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Purpose: A proposed mechanism for the enhanced effectiveness of hyperthermia and doxorubicin (Dox) combinations is increased intracellular Dox concentrations resulting from heat-induced cell stress. The purpose of this study was to determine whether specific varied Dox and heat combinations produce measurable effects greater than the additive combination, and whether these effects can be attributed to heat-induced increases in intracellular Dox concentrations. Methods: HCT116, HT29 and CT26 cells were exposed to Dox and water bath heating independently. A clonogenic survival assay was used to determine cell killing and intracellular Dox concentrations were measured in HCT116 cells with mass spectrometry. Cells were exposed to heating at 42 °C (60 min) and 0.5 µg/ml of Dox at varying intervals. Synergy was determined by curve-fitting and isobologram analysis. Results: All cell lines displayed synergistic effects of combined heating and Dox. A maximum synergistic effect was achieved with simultaneous cell exposure to Dox and heat. For exposures at 42 °C, the synergistic effect was most pronounced at Dox concentrations <0.5 µg/ml. Increased intracellular concentrations of Dox in HCT116 cells caused by heat-stress did not generate a concomitant thermal enhancement. Conclusions: Simultaneous exposure of HCT116 cells to heating and Dox is more effective than sequential exposure. Heat-induced cell responses are accompanied by increased intracellular Dox concentrations; however, clonogenic survival data do not support this as the cause for synergistic cytotoxicity.

Aim: To evaluate the pharmacokinetic profile (PK) and embolization effect of 70-150-μm doxorubicin eluting beads (DEBs) following intra-arterial injection (i.a.) in the rabbit liver VX2 tumour model., Materials and Methods: In this ACUC-approved study, 25 white New Zealand rabbits were randomly assigned into a small DEB group (SDB, n = 7, 70-150-μm DEBs), large DEB group (LDB, n = 7, 100-300-μm DEBs), untreated controls (n = 7), and doxorubicin controls (n = 4, without tumour, received i.a. 12.5 mg doxorubicin). Plasma PK was assessed up to 180 min post-injection. Drug tissue and liver enzyme levels, radiologic tumor response and histopathologic tumour necrosis were assessed at 7 days., Results: Mean tumour doxorubicin concentrations were 922.83 nM (SD = 722.05) and 361.48 nM (SD = 473.23) for the SDB and LDB, respectively (p = 0.005). There was no statistically significant difference in tumour doxorubicinol, plasma doxorubicin and doxorubicinol PK values. More beads were observed in the SDB tumours (p = 0.01). Liver enzymes increased and gradually declined over the observation period, with significantly higher values in the SDB., Conclusion: In this preclinical study, plasma PK of i.a.-injected 70-150-μm DEBs was not different than that of 100-300-μm DEBs. More beads and higher tissue doxorubicin levels were observed in the SDB tumours., Key Points: • Small and large doxorubicin-eluting beads show similar plasma pharmacokinetic profiles. • Higher tissue doxorubicin levels were observed in the small bead group. • Liver enzymes were overall significantly higher in the small bead group.

Purpose: To investigate whether C-arm dual-phase cone-beam computed tomography (CT) performed during transcatheter arterial chemoembolization (TACE) with doxorubicin-eluting beads can help predict tumor response at 1-month follow-up in patients with hepatocellular carcinoma (HCC)., Materials and Methods: This prospective study was compliant with HIPAA and approved by the institutional review board and animal care and use committee. Analysis was performed retrospectively on 50 targeted HCC lesions in 29 patients (16 men, 13 women; mean age, 61.9 years ± 10.7) treated with TACE with drug-eluting beads. Magnetic resonance (MR) imaging was performed at baseline and 1 month after TACE. Dual-phase cone-beam CT was performed before and after TACE. Tumor enhancement at dual-phase cone-beam CT in early arterial and delayed venous phases was assessed retrospectively with blinding to MR findings. Tumor response at MR imaging was assessed according to European Association for the Study of the Liver (EASL) guidelines. Two patients were excluded from analysis because dual-phase cone-beam CT scans were not interpretable. Logistic regression models for correlated data were used to compare changes in tumor enhancement between modalities. The radiation dose with dual-phase cone-beam CT was measured in one pig., Results: At 1-month MR imaging follow-up, complete and/or partial tumor response was seen in 74% and 76% of lesions in the arterial and venous phases, respectively. Paired t tests used to compare images obtained before and after TACE showed a significant reduction in tumor enhancement with both modalities (P < .0001). The decrease in tumor enhancement seen with dual-phase cone-beam CT after TACE showed a linear correlation with MR findings. Estimated correlation coefficients were excellent for first (R = 0.89) and second (R = 0.82) phases. A significant relationship between tumor enhancement at cone-beam CT after TACE and complete and/or partial tumor response at MR imaging was found for arterial (odds ratio, 0.95; 95% confidence interval [CI]: 0.91, 0.99; P = .023) and venous (odds ratio, 0.96; 95% CI: 0.93, 0.99; P = .035) phases with the multivariate logistic regression model. Radiation dose for two dual-phase cone-beam CT scans was 3.08 mSv., Conclusion: Intraprocedural C-arm dual-phase cone-beam CT can be used immediately after TACE with doxorubicin-eluting beads to predict HCC tumor response at 1-month MR imaging follow-up.

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Purpose: To assess whether porosity and compressibility of calibrated spherical polyvinyl alcohol (PVA) microspheres affect doxorubicin plasma and tumor concentrations after transcatheter arterial chemoembolization (TACE) in a VX2 rabbit model., Materials and Methods: Fifteen rabbits were divided into three groups of five rabbits each. Three different types of calibrated spherical PVA microspheres with variable levels of porosity and compressibility were blindly evaluated. TACE was performed by injecting a mixture of doxorubicin (5 mg) and iodized oil (0.5 mL) followed by injection of the embolic material (0.3-0.5 mL). Plasma concentrations of doxorubicin and doxorubicinol were analyzed 20, 40, 60, and 120 minutes and 2 days after TACE, and liver tissue and tumor doxorubicin concentrations were measured 2 days after TACE., Results: All calibrated spherical PVA microspheres showed similar patterns of plasma doxorubicin and doxorubicinol release and tumor concentration of doxorubicin. There were no significant differences of drug levels in either plasma or tumor in each group (P > .05)., Conclusions: After TACE in a rabbit model of liver cancer, testing of three different types of spherical PVA microspheres with varying degrees of porosity and compressibility showed no significant differences in the plasma doxorubicin release pattern and tumor doxorubicin uptake.

Background: In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2)., Purpose: The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB., Results: Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 micromol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal., Conclusions: Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.

Chemoembolization with drug-eluting particles has been recently introduced in the field of interventional oncology. In this review, we will describe the pharmacokinetic properties and efficacy of all commercially available or under investigation drug-eluting particles and discuss the potentials and future of this new form of transcatheter arterial therapy for liver cancer. [Copyright &y& Elsevier]