Elsevier

Journal of Controlled Release

Volume 83, Issue 3, 30 October 2002, Pages 415-425
Journal of Controlled Release

Noninvasive monitoring of local drug release in a rabbit radiofrequency (RF) ablation model using X-ray computed tomography

https://doi.org/10.1016/S0168-3659(02)00216-XGet rights and content

Abstract

In this study, X-ray computed tomography (CT) was utilized as a noninvasive method to directly examine local drug release kinetics in livers before and following radiofrequency thermal ablation. Iohexol, a CT contrast agent, was used as a drug-mimicking molecule. Release of iohexol in healthy and ablated rabbit livers over 48 h was quantified and correlated with the release profiles from phosphate-buffered saline (PBS) in vitro. The results show that iohexol release in ablated livers is significantly slower than both release in normal livers and in vitro. The time at which 50% of the drug was released (t1/2) into ablated liver (20.6±5.9 h) was 1.7 times longer than in normal liver (12.1±5.4 h) and approximately two times longer than that in PBS (10.1±1.2 h). The slower release in ablated livers is a result of severe tissue damage inflicted by thermal ablation, as supported by histological examination. This data suggests that a noninvasive imaging method provides a superior measurement over in vitro release studies in accurately quantifying the local release kinetics of an agent in an altered physiological system in vivo. Because the development of a successful local drug therapy is dependent on the understanding of the agent release kinetics at the implantation site, the noninvasive data may be indispensable in effectively predicting the implant behavior in a physiological system.

Introduction

Rapid development of imaging techniques and interventional procedures has led to a multitude of exciting and unconventional opportunities for the minimally invasive treatment of solid tumors [1], [2], [3], [4]. Stemming from the high number of unresectable tumor cases, image-guided thermal ablation has emerged as the cutting-edge treatment of liver, pancreas and prostate cancers [5], [6], [7], [8], [9], [10]. In this procedure, the percutaneous insertion of a needle electrode to the site of a tumor is guided by an imaging method such as CT or MRI. Electric current at radiofrequency is applied through the needle directly to the tumor, leading to increased temperature and coagulative necrosis [8], [9], [10]. This method has been widely documented and early clinical trials have shown it to be a promising treatment for hepatocellular carcinoma among others [7], [11], [12], [13], [14]. Studies have shown that although RF ablation is able to destroy the majority of tumor tissue, tumor recurrence has been reported in many cases due to the incomplete elimination of all the cancer cells. Factors such as peripheral cooling of the tumor by blood flow limit the volume of ablation, which may in turn lead to local tumor recurrence at the distal ablation boundary and a need for adjuvant chemotherapeutic treatments [8], [15], [16], [17], [18], [19].

Our current research addresses this potential shortcoming with the development of a local chemotherapy for potential use in tumors that have been treated with RF ablation [20], [21]. Direct intratumoral delivery of a drug has the potential to increase the efficiency of delivery and improve drug efficacy while minimizing the undesirable toxic side-effects usually associated with systemic chemotherapy. Local drug therapy has been studied extensively and is well documented for tissues such as the brain [22], [23], [24], [25], [26]. However, in the case of thermally ablated tissue, the local tissue structure and function has been drastically altered by cellular necrosis, and the resulting effect on drug pharmacokinetics in vivo has yet to be determined.

Here we report on the application of the CT method in examining the release kinetics of an agent from a polymer millirod into viable or thermally ablated rabbit livers. Application of the CT method in drug concentration measurement in live animals was validated previously by our group with excellent results [27], [28]. We showed that concentration of a model agent inside millirods measured by CT agreed within 8% with that measured by UV–Vis following removal of the implants and extraction of remaining iohexol [27]. In this study, the polymer millirod consists of a biodegradable polymer matrix entrapping iohexol (Omnipaque®), a CT contrast agent. Iohexol was used as a model drug because of its excellent X-ray attenuation properties and low cost. The device was fabricated in the geometry of a cylindrical millirod to eventually allow minimally invasive implantation by a tissue biopsy needle under image-guidance. The present study provides valuable insight regarding the effect of RF ablation on the tissue structure and drug release kinetics. We tested the hypothesis that the tissue damage inflicted by the ablation procedure will have a significant effect on the drug release rate from the implant, and thus must be taken into account when designing the therapeutic system for its clinical application. X-ray computed tomography (CT) was utilized as a noninvasive method to directly examine local drug release kinetics in livers prior to and following radiofrequency thermal ablation.

Section snippets

Materials

Poly(d,l-lactide-co-glycolide) (PLGA, lactide: glycolide=1:1, 0.65 dl/g inherent viscosity) was purchased from Birmingham Polymers (Birmingham, AL). Iohexol (Omnipaque®, MW 821.14, 46.4% iodine) was purchased from Nycomed Amersham Imaging (Oslo, Norway) and poly(vinyl alcohol) (PVA, 13–23 kDa) was purchased from Aldrich (Milwaukee, WI). d(+)-Glucose was purchased from Fluka (Milwaukee, WI). Phosphate-buffered saline (PBS) and methylene chloride were obtained from Fisher Scientific (Pittsburgh,

In vivo characterization of local iohexol release in normal and ablated livers

Using our millirods with 10% iohexol and 30% glucose and optimal imaging parameters, we examined the release kinetics of iohexol from PLGA millirods in normal and ablated rabbit livers. CT was used to monitor the iohexol release in vivo over 48 h in the same animal (n=6 in normal livers, n=4 in ablated livers). Fig. 1A shows representative CT images of the iohexol millirods implanted in a normal and ablated lobe of the rabbit liver after 48 h. Qualitative examination shows that a higher amount

Discussion

The effect of tissue environment on drug release kinetics presents a unique challenge for the development of local drug delivery systems. Each tissue environment has a distinctive set of physiological parameters that affect the local release of a drug from the implant, and these effects must be evaluated before a successful local release system is produced. Here, we examined the influence of thermal ablation of the liver on the local drug release kinetics. Tissue damage caused by RF ablation is

Conclusions

Computed tomography was used to noninvasively monitor the release of a CT contrast agent (serving as a model drug) from a local drug delivery device into healthy and thermally ablated livers. It was found that iohexol release in ablated livers is significantly slower than that in normal livers, an observation correlating with the destruction of liver vasculature by thermal ablation. Importantly, the altered release profiles in ablated tissue cannot be accurately predicted by in vitro release

Acknowledgements

We would like to thank Les Ciancibello for his help with the CT image acquisition, Nancy Edgehouse for histological sample processing and Dr. James Anderson for his help in the histology analysis. Funding for this work was provided by the National Institutes of Health (R21 CA93993).

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