytosis enhances the drug delivery effect of CPT‐loaded P‐MSNs by improving cell killing.

Effective and rapid treatment of tularemia is needed to reduce morbidity and mortality of this potentially fatal infectious disease. The etiologic agent, Francisella tularensis, is a facultative intracellular bacterial pathogen which infects and multiplies to high numbers in macrophages. Nanotherapeutics are particularly promising for treatment of infectious diseases caused by intracellular pathogens, whose primary host cells are macrophages, because nanoparticles preferentially target and are avidly internalized by macrophages. A mesoporous silica nanoparticle (MSN) has been developed functionalized with disulfide snap-tops that has high drug loading and selectively releases drug intracellularly in response to the redox potential. These nanoparticles, when loaded with Hoechst fluorescent dye, release their cargo exclusively intracellularly and stain the nuclei of macrophages. The MSNs loaded with moxifloxacin kill F. tularensis in macrophages in a dose-dependent fashion. In a mouse model of lethal pneumonic tularemia, MSNs loaded with moxifloxacin prevent weight loss, illness, and death, markedly reduce the burden of F. tularensis in the lung, liver, and spleen, and are significantly more efficacious than an equivalent amount of free drug. An important proof-of-principle for the potential therapeutic use of a novel nanoparticle drug delivery platform for the treatment of infectious diseases is provided.

Universal CMRx assessment is needed to identify and reduce complex regimens, and, thus, improve safety. The authors highlight commonalities among five scales to help build consensus. Common components (i.e., regimen factors) included dosing frequency, units per dose, and non-oral routes. Elements (e.g., twice daily) of these components (e.g., dosing frequency) and scoring varied. Patient-specific factors (e.g., dexterity, cognition) were not addressed, which is a shortcoming of current scales and a challenge for future scales. As CMRx has important outcomes, notably adherence and healthcare utilization, a standardized tool has potential for far-reaching clinical, research, and patient-safety impact.