In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels. Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique.

Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P-glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT-11) and a NO-releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp-mediated MDR reversal agent. The site-specific drug release and the NO-reduced Pgp-mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell-killing threshold, eventually inducing its antitumor activity. These results reveal that this pH-responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.

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Our results demonstrate no significant differences in functional outcome and nonunion rates between nails and plates fixation for displaced midshaft clavicular fractures.

Hydrogen gas can reduce cytotoxic reactive oxygen species (ROS) that are produced in inflamed tissues. Inspired by natural photosynthesis, this work proposes a multicomponent nanoreactor (NR) that comprises chlorophyll a, l-ascorbic acid, and gold nanoparticles that are encapsulated in a liposomal (Lip) system that can produce H gas in situ upon photon absorption to mitigate inflammatory responses. Unlike a bulk system that contains free reacting molecules, this Lip NR system provides an optimal reaction environment, facilitating rapid activation of the photosynthesis of H gas, locally providing a high therapeutic concentration thereof. The photodriven NR system reduces the degrees of overproduction of ROS and pro-inflammatory cytokines both in vitro in RAW264.7 cells and in vivo in mice with paw inflammation that is induced by lipopolysaccharide (LPS). Histological examinations of tissue sections confirm the ability of the NR system to reduce LPS-induced inflammation. Experimental results indicate that the Lip NR system that can photosynthesize H gas has great potential for mitigating oxidative stress in tissue inflammation.

Inflammation is associated with many diseases, in which activated inflammatory cells produce various reactive oxygen species (ROS), including H2O2. This work proposes an ultrasensitive ROS-responsive hollow microsphere (HM) carrier that contains an anti-inflammatory drug, an acid precursor consisting of ethanol and FeCl2, and sodium bicarbonate (SBC) as a bubble-generating agent. In cases of inflamed osteoarthritis, the H2O2 at low concentration diffuses through the HMs to oxidize their encapsulated ethanol in the presence of Fe(2+) by the Fenton reaction, establishing an acidic milieu. In acid, SBC decomposes to form CO2 bubbles, disrupting the shell wall of the HMs and releasing the anti-inflammatory drug to the problematic site, eventually protecting against joint destruction. These results reveal that the proposed HMs may uniquely exploit biologically relevant concentrations of H2O2 and thus be used for the site-specific delivery of therapeutics in inflamed tissues.

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Bubbling over: After endocytosis and intracellular trafficking to lysosomes, liposomes containing ammonium bicarbonate can be thermally triggered to generate CO2 bubbles (see scheme). These bubbles grow rapidly and collapse violently to induce transient cavitation, a process that can disrupt the lysosomal membrane and release lysosomal proteases, thus leading to cell necrosis.