Mass Spectrometry Imaging Characterization of Ethiodized Oil, a Radiopaque Hydrophobic Multipurpose Liquid Used in Cancer Therapy

https://openworks.mdanderson.org/sumexp21/1226/thumbnail.jp

Cross‐sectional areas of deep/core veins are smaller at lower core body temperatures

The cardiovascular system plays a crucial role in thermoregulation. Deep core veins, due to their large size and role in returning blood to the heart, are an important part of this system. The response of veins to increasing core temperature has not been adequately studied in vivo. Our objective was to noninvasively quantify in C57BL/6 mice the response of artery‐vein pairs to increases in body temperature. Adult male mice were anesthetized and underwent magnetic resonance imaging. Data were acquired from three colocalized vessel pairs (the neck [carotid/jugular], torso [aorta/inferior vena cava (IVC)], periphery [femoral artery/vein]) at core temperatures of 35, 36, 37, and 38°C. Cross‐sectional area increased with increasing temperature for all vessels, excluding the carotid. Average area of the jugular, aorta, femoral artery, and vein linearly increased with temperature (0.10, 0.017, 0.017, and 0.027 mm2/°C, respectively; P < 0.05). On average, the IVC has the largest venous response for area (18.2%/°C, vs. jugular 9.0 and femoral 10.9%/°C). Increases in core temperature from 35 to 38 °C resulted in an increase in contact length between the aorta/IVC of 29.3% (P = 0.007) and between the femoral artery/vein of 28.0% (P = 0.03). Previously unidentified increases in the IVC area due to increasing core temperature are biologically important because they may affect conductive and convective heat transfer. Vascular response to temperature varied based on location and vessel type. Leveraging noninvasive methodology to quantify vascular responses to temperature could be combined with bioheat modeling to improve understanding of thermoregulation.Cardiovascular system plays a crucial role in thermoregulation; however, the response of deep/core arteries and veins to increasing core temperature has not been adequately studied in vivo. Vessel area and strain were measured noninvasively in murine models to quantify the response of artery–vein pairs to increases in body temperature. Previously unidentified increases in the IVC area due to increasing core temperature are biologically important because they may affect conductive and convective heat transfer.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145570/1/phy213839.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145570/2/phy213839-sup-0004-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145570/3/phy213839_am.pd

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model

<div><p>Hepatocellular carcinoma (HCC) is the 2^nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.</p></div

Combining Chemistry and Engineering for Hepatocellular Carcinoma: Nano-Scale and Smaller Therapies

Primary liver cancer, or hepatocellular carcinoma (HCC), is a major worldwide cause of death from carcinoma. Most patients are not candidates for surgery and medical therapies, including new immunotherapies, have not shown major improvements since the modest benefit seen with the introduction of sorafenib over a decade ago. Locoregional therapies for intermediate stage disease are not curative but provide some benefit. However, upon close scrutiny, there is still residual disease in most cases. We review the current status for treatment of intermediate stage disease, summarize the literature on correlative histopathology, and discuss emerging methods at micro-, nano-, and pico-scales to improve therapy. These include transarterial hyperthermia methods and thermoembolization, along with microfluidics model systems and new applications of mass spectrometry imaging for label-free analysis of pharmacokinetics and pharmacodynamics

Linear regression results of tumor growth.

<p>Linear regression results of tumor growth.</p

Schematic of P1 and P2 particles.

<p>G5 PAMAM dendrimers are functionalized with N-acetylgalactosamine (NAcGal)_β-terminated PEG brushes attached to G5 via an acid-labile cis-aconitic (<i>c</i>) spacer to facilitate selective binding to the asialoglycoprotein receptor (ASGPR) overexpressed on hepatic cancer cells. Doxorubicin (DOX) molecules are also attached via two different enzyme-sensitive linkages to form either <b>P1</b> [(NAcGal_β-PEG<i>c</i>)_16.6-G5-(L3-DOX)_11.6] or <b>P2</b> [(NAcGal_β-PEG<i>c</i>)_16.6-G5-(L4-DOX)_13.4] particles.</p

Intratumoral delivery of P1 and P2 particles achieves antitumor activity comparable to free DOX.

<p>We measured the antitumor activity of P1 and P2 particles after intratumoral (i.t.) delivery to ectopic HepG2 tumors developed in nod scid gamma (NSG) mice, in order to mimic the clinical delivery of DOX through hepatic arterial infusion. <b>(A)</b> When tumors reached 50–100 mm³ in volume, animals were randomly divided into treatment groups of either saline, P1, P2, or free DOX, with each group receiving a DOX-equivalent dose of 1 mg/kg injected twice daily for 21 days. We monitored tumor volume every 3 days through day 30, and normalized tumor volumes to their starting volume at day 0. <b>(B)</b> Results show that saline-treated tumors reached a change in tumor volume of 1501 ± 115% by day 30, while P1, P2, and free DOX treatments inhibited tumor growth by 76.1%, 72.9%, and 58.6%, respectively, compared to the saline controls. Linear regression results show that while free DOX inhibits tumor growth by 2.5-fold over the entire treatment period, P1 and P2 particles inhibit growth 5.1- and 4.4-fold, respectively. Results are presented as a mean of five replicates ± standard error of the mean (SEM). Two-way ANOVA was used to determine statistical significance between the saline group compared to free DOX (*), P1 (#), or P2 () at each timepoint, and is denoted by *, #, or for p<0.05, **, ##, or $$ for p<0.01, and ***, ###, or $$ $ for p<0.001.</p

Measurement of cardiac function by MR imaging.

<p>We measured the cardiac function of mice undergoing treatment by saline, P1, P2, or free DOX. (<b>A</b>) Treatment and imaging regimen used. Healthy, NSG mice were randomly divided into four groups and assessed for their baseline cardiac function using magnetic resonance imaging (MRI). Starting at day 0, mice were given intraperitoneal (i.p.) injections of one of the four treatments every 48 hours for 21 days. We imaged the hearts weekly during treatment and also one week post-treatment. (<b>B</b>) Representative, long axis acquisitions at end-diastole and end-systole of mice treated by control, P1, P2, or free DOX at the final week of imaging possible. (<b>C</b>) For each 2D short-axis slice, a cardiac-gated and respiratory compensated 2D CINE acquisition with 12 frames was performed and the endocardial area of each frame defined using Analyze. The end-diastolic and end-systolic areas were found in each slice and are represented by the highlighted region of interest (ROI). LVEDV, LVESV, SV, and CO were then found using Eqs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181944#pone.0181944.e002" target="_blank">1</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181944#pone.0181944.e005" target="_blank">4</a>.</p