Spotlight pubs.acs.org/crt
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DUO-TREATED, LONG-LASTING MOSQUITO NET EFFECTIVELY CONTROLS AND STERILIZES INSECTICIDE-RESISTANT MOSQUITOES Long-lasting insecticidal mosquito nets are used for malaria prevention. These nets are typically treated with pyrethroids, which safely, rapidly, and effectively repel mosquitoes. Unfortunately, there are rising numbers of pyrethroid-resistant mosquitoes, and most nonpyrethroid insecticides are unable to prevent blood feeding. The Olyset Duo is a new net treated with a pyrethroid called permethrin, which is toxic to adult mosquitoes, and pyriproxyfen, which regulates insect growth and prevents oocyte maturation in female insects. Corine Ngufor, Mark Rowland, and their collaborators reported on the efficacy of Olyset Duo compared to that of mosquito nets treated with pyrethroid or pyriproxyfen alone ((2016) Sci. Transl. Med., Vol. 8, 356ra121). As a mosquito net has a lifespan of ∼3 years, the authors assessed the Olyset Duo for efficacy against Anopheles gambiae female mosquitoes when it was unwashed and washed 20 times. In the laboratory, the mortality rate was 100% for pyrethroid-susceptible mosquitoes exposed to the unwashed Olyset Duo for 3 min, and 85% for those exposed to the washed net. The unwashed and washed nets inhibited mosquitoes from bloodfeeding by 100% and 94%, respectively. In the field, the Olyset Duo was more effective against pyrethroid-resistant A. gambiae mosquitoes than pyrethroid nets. While it did not prevent more mosquitoes from passing through the net, the duo-treated net was more effective at blocking the mosquitoes from feeding and had a higher rate of mosquito mortality. The unwashed Olyset Duo net also significantly reduced the number of offspring from exposed female mosquitoes. Overall, the Olyset Duo yielded a 94% reduction in reproductive rate with unwashed nets and 78% with washed ones. As the mixed-treated net reduces blood feeding of pyrethroid-resistant mosquitoes, has improved mortality against them, and effectively sterilizes exposed survivors, it is expected to improve on pyrethroid-resistant mosquito population control. Abigail Druck Shudofsky
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ANTICANCER DRUG CONJUGATE SELECTIVELY TARGETS AND INHIBITS THE INTRACELLULAR PROTEIN COX-2 IN IN VIVO TUMORS
nontumorigenic primary human mammary epithelial cell cultures, chemocoxib A was also active against many other neoplastic cell types, regardless of COX-2 expression level. In vivo, however, chemocoxib A demonstrated COX-2-dependent selectivity; it was ineffective against COX-2-negative tumors in mice after 14 d of treatment, yet reduced COX-2 positive tumor growth by 50% without any systemic toxicity. The success of chemocoxib A provides proof-of-concept for the strategy of targeting an intracellular protein in vivo with an antitumor agent. Abigail Druck Shudofsky
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NANOPARTICLE DRUG CARRIERS EXHIBIT CELL TYPE-DEPENDENT DELIVERY BASED ON THEIR PHYSIOCHEMICAL PROPERTIES
Adapted from M. J. Uddin et al. (2016) ACS Chem. Biol., DOI: 10.1021/acschembio.6b00560. Copyright 2016 American Chemical Society.
The enzyme cyclooxygenase-2 (COX-2) is an intracellular protein highly expressed in a range of malignant tumors. Jashim Uddin, Lawrence J. Marnett, and their team synthesized and evaluated a series of chemotherapeutic agents targeting COX-2 in cancer cells and discovered a podophyllotoxin−indomethacin conjugate named chemocoxib A that displays selective antitumor activity in vivo ((2016) ACS Chem. Biol., DOI: 10.1021/acschembio.6b00560). The researchers tethered derivatives of indomethacin, a slow, tight-binding COX inhibitor, to the nonalkaloid toxin lignan podophyllotoxin, which is inactive against COX-2. These conjugates successfully inhibited COX-2 selectively in vitro. One of these, chemocoxib A, displayed high potency in inhibiting COX-2 ex vivo in intact cells of head and neck squamous cell carcinoma and dramatically reduced the number of cells present 48 h post-treatment. While this reduction was not observed in © 2016 American Chemical Society
Figure courtesy of Dr. Yunfeng Yan.
The ideal anticancer drugs act selectively on cancer cells instead of indiscriminately killing all dividing cells. A team led by Daniel J. Siegwart hypothesized that polymeric delivery drug carriers could establish cellular specificity based on their physicochemical properties. They discovered polyester siRNA polyplex nanoparticles which were able to provide selective cancer therapy in vitro and in vivo, thereby improving therapeutic efficacy and reducing off-target effects ((2016) PNAS, 113, E5702−E5710). Published: November 21, 2016 1791
DOI: 10.1021/acs.chemrestox.6b00408 Chem. Res. Toxicol. 2016, 29, 1791−1792
Chemical Research in Toxicology
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conformations, preventing transactivation. They found that when they tethered the two molecules with 3−6 polyethylene glycol (PEG) units (∼5 Å each), the inhibitors had in vitro potencies within 2-fold of an unlinked vemurafenib analogue. The researchers used the 6-PEG chemically linked compound (Vem-6-Vem) to treat melanoma cells with wild-type or BRAFV600E and found that it was able to potently and specifically inhibit the mutant-BRAFcontaining melanoma cells. The scientists resolved the crystal structures of the BRAFV600E kinase domain bound to Vem-6-Vem and Vem-3-Vem and found that the linked inhibitors altered the dimeric configuration of the two BRAFV600E molecules, shifting them to an inactive conformation which was unable to be transactivated. Further functionalizing the linker region with a bis-amide strengthened the hydrogen bond interaction between the drug and the kinase and increased the potency of the linked vemurafenib.
The scientists designed a combinatorial library containing 840 biocompatible functional polyesters which could all deliver siRNA-based therapies but had diverse structures and chemical identities. The authors used these nanoparticles to deliver a toxic siRNA targeting ubiquitin B (siUBB), which causes cell death in all cell types, to a matched pair of tumor and normal lung cell lines derived from an individual patient. The researchers identified 137 cancer-cell specific polymers which preferentially delivered siRNA to cancer cells over normal cells. This cellular selectivity was dependent on the physical chemistry of the nanoparticles vehicles and did not require any cell-specific targeting motifs (see figure for a representative cancer-selective polymer). Excitingly, cancer-cell selectivity directly translated to increased efficacy and tumor growth suppression. Low doses of the selective siUBB-carrying nanoparticles were able to inhibit the formation of tumor colonies in vitro and significantly suppressed cancer growth in vivo when injected intratumorally in mice, with no appreciable toxicity. These results are due to enhanced endocytic uptake of the delivery vehicles and prolonged retention in tumor cells, resulting in siUBB-mediated apoptosis. Intravenous and aerosolized delivery of the siUBB in selective nanoparticles also mediated gene silencing in xenograft and orthotopic lung tumors. This research demonstrates that the physicochemistry of nanoparticle delivery vehicles can be utilized to target cells and increase the selectivity of cancer therapy.
Abigail Druck Shudofsky
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SINGLE-DOSE TRANSTYMPANIC DRUG DELIVERY SYSTEM DELIVERS SUSTAINED LOCAL ANTIBIOTIC TREATMENT FOR MIDDLE EAR INFECTIONS
Abigail Druck Shudofsky
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Figure courtesy of Dr. Rong Yang.
CHEMICALLY LINKED INHIBITORS TRAP MUTATED KINASE DIMERS IN INACTIVE CONFORMATIONS
Otitis media, or middle ear infection, is highly prevalent in babies and young children. It is typically treated with a 10-day course of oral antibiotics which can be extremely difficult to administer to young children and may result in systemic side effects and drug resistance. While local therapeutic delivery to the middle ear would be advantageous, the tympanic membrane (TM) is permeable only to tiny lipophilic molecules. A team led by Daniel S. Kohane developed a biocompatible hydrogel drug delivery system which maximized antibiotic flow across the tympanic membrane and allowed a controlled release of medication over 7 days ((2016) Sci. Transl. Med., 8, 356ra120). This method would allow the application of an entire course of antimicrobial therapy in a single dosage. The authors designed the hydrogel drug delivery system containing the broad-spectrum antibiotic ciprofloxacin; FDAapproved chemical permeation enhancers which increases transTM antibiotic flux; and the pentablock copolymer poloxamer 407− polybutylphosphoester (P407-PBP) (see figure). This formulation resulted in a solution which flowed easily upon application but quickly gelled on the TM and persisted there. The authors tested the efficacy of their hydrogel delivery system by inoculating Haemophilus inf luenza, a common cause of otitis media, directly into the middle ear of chinchillas, then applying either ciprofloxacin alone or the hydrogel system through the auditory canal. While only 62.5% of animals treated with ciprofloxacin alone had cleared the infection by day 7, 100% of animals treated with the hydrogel system had cleared the infection within 24 h without demonstrating any indication of systemic drug distribution. Furthermore, infected TMs exposed to 7 days of hydrogel treatment looked histologically similar to healthy, untreated TMs, suggesting that a single-dose of the biocompatible local antibiotic treatment could treat otitis media.
Reprinted from M. Grasso et al. (2016) ACS Chem. Biol., DOI: 10.1021/acschembio.6b00529. Copyright 2016 American Chemical Society.
BRAF kinase is a member of the MAPK signaling pathway, which regulates cellular proliferation. BRAF, which usually signals as a dimer, is mutated in a significant number of cancers, with ∼90% of these mutations containing a single point mutation (BRAFV600E), which triggers an active protein conformation. Cancer patients treated with BRAFV600E-selective inhibitors like the drug vemurafenib have extended survival but tend to develop drug resistance. One such resistance mechanism arises when an inactive inhibitorbound BRAFV600E subunit transactivates the nondrug-bound subunit associated with it into an active conformation. Ronen Marmorstein, Jeffrey D. Winkler, Jessie Villanueva, and members of their laboratories demonstrated that chemically linked vemurafenib inhibitors can promote an inactive BRAFV600E dimeric conformation, inhibiting transactivation and subsequent MAPK signaling ((2016) ACS Chem. Biol., DOI: 10.1021/acschembio.6b00529). The kinase active sites on each dimer subunit are separated by ∼30 Å, and the authors hypothesized that two covalently linked vemurafenib molecules could simultaneously inhibit both sub units by binding their active sites or trapping them in inactive
Abigail Druck Shudofsky 1792
DOI: 10.1021/acs.chemrestox.6b00408 Chem. Res. Toxicol. 2016, 29, 1791−1792
