Exploitation of Sulfated Glycosaminoglycan Status for Precision Medicine of Triplatin in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive and when metastatic is often drug-resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for patients with TNBC. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models, including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models with the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases, and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC.

Characterization of E-cigarette coil temperature and toxic metal analysis by infrared temperature sensing and scanning electron microscopy - energy-dispersive X-ray.

INTRODUCTION: Electronic cigarettes (e-cigarettes) have rapidly evolved since their introduction to the U.S. market. The rebuildable atomizer (RBA) offers user-driven modification to the heating element (coil) and wicking systems. Different coil materials can be chosen based on user needs and preferences. However, the heating element of an e-cigarette is believed to be one-source for toxic metal exposure. METHODS: E-cigarette coils from Kanthal and nichrome wires were constructed in a contact and non-contact configuration and heated at four voltages. The maximum temperatures of the coils were measured by infrared temperature sensing when dry and when saturated with 100% vegetable glycerin or 100% propylene glycol. The metal composition of each coil was analyzed with Scanning Electron Microscopy-Energy-Dispersive X-Ray (SEM-EDX) when new, and subsequently after 1, 50, and 150 heat cycles when dry. RESULTS: The coils reached temperatures above 1000 °C when dry, but were below 300 °C in both liquid-saturated mediums. Metal analysis showed a decrease of 9-19% chromium and 39-58% iron in Kanthal wire and a decrease of 12-14% iron and 39-43% nickel in nichrome wire after 150 heat cycles. Significant metal loss was observed after one heat cycle for both coil alloys and configurations. CONCLUSIONS: The loss of metals from these heat cycles further suggests that the metals from the coils are potentially entering the aerosol of the e-cigarette, which can be inhaled by the user.

Author Correction: The Effect of Electronic Cigarette User Modifications and E-liquid Adulteration on the Particle Size Profile of an Aerosolized Product.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Effect of Electronic Cigarette User Modifications and E-liquid Adulteration on the Particle Size Profile of an Aerosolized Product.

Electronic cigarettes (e-cigarettes) are an alternate nicotine delivery system that generate a condensation aerosol to be inhaled by the user. The size of the droplets formed in the aerosol can vary and contributes to drug deposition and ultimate bioavailability in the lung. The growing popularity of e-cigarette products has caused an increase in internet sources promoting the use of drugs other than nicotine (DOTNs) in e-cigarettes. The purpose of this study was to determine the effect of various e-cigarette and e-liquid modifications, such as coil resistance, battery voltage, and glycol and drug formulation, on the aerosol particle size. E-liquids containing 12 mg/mL nicotine prepared in glycol compositions of 100% propylene glycol (PG), 100% vegetable glycerin (VG), or 50:50 PG:VG were aerosolized at three voltages and three coil resistances. Methamphetamine and methadone e-liquids were prepared at 60 mg/mL in 50:50 PG:VG and all e-liquids were aerosolized onto a 10 stage Micro-Orifice Uniform Deposit Impactor. Glycol deposition correlated with drug deposition, and the majority of particles centered between 0.172-0.5 µm in diameter, representing pulmonary deposition. The 100% PG e-liquid produced the largest aerosol particles and the 100% VG and 50:50 PG:VG e-liquids produced ultra-fine particles <0.3 µm. The presence of ultrafine particles indicates that drugs can be aerosolized and reach the pulmonary alveolar regions, highlighting a potential for abuse and risk of overdose with DOTNs aerosolized in an e-cigarette system.

Evaluation of Nicotine and the Components of e-Liquids Generated from e-Cigarette Aerosols.

Electronic cigarettes (e-cigs) deliver nicotine in an aerosol to the user that simulates the smoke of traditional cigarettes purportedly without the pathology of inhaling tobacco smoke due to the absence of combustion. Advanced versions of e-cigs enable the user to potentially moderate the concentration of drug in the aerosol by selecting from a range of voltages on the power supply. A method was developed to trap the aerosol produced by a KangerTech AeroTank, 1.8 Ω preassembled atomizer in order to analyze the concentration of nicotine and to evaluate the constituents of the aerosol at various voltages on the power supply. A 12-mg/mL formulation of nicotine in 50:50 propylene glycol (PG):vegetable glycerin (VG) was used to produce aerosol at 3.9, 4.3 and 4.7 V. The aerosol was trapped in a simple glass assemblage and analyzed by a 3200 Q Trap HPLC-MS-MS. The dose of nicotine delivered in the aerosol at 3.9, 4.3 and 4.7 V was determined to be 88 ± 12 µg, 91 ± 15 µg and 125 ± 22 µg. The average recovery of nicotine in the trap across the voltages was 99.8%. The glass trap system was an effective device for collecting the aerosol for analysis and an increase in drug yield was observed with increasing voltage from the power supply on the e-cig. The glass trap system was also used in combination with a 100-µm solid-phase microextraction fiber to capture the aerosol and analyze it via DART-MS and GC-MS. Four commercial e-liquids labeled to contain nicotine were aerosolized at 4.3 V. The pharmacologically active ingredient, nicotine, as well as PG, VG and a number of flavoring agents found in these formulations were identified.