NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly.

Despite their potential for a variety of applications, copper nanoparticles induce very strong inflammatory responses and cellular toxicity following aerosolized delivery. Coating metallic nanoparticles with polysaccharides, such as biocompatible and antimicrobial chitosan, has the potential to reduce this toxicity. In this study, copper nanoparticles were coated with chitosan using a newly developed and facile method. The presence of coating was confirmed using x-ray photoelectron spectroscopy (XPS), rhodamine tagging of chitosan followed by confocal fluorescence imaging of coated particles, observed increases in particle size and zeta potential. Further physical and chemical characteristics were evaluated using dissolution and x-ray diffraction (XRD) studies. The chitosan coating was shown to significantly reduce the toxicity of copper nanoparticles after 24 and 52 hours and the generation of reactive oxygen species as assayed by DHE oxidation after 24 hours in vitro. Conversely, inflammatory response, measured using the number of white blood cells, total protein, and cytokines/chemokines in the broncheoalveolar fluid of mice exposed to chitosan coated versus uncoated copper nanoparticles, was shown to increase, as was the concentration of copper ions. These results suggest that coating metal nanoparticles with mucoadhesive polysaccharides (e.g. chitosan) could increase their potential for use in controlled release of copper ions to cells, but will result in a higher inflammatory response if administered via the lung.

The increasing use of copper oxide (CuO) nanoparticles (NPs) in medicine and industry demands an understanding of their potential toxicities. In this study, we compared the in vitro cytotoxicity of CuO NPs of two distinct sizes (4 and 24 nm) using the A549 human lung cell line. Despite possessing similar surface and core oxide compositions, 24 nm CuO NPs were significantly more cytotoxic than 4 nm CuO NPs. The difference in size may have affected the rate of entry of NPs into the cell, potentially influencing the amount of intracellular dissolution of Cu2+ and causing a differential impact on cytotoxicity.

Mitochondria are a promising therapeutic target for the detection, prevention and treatment of various human diseases such as cancer, neurodegenerative diseases, ischemia-reperfusion injury, diabetes and obesity. To reach mitochondria, therapeutic molecules need to not only gain access to specific organs, but also to overcome multiple barriers such as the cell membrane and the outer and inner mitochondrial membranes. Cellular and mitochondrial barriers can be potentially overcome through the design of mitochondriotropic particulate carriers capable of transporting drug molecules selectively to mitochondria. These particulate carriers or vectors can be made from lipids (liposomes), biodegradable polymers, or metals, protecting the drug cargo from rapid elimination and degradation in vivo. Many formulations can be tailored to target mitochondria by the incorporation of mitochondriotropic agents onto the surface and can be manufactured to desired sizes and molecular charge. Here, we summarize recently reported strategies for delivering therapeutic molecules to mitochondria using various particle-based formulations.

Abstract. Metastatic breast cancer is currently incurable, and available therapies are associated with severe toxicities. Induction of protective anti-tumor immunity is a promising therapeutic approach for disseminated breast cancer, as immune responses are (i) systemic; (ii) antigen-specific; and (iii) capable of generating long-lived "memory" populations that protect against future tumor recurrences. Pursuant with this approach, we have developed a novel heterologous prime/boost vaccination regimen that reduces spontaneous lung metastases in mice with established murine 4T1 adenocarcinoma breast tumors. In our studies, mice were orthotopically challenged with luciferase-expressing 4T1 tumor cells; luciferase expression was retained in vivo, enabling us to quantitatively track metastatic tumor growth via bioluminescent imaging. On day 6 post-challenge, mice received a therapeutic "prime" consisting of bulk tumor lysates encapsulated in poly(lactic-co-glycolic) acid (PLGA) microparticles (MPs). On day 11, mice received a "boost" composed of free tumor lysates plus a cocktail of Toll-like receptor (TLR)-stimulating adjuvants. Tumor progression was monitored in vaccinated and untreated mice for 25 days, a time at which 100% of untreated mice had detectable lung tumors. PLGA MPs injected subcutaneously trafficked to draining lymph nodes and were efficiently phagocytosed by dendritic cells (DCs) within 48 h. Our combination therapy reduced metastatic lung tumor burdens by 42% and did not induce autoimmunity. These findings illustrate that vaccines based upon MP delivery of tumor lysates can form the basis of an effective treatment for metastatic breast cancer and suggest that similar approaches may be both efficacious and well-tolerated in the clinic.

Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumor suppressor p53. Our objective was to engender synthetic lethality to paclitaxel, the frontline treatment for endometrial cancer, in tumors with mutant p53 and enhance therapeutic efficacy using polymeric nanoparticles. First we identified the optimal nanoparticle formulation through comprehensive analyses of release profiles, cellular uptake and cell viability studies. Not only were paclitaxel-loaded nanoparticles superior to paclitaxel in solution, but the combination of paclitaxel-loaded nanoparticles with the antiangiogenic molecular inhibitor, BIBF-1120, promoted synthetic lethality specifically in cells with loss of function p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in marked inhibition of tumor progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF-1120- and paclitaxel-loaded nanoparticles as a therapeutic opportunity for loss of function p53 cancers.

Amorphous silica nanoparticles (NPs) possess unique material properties that make them ideal for many different applications. However, the impact of these materials on human and environmental health needs to be established. We investigated nonporous silica NPs both bare and modified with amine functional groups (3-aminopropyltriethoxysilane (APTES)) in order to evaluate the effect of surface chemistry on biocompatibility. In vitro data showed there to be little to no cytotoxicity in a human lung cancer epithelial cell line (A549) for neither bare silica NPs nor amine-functionalized NPs using doses based on both mass concentration (below 200 μg/mL) and exposed total surface area (below 14 m2/L). To assess lung inflammation, C57/B16 mice were administered bare and amine-functionalized silica NPs via intra-tracheal instillation. Two doses (0.1 and 0.5 mg NPs/mouse) were tested using the in vivo model. At the higher dose used, bare silica NPs elicited a significantly higher inflammatory response, as evidence by increased neutrophils and total protein in bronchoalveolar (BAL) fluid compared to amine-functionalized NPs. From this study, we conclude that functionalization of nonporous silica NPs with APTES molecules reduces murine lung inflammation and improves the overall biocompatibility of the nanomaterial.

ABSTRACT. In situ immunization is based on the concept that it is possible to break immune tolerance by inducing tumor cell death in situ in a manner that provides antigen-presenting cells such as dendritic cells (DCs) with a wide selection of tumor antigens that can then be presented to the immune system and result in a therapeutic anticancer immune response. We designed a comprehensive approach to in situ immunization using poly(lactic-co-glycolic acid) (PLGA)-biodegradable microparticles (MPs) loaded with doxorubicin (Dox) and CpG oligodeoxynucleotides (CpG) that deliver Dox (chemotherapy) and CpG (immunotherapy) in a sustained-release fashion when injected intratumorally. Dox induces immunogenic tumor cell death while CpG enhances tumor antigen presentation by DCs. PLGA MPs allow their safe co-delivery while evading the vesicant action of Dox. In vitro, we show that Dox/CpG MPs can kill B and T lymphoma cells and are less toxic to DCs. In vivo, Dox/CpG MPs combined with antibody therapy to enhance and maintain the T cell response generated systemic immune responses that suppressed injected and distant tumors in a murine B lymphoma model, leading to tumor-free mice. The combination regimen was also effective at reducing T cell lymphoma and melanoma tumor burdens. In conclusion, Dox/CpG MPs represent an efficient and safe tool for in situ immunization that could provide a promising component of immunotherapy for patients with a variety of types of cancer.