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Real-time Electrochemical Monitoring



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Contents lists available at ScienceDirect Journal of Controlled Release j o u r n a l h o m e p a g e w w w e l s ev i e r c o m l o c a t e j c o n r e l Real time electrochemical monitoring of drug release from therapeutic nanoparticles Laura Mora a c Karin Y Chumbimuni Torres a Corbin Clawson b Lucas Hernandez c Liangfang Zhang a Joseph Wang a a b c Department of Nanoengineering University of California San Diego La Jolla CA 92093 USA Department of Bioengineering University of California San Diego La Jolla CA 92093 USA Department of Analytical Chemistry Universidad Aut noma de Madrid 28049 Cantoblanco Madrid Spain a r t i c l e i n f o Article history Received 8 May 2009 Accepted 2 August 2009 Available online 11 August 2009 Keywords Nanomedicine Drug release Real time monitoring Voltammetry Liposome Nanoparticles Doxorubicin a b s t r a c t An electrochemical protocol for real time monitoring of drug release kinetics from therapeutic nanoparticles NPs is described The method is illustrated for repetitive square wave voltammetric measurements of the reduction of doxorubicin released from liposomes at a glassy carbon electrode Such operation couples high sensitivity down to 20 nM doxorubicin with high speed and stability It can thus monitor in real time the drug release from NP carriers including continuous measurements in diluted serum Such direct and continuous monitoring of the drug release kinetics from therapeutic NPs holds great promise for designing new drug delivery NPs with optimal drug release properties These NPs can potentially be used to deliver many novel compounds such as marine life derived drugs and hydrophobic drugs with limited water solubility that are usually dif cult to be characterized by traditional analytical tools 2009 Elsevier B V All rights reserved 1 Introduction Nanoparticle NP based drug delivery has attracted tremendous attention from both academic and industrial investigators in the past two decades because of its many favorable characteristics 1 2 It improves the solubility of poorly water soluble drugs prolongs in vivo drug circulation half life reduces the frequency of administration by releasing drugs in a sustained manner and minimizes adverse systemic effects by delivering drugs preferentially to the target tissues As a result numerous NP platforms have been developed or proposed for drug delivery applications including for example liposomes solid lipid NPs polymeric NPs dendrimers silica NPs and nanoemulsions 3 4 For all of these therapeutic NPs their drug release kinetics is a key factor that determines their therapeutic index and potential for clinical use 2 5 Drug release kinetics represents how fast the drug molecules are released from the therapeutic NPs Such a release pro le is commonly plotted as the weight ratio of the cumulative released drugs to the total drug payload over time 6 Direct real time measurements are highly desirable for obtaining reliable assessment of the drug release kinetics While several analytical techniques have been employed to quantify the amount of drugs released from therapeutic NPs 7 10 none of these offers a direct continuous monitoring capability High performance liquid chromatography HPLC holds the most popular Corresponding authors E mail addresses zhang ucsd edu L Zhang josephwang ucsd edu J Wang 0168 3659 see front matter 2009 Elsevier B V All rights reserved doi 10 1016 j jconrel 2009 08 002 ity in quantifying drugs by directly reading their characteristic UV absorbance upon elution from a proper HPLC column 11 HPLC thus lacks the real time monitoring capability and suffers from high procurement and operational costs lengthy training required excessive downtimes and lack of a universal sensitive detector 12 A uorometer or scintillation counter can also quantify drugs by reading the uorescence emission or the ionizing radiation of drug molecules respectively if they are pre labeled with a uorescent or radioisotope tag However tagging drug molecules may alter their diffusion rate and release kinetics To measure drug release kinetics therapeutic NPs are commonly loaded into a dialysis device with a molecular weight cut off larger than the size of the drug molecules 6 13 Then the NPs are dialyzed against PBS buffer continuously The released drugs diffuse out of the dialysis device driven by osmotic pressure between the two sides of the dialysis membrane At selected time intervals a small volume of the dialysis solution is collected to quantify the drugs released from the NPs using one of the techniques mentioned above Alternatively one can also collect an aliquot of the NP suspension inside the dialysis device and subsequently break down the NPs to quantify the drugs remaining in the NPs 13 While these techniques are capable of quantifying drug loading yield and release pro le they usually involve complex procedures and require labor intensive sample preparation In addition before measurements the drugs have to be separated from the NPs by using a dialysis membrane or a centrifugal machine These can negatively affect the accuracy of the measurements because drugs can absorb to the dialysis membranes or the high centrifugal force may induce additional drug release from the NANOMEDICINE Journal of Controlled Release 140 2009 69 73 NANOMEDICINE 70 L Mora et al Journal of Controlled Release 140 2009 69 73 NPs 14 More importantly none of these techniques can monitor directly the real time drug release as desired for obtaining the most accurate drug release kinetics pro le The sample preparation time for the various techniques also prohibits repetitive measurements at short time intervals Therefore it is highly desirable to develop new methods that monitor directly and continuously the drug release kinetics from therapeutic NPs while concurrently simplifying the process and minimizing the errors and costs incurred in the collection and handling of individual sample aliquots In this study we describe an effective electrochemical protocol for direct real time monitoring of drug release kinetics from therapeutic NPs Electrochemical devices offer a fast return of the chemical information and have been widely used for continuous industrial and environmental monitoring applications 15 For example electrochemical sensors such as pH and oxygen electrodes have been used routinely for several decades for real time measurements Continuous electrochemical in vivo monitoring of drug concentration has also been


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