The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol ® and doxorubicin loaded into DC Bead ® are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.The global incidence of liver cancer is increasing and this type of cancer has a poor prognosis and is ranked as the third most common lethal cancer form [1,2]. The recommended treatment for hepatocellular carcinoma (HCC), a primary liver cancer, is dependent on the stage of the disease [3]. For unresectable, intermediate stage HCC, transarterial chemoembolization (TACE) is recommended. TACE involves the delivery of the cytostatic agent(s) in a drug-delivery system (DDS) to the tumor via the hepatic artery (HA) [3]. In contrast to normal liver tissue, which has a dual blood supply from the HA and the portal vein [4], HCC is typically mainly vascularized by the HA. Local drug administration by the TACE DDS is expected to increase the specificity of the tumor response while reducing the frequency of side effects and morbidity compared with systemic dosed treatments [4]. Embolization, caused by the DDS, obstructs the blood flow in the tumor, induces hypoxia, and results in increased drug concentrations and prolonged residence times in the tumortarget area [4]. Patients with untreated HCC that has not invaded the portal vein or spread extrahepatically have an expected median survival of approximately 16 months. With current palliative TACE strategies, the expected median survival is prolonged by approximately 4 months [3].To date, several DDSs delivering various chemotherapeutic drug(s) and pharmaceutical excipients have been developed and clinically evaluated for TACE therapy [5]. A review of these options of TACE DDSs is warranted in that it would form the basis for optimizing tumor-targeted therapy for HCC treatment, and subsequent development of novel, tumor-targeted DDSs and dosing strategies. Two common DDSs used for TACE therapy for intermediate stage HCC involve cytostatic agents emulsified in Lipiodol ® (LIP) or loaded into drugeluting beads. LIP is an iodized poppy seed oil derivative visible on x-ray, and after administration, the contrast is preferentially retained in tumor tissue [6,7]. The combination of the cytostatic agent emulsified in LIP can be administered with or without additional embolizing materials, generating complete or partial embolization of the targeted tumor-feeding vessel(s) [3,8]. DC Bead ® (DCB) is one of several commercially available drug-eluting embolizing bead systems [9]. Positively charged chemotherapeutic drugs can be ...

The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

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We have evaluated a miniaturized in vitro method, based on the μDISS Profiler™ technique that enables on-line monitoring of drug release from a 21 μl sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

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