- Email: [email protected]
Targeting of coenzyme Q10 via d -alpha-tocopheryl polyethylene glycol 1000 succinate-based nanoemulsion to the heart
Materials Letters 109 (2013) 20–22
Contents lists available at SciVerse ScienceDirect
Materials Letters journal homepage: www.elsevier.com/locate/matlet
Targeting of coenzyme Q10 via D-alpha-tocopheryl polyethylene glycol 1000 succinate-based nanoemulsion to the heart Huafeng Zhou a,b, Jing Zhang b, Qingxian Jin c, Guoqing Liu a, Yingfang Long b, Mingxing Duan b, Qiang Xia a,n a
State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China State-key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China c Henan Provincial Key Laboratory of Surface and Interface Science, Zhengzhou University of Light Industry, Zhengzhou 450002, China b
art ic l e i nf o
a b s t r a c t
Article history: Received 27 December 2012 Accepted 14 July 2013 Available online 19 July 2013
D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of natural vitamin E, has been intensively used in drug delivery systems. TPGS (CoQ10-NE-TPGS) and lecithin-based (CoQ10-NE-LC) coenzyme Q10-loaded nanoemulsions were prepared by hot high-pressure homogenization (HPH) and tested for their ability to target heart tissue. Both formulations yielded particles 50 nm in diameter. CoQ10 in both the formulations was in a supercooled melt state without crystallization. CoQ10-NE-TPGS more effectively delivered CoQ10 to heart tissue than CoQ10-NE-LC after intravenous administration. CoQ10 concentration in the heart was 2.8-fold higher at 5 min after intravenous administration of CoQ10-NE-TPGS compared to CoQ10-NE-LC. Higher tissue levels were maintained for 90 min after injection. These data suggest that CoQ10-NE-TPGS could be a potential vehicle for rapid delivery of CoQ10 to heart tissue. & 2013 Published by Elsevier B.V.
Keywords: Biomaterials Nanocomposites Polymers Drug delivery Thermal analysis
1. Introduction Coenzyme Q10 (CoQ10), an endogenous antioxidant, has been proposed as a potential preventive or curative treatment for cardiovascular diseases, including cardiomyopathy, coronary artery disease, myocardial infarction, myocardial ischemia, and heart failure [1–3]. However, the time necessary to achieve a sufficient concentration of CoQ10 in the heart following oral administration may preclude its effectiveness for acute cardiac events. Unfortunately, there has been little work demonstrating the rapid distribution of CoQ10 to the heart when administered intravenously [4,5]. D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is a safe pharmaceutical adjuvant that has been widely applied in developing various drug delivery systems (DDS), such as micelles, liposomes, nanoparticles, and prodrug carriers [6–8]. Studies have shown that TPGS-based DDSs elicit sustained and controlled delivery of anticancer drugs to target tumor tissue with high therapeutic efficacy when administered intravenously [9,10]. However, few studies have focused on targeting TPGS-based DDSs to non-cancerous tissue. Thus, the aims of this study were to
n
Corresponding author. Tel./fax: +86 512 62867117. E-mail address: [email protected] (Q. Xia).
0167-577X/$ - see front matter & 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.matlet.2013.07.057
develop a TPGS-based CoQ10 nanoemulsion (CoQ10-NE) and to investigate its ability to target the heart in vivo.
2. Experimental Preparation and characterization of CoQ10-NE: 3 g CoQ10 and 3 g LC (Cargill, USA) or TPGS (Eastman Chemical, USA) were dissolved in 3 g of caprylic/capric triglyceride (CCTG) at 60 1C. The CoQ10 lipid phase was added to 100 ml glycerol aqueous solution (45%; w/w) at 60 1C and emulsified by stirring at 1500 rpm for 1 min. The resulting pre-emulsion was homogenized by hot (60 1C) highpressure homogenization (HPH, NS1001L, Niro Soavi, Italy) for 6 cycles at 1200 bar. The final dispersion was cooled at ambient conditions to room temperature to obtain CoQ10-NE-LC or CoQ10NE-TPGS. CoQ10-NE-LC and CoQ10-NE-TPGS were stored in sealed brown bottles at 5 1C. The mean particle size and zeta potential of the CoQ10-NEs were analyzed using Malvern Zetasizer 2000 (Malvern, UK) at 25 1C. DSC was performed using a DSC Q2000 apparatus (TA, USA) at a heating rate of 5 1C/min from 0 1C to 80 1C. Pharmacokinetics and tissue distribution: Animal studies were performed in the laboratory animal facility of Life Science School of Tsinghua University, which has obtained Animal Welfare Assurance from Office of Laboratory Animal Welfare (OLAW). All animal studies performed were approved by the local ethics committee.
H. Zhou et al. / Materials Letters 109 (2013) 20–22
Two groups (n ¼6 each) of male Sprague–Dawley rats (weighing 250 7 10 g) were anesthetized with chloral hydrate, and their jugular veins were cannulated for blood sampling. CoQ10-NE-LC or CoQ10-NE-TPGS (0.4 mg/kg) was administered by tail vein injection, and 0.5-ml blood samples were collected at discrete time points. Each sample was centrifuged at 3000 rpm for 10 min; plasma samples were stored at 20 1C until further analysis. Separately, 2 groups (n ¼12 each) of rats were used to study the tissue distribution of CoQ10-NE-LC or CoQ10-NE-TPGS. The rats were killed 5 or 90 min (n ¼6 per nanoemulsion for each time point) after intravenous administration of CoQ10-NE-LC or CoQ10NE-TPGS (0.4 mg/kg); hearts, livers, and kidneys were immediately excised, weighed, and sheared into pieces. Each tissue sample was homogenized and centrifuged at 6000 rpm for 10 min; the upper solution sample of each tissue was stored at 20 1C until further analysis. Extraction and concentration analyses: A mixture of 0.1 ml of plasma or tissue sample and 0.1 ml of internal standard solution (1 μg/ml idebenone methanol solution) was placed in an Eppendorf microtube. Methanol (0.8 ml) was added to precipitate the proteins, and the microtube was vortexed for 1 min, and centrifuged for 10 min at 12,000 rpm. The concentration of CoQ10 in the supernatant was analyzed using a liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization (ESI) system from Agilent [11]. The separation of CoQ10 was performed on an Agilent Zorbax SB-C18 rapid resolution HD (50 mm 2.1 mm, 1.8-μm particle size) with the mobile phase containing methanol, 2-propanol, and formic acid (90:10:0.2, v/v/v) at a flow rate of 0.5 ml/min over 15 min.
21
Fig. 1. Differential scanning calorimetry curves of bulk material CoQ10, mixture of CoQ10 and CCGT (1:1), and CoQ10-NE dispersions at a heating rate of 5 1C/min after 24 h storage at 8 1C.
3. Results and discussion Physicochemical properties of CoQ10-NE are shown in Table 1. The average diameters of CoQ10-NE-TPGS and CoQ10-NE-LC particles were similar. However, CoQ10-NE-TPGS possessed a narrower size distribution than CoQ10-NE-LC. The zeta potential results indicated that both were negatively charged. TPGS is a nonionic surfactant with a hydrophile–lipophile balance (HLB) value of 13.2, whereas LC is an ionic surfactant with a HLB value of 7–10. The water phase with TPGS exerts lower surface tension, resulting in better emulsifying capacity. Four hours after 10-fold dilution with phosphate-buffered saline (PBS) or serum, the particle sizes of CoQ10-NE-LC and CoQ10-NE-TPGS in PBS were 7074 nm and 477 2 nm, respectively, and the corresponding values for particle sizes in serum were 76 74 nm and 477 3 nm. Because CoQ10-NE was prepared using hot HPH, crystallization of CoQ10 is important for drug-loading efficiency and for formulation stability at lower temperatures. To better understand the crystallization status of CoQ10, the thermal behavior of CoQ10 in different formulations was measured using DSC (Fig. 1). The DSC analysis of bulk material CoQ10 revealed a melting point at 48.4 1C and an onset at about 42.5 1C. In a mixture with CCGT at a weight ratio of 1:1, the melting point of CoQ10 declined to 41.1 1C, with an onset at approximately 27.6 1C. However, when incorporated into nanoemulsions, the melting peaks of CoQ10 were absent from the DSC curves with no heating enthalpy, indicating a high likelihood Table 1 Particle size, polydispersity index (PI), and zeta potential of CoQ10-NE by photon correlation spectroscopy on the day of production.
CoQ10-NE-TPGS CoQ10-NE-LC
Particle size (nm)
PI
Zeta potential (mV)
467 3 547 5
0.1917 0.013 0.550 7 0.051
(19.2 70.5) (41.5 70.4)
Fig. 2. Mean plasma concentration-time profiles of CoQ10 after intravenous administration of CoQ10-NE-TPGS or CoQ10-NE-LC (0.4 mg/kg) in Sprague–Dawley rats (n¼6, mean7 SD).
of supercooled melts. Standard DSC measurements are regularly performed in order to ensure and quantify the crystalline status; if no melting peak is detectable upon heating, the formation of a supercooled melt is highly likely [12]. The concentrations of CoQ10 in the plasma declined biexponentially and were higher for CoQ10-NE-TPGS than CoQ10-NE-LC at all time points, especially at the early time points (Fig. 2). Pharmacokinetic parameters were calculated using a 3-compartment model, which demonstrated a very fast distribution phase followed by 2 elimination phases—slow and very slow. Compared to CoQ10-NELC, CoQ10-NE-TPGS had a 2.3-fold greater area under the curve (AUC). The apparent volume of distribution (Vss) and clearance (CL) of CoQ10-NE-TPGS were 24.5% and 24.5% lower than the corresponding values for CoQ10-NE-LC. CoQ10 had a rapid and wide distribution in tissues. The rank order of CoQ10 concentration after intravenous administration of CoQ10NE-TPGS or CoQ10-NE-LC was heart4kidney4liver (Fig. 3). The targeting capacity of CoQ10-NE-TPGS for the heart was greater than that for CoQ10-NE-LC; at 5 min after intravenous administration, the heart tissue concentration of CoQ10 from CoQ10-NE-TPGS was 2.8-
22
H. Zhou et al. / Materials Letters 109 (2013) 20–22
Fig. 3. Mean concentration of CoQ10 in heart, liver, and kidney tissue at 5 min (A) or 90 min (B) after the intravenous administration of CoQ10-NE-TPGS or CoQ10-NE-LC (0.4 mg/kg) in rats (n ¼6, mean 7 SD), *p o 0.05 vs. CoQ10-NE-LC.
fold higher than that of CoQ10 from CoQ10-NE-LC. Distribution of CoQ10 to the liver or kidney was similar between the 2 nanoemulsions. At 90 min after intravenous administration, the concentration of CoQ10 in the heart tissue decreased by 43% for CoQ10-NE-TPGS; the level of CoQ10 from CoQ10-NE-TPGS in the heart was still 1.9-fold higher than that of CoQ10 from CoQ10-NE-LC (3.271.2 μg/g). Tissue concentrations of CoQ10 from both dispersions were slightly increased in the liver, but decreased in the kidney. LC-based liposomes and microemulsions have been used to target CoQ10 to heart tissue [4,5]. In our study, CoQ10-NE-TPGS had a higher systemic exposure and more effectively targeted CoQ10 to the heart than CoQ10-NE-LC. Coating nanoparticles with polyethylene glycol 1000 reduces their uptake and clearance by the reticuloendothelial system, prolongs their residence time in the circulation, and results in higher plasma levels [13]. Additionally, myocardial tissue is rich in developed vasculature physiologically, the spontaneous accumulation in heart tissue via penetrating through vasculature effect is higher the other tissue [14]. Furthermore, the fact that TPGS inhibits P-glycoprotein may partially explain its ability to deliver higher concentrations of therapeutics [15]. To date, the slow accumulation of CoQ10 in heart tissue after oral administration has hampered its clinical application for treating acute heart disease. Our data suggest that CoQ10NE-TPGS administered intravenously may meet the clinical need to rapidly raise heart levels of CoQ10 to effectively treat acute cardiac events. 4. Conclusions CoQ10-containing nanoemulsions were prepared by hot HPH to yield particles with an approximate diameter of 50 nm. CoQ10-NETPGS more effectively delivered CoQ10 to heart tissue than CoQ10NE-LC after intravenous administration; higher tissue levels were
maintained for 90 min after injection. These data suggest that CoQ10-NE-TPGS might be a potential vehicle to deliver CoQ10 with great clinical benefit to treat acute heart disease.
Acknowledgment This research was funded by the International Scientific Cooperation Project from Ministry of Science and Technology of China (2008DFB50060) and Suzhou International Science and Technology Cooperation Program (SH201204). References [1] Pepe S, Marasco SF, HaAs SJ, Sheran FL, Krum H, Rosenfeldt FL. Mitochondrion 2007;7:S154–67. [2] Singh U, Devaraj S, Jialal I. Nutrition Reviews 2007;65:286–93. [3] Singh RB, Wander GS, Rastogi A, Shukla PK, Mittal A, Sharma JP, et al. Cardiovascular Drugs and Therapy 1998;12:347–53. [4] Verma DD, Hartner WC, Thakkar V, Levchenko TS, Torchilin VP. Pharmaceutical Research 2007;24:2131–7. [5] Takada M, Yuzuriha T, Katayama K, Yamato C, Koyama N. Journal of Nutritional Science and Vitaminology 1985;31:115–20. [6] Zhang Z, Tan S, Feng SS. Biomaterials 2012;33:4889–906. [7] Zhang Z, Mei L, Feng SS. Nanomedicine 2012;7:1645–7. [8] Feng SS, Zhao LY, Zhang ZP, Bhakta G, Win KY, Dong YC, et al. Chemical Engineering Science 2007;62:664–8. [9] Ma Y, Huang L, Song C. Polymer 2010;51:5952–9. [10] Huang L, Chen H, Zheng Y, Song X, Liu R, Liu K, et al. Integrative Biology 2011;3:993–1002. [11] Ruiz-Jiménez J, Priego-Capote F, Quesada JM. Journal of Chromatography A 2007;1175:242–8. [12] Kuntsche J, Koch MHJ, Fahr A, Bunjes H. European Journal of Pharmaceutical Sciences 2009;38:238–48. [13] Takahama H, Minamino T, Asanuma H, Fujita M, Asai T, Wakeno M, et al. Journal of the American College of Cardiology 2009;53:709–17. [14] Lukyanov AN, Hartner WC, Torchilin VP. Journal of Controlled Release 2004;94:187–93. [15] Parhi P, Mohanty C, Sahoo SK. Acta Biomaterialia 2011;7:3656–69.
Contents lists available at SciVerse ScienceDirect
Materials Letters journal homepage: www.elsevier.com/locate/matlet
Targeting of coenzyme Q10 via D-alpha-tocopheryl polyethylene glycol 1000 succinate-based nanoemulsion to the heart Huafeng Zhou a,b, Jing Zhang b, Qingxian Jin c, Guoqing Liu a, Yingfang Long b, Mingxing Duan b, Qiang Xia a,n a
State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China State-key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China c Henan Provincial Key Laboratory of Surface and Interface Science, Zhengzhou University of Light Industry, Zhengzhou 450002, China b
art ic l e i nf o
a b s t r a c t
Article history: Received 27 December 2012 Accepted 14 July 2013 Available online 19 July 2013
D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of natural vitamin E, has been intensively used in drug delivery systems. TPGS (CoQ10-NE-TPGS) and lecithin-based (CoQ10-NE-LC) coenzyme Q10-loaded nanoemulsions were prepared by hot high-pressure homogenization (HPH) and tested for their ability to target heart tissue. Both formulations yielded particles 50 nm in diameter. CoQ10 in both the formulations was in a supercooled melt state without crystallization. CoQ10-NE-TPGS more effectively delivered CoQ10 to heart tissue than CoQ10-NE-LC after intravenous administration. CoQ10 concentration in the heart was 2.8-fold higher at 5 min after intravenous administration of CoQ10-NE-TPGS compared to CoQ10-NE-LC. Higher tissue levels were maintained for 90 min after injection. These data suggest that CoQ10-NE-TPGS could be a potential vehicle for rapid delivery of CoQ10 to heart tissue. & 2013 Published by Elsevier B.V.
Keywords: Biomaterials Nanocomposites Polymers Drug delivery Thermal analysis
1. Introduction Coenzyme Q10 (CoQ10), an endogenous antioxidant, has been proposed as a potential preventive or curative treatment for cardiovascular diseases, including cardiomyopathy, coronary artery disease, myocardial infarction, myocardial ischemia, and heart failure [1–3]. However, the time necessary to achieve a sufficient concentration of CoQ10 in the heart following oral administration may preclude its effectiveness for acute cardiac events. Unfortunately, there has been little work demonstrating the rapid distribution of CoQ10 to the heart when administered intravenously [4,5]. D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is a safe pharmaceutical adjuvant that has been widely applied in developing various drug delivery systems (DDS), such as micelles, liposomes, nanoparticles, and prodrug carriers [6–8]. Studies have shown that TPGS-based DDSs elicit sustained and controlled delivery of anticancer drugs to target tumor tissue with high therapeutic efficacy when administered intravenously [9,10]. However, few studies have focused on targeting TPGS-based DDSs to non-cancerous tissue. Thus, the aims of this study were to
n
Corresponding author. Tel./fax: +86 512 62867117. E-mail address: [email protected] (Q. Xia).
0167-577X/$ - see front matter & 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.matlet.2013.07.057
develop a TPGS-based CoQ10 nanoemulsion (CoQ10-NE) and to investigate its ability to target the heart in vivo.
2. Experimental Preparation and characterization of CoQ10-NE: 3 g CoQ10 and 3 g LC (Cargill, USA) or TPGS (Eastman Chemical, USA) were dissolved in 3 g of caprylic/capric triglyceride (CCTG) at 60 1C. The CoQ10 lipid phase was added to 100 ml glycerol aqueous solution (45%; w/w) at 60 1C and emulsified by stirring at 1500 rpm for 1 min. The resulting pre-emulsion was homogenized by hot (60 1C) highpressure homogenization (HPH, NS1001L, Niro Soavi, Italy) for 6 cycles at 1200 bar. The final dispersion was cooled at ambient conditions to room temperature to obtain CoQ10-NE-LC or CoQ10NE-TPGS. CoQ10-NE-LC and CoQ10-NE-TPGS were stored in sealed brown bottles at 5 1C. The mean particle size and zeta potential of the CoQ10-NEs were analyzed using Malvern Zetasizer 2000 (Malvern, UK) at 25 1C. DSC was performed using a DSC Q2000 apparatus (TA, USA) at a heating rate of 5 1C/min from 0 1C to 80 1C. Pharmacokinetics and tissue distribution: Animal studies were performed in the laboratory animal facility of Life Science School of Tsinghua University, which has obtained Animal Welfare Assurance from Office of Laboratory Animal Welfare (OLAW). All animal studies performed were approved by the local ethics committee.
H. Zhou et al. / Materials Letters 109 (2013) 20–22
Two groups (n ¼6 each) of male Sprague–Dawley rats (weighing 250 7 10 g) were anesthetized with chloral hydrate, and their jugular veins were cannulated for blood sampling. CoQ10-NE-LC or CoQ10-NE-TPGS (0.4 mg/kg) was administered by tail vein injection, and 0.5-ml blood samples were collected at discrete time points. Each sample was centrifuged at 3000 rpm for 10 min; plasma samples were stored at 20 1C until further analysis. Separately, 2 groups (n ¼12 each) of rats were used to study the tissue distribution of CoQ10-NE-LC or CoQ10-NE-TPGS. The rats were killed 5 or 90 min (n ¼6 per nanoemulsion for each time point) after intravenous administration of CoQ10-NE-LC or CoQ10NE-TPGS (0.4 mg/kg); hearts, livers, and kidneys were immediately excised, weighed, and sheared into pieces. Each tissue sample was homogenized and centrifuged at 6000 rpm for 10 min; the upper solution sample of each tissue was stored at 20 1C until further analysis. Extraction and concentration analyses: A mixture of 0.1 ml of plasma or tissue sample and 0.1 ml of internal standard solution (1 μg/ml idebenone methanol solution) was placed in an Eppendorf microtube. Methanol (0.8 ml) was added to precipitate the proteins, and the microtube was vortexed for 1 min, and centrifuged for 10 min at 12,000 rpm. The concentration of CoQ10 in the supernatant was analyzed using a liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization (ESI) system from Agilent [11]. The separation of CoQ10 was performed on an Agilent Zorbax SB-C18 rapid resolution HD (50 mm 2.1 mm, 1.8-μm particle size) with the mobile phase containing methanol, 2-propanol, and formic acid (90:10:0.2, v/v/v) at a flow rate of 0.5 ml/min over 15 min.
21
Fig. 1. Differential scanning calorimetry curves of bulk material CoQ10, mixture of CoQ10 and CCGT (1:1), and CoQ10-NE dispersions at a heating rate of 5 1C/min after 24 h storage at 8 1C.
3. Results and discussion Physicochemical properties of CoQ10-NE are shown in Table 1. The average diameters of CoQ10-NE-TPGS and CoQ10-NE-LC particles were similar. However, CoQ10-NE-TPGS possessed a narrower size distribution than CoQ10-NE-LC. The zeta potential results indicated that both were negatively charged. TPGS is a nonionic surfactant with a hydrophile–lipophile balance (HLB) value of 13.2, whereas LC is an ionic surfactant with a HLB value of 7–10. The water phase with TPGS exerts lower surface tension, resulting in better emulsifying capacity. Four hours after 10-fold dilution with phosphate-buffered saline (PBS) or serum, the particle sizes of CoQ10-NE-LC and CoQ10-NE-TPGS in PBS were 7074 nm and 477 2 nm, respectively, and the corresponding values for particle sizes in serum were 76 74 nm and 477 3 nm. Because CoQ10-NE was prepared using hot HPH, crystallization of CoQ10 is important for drug-loading efficiency and for formulation stability at lower temperatures. To better understand the crystallization status of CoQ10, the thermal behavior of CoQ10 in different formulations was measured using DSC (Fig. 1). The DSC analysis of bulk material CoQ10 revealed a melting point at 48.4 1C and an onset at about 42.5 1C. In a mixture with CCGT at a weight ratio of 1:1, the melting point of CoQ10 declined to 41.1 1C, with an onset at approximately 27.6 1C. However, when incorporated into nanoemulsions, the melting peaks of CoQ10 were absent from the DSC curves with no heating enthalpy, indicating a high likelihood Table 1 Particle size, polydispersity index (PI), and zeta potential of CoQ10-NE by photon correlation spectroscopy on the day of production.
CoQ10-NE-TPGS CoQ10-NE-LC
Particle size (nm)
PI
Zeta potential (mV)
467 3 547 5
0.1917 0.013 0.550 7 0.051
(19.2 70.5) (41.5 70.4)
Fig. 2. Mean plasma concentration-time profiles of CoQ10 after intravenous administration of CoQ10-NE-TPGS or CoQ10-NE-LC (0.4 mg/kg) in Sprague–Dawley rats (n¼6, mean7 SD).
of supercooled melts. Standard DSC measurements are regularly performed in order to ensure and quantify the crystalline status; if no melting peak is detectable upon heating, the formation of a supercooled melt is highly likely [12]. The concentrations of CoQ10 in the plasma declined biexponentially and were higher for CoQ10-NE-TPGS than CoQ10-NE-LC at all time points, especially at the early time points (Fig. 2). Pharmacokinetic parameters were calculated using a 3-compartment model, which demonstrated a very fast distribution phase followed by 2 elimination phases—slow and very slow. Compared to CoQ10-NELC, CoQ10-NE-TPGS had a 2.3-fold greater area under the curve (AUC). The apparent volume of distribution (Vss) and clearance (CL) of CoQ10-NE-TPGS were 24.5% and 24.5% lower than the corresponding values for CoQ10-NE-LC. CoQ10 had a rapid and wide distribution in tissues. The rank order of CoQ10 concentration after intravenous administration of CoQ10NE-TPGS or CoQ10-NE-LC was heart4kidney4liver (Fig. 3). The targeting capacity of CoQ10-NE-TPGS for the heart was greater than that for CoQ10-NE-LC; at 5 min after intravenous administration, the heart tissue concentration of CoQ10 from CoQ10-NE-TPGS was 2.8-
22
H. Zhou et al. / Materials Letters 109 (2013) 20–22
Fig. 3. Mean concentration of CoQ10 in heart, liver, and kidney tissue at 5 min (A) or 90 min (B) after the intravenous administration of CoQ10-NE-TPGS or CoQ10-NE-LC (0.4 mg/kg) in rats (n ¼6, mean 7 SD), *p o 0.05 vs. CoQ10-NE-LC.
fold higher than that of CoQ10 from CoQ10-NE-LC. Distribution of CoQ10 to the liver or kidney was similar between the 2 nanoemulsions. At 90 min after intravenous administration, the concentration of CoQ10 in the heart tissue decreased by 43% for CoQ10-NE-TPGS; the level of CoQ10 from CoQ10-NE-TPGS in the heart was still 1.9-fold higher than that of CoQ10 from CoQ10-NE-LC (3.271.2 μg/g). Tissue concentrations of CoQ10 from both dispersions were slightly increased in the liver, but decreased in the kidney. LC-based liposomes and microemulsions have been used to target CoQ10 to heart tissue [4,5]. In our study, CoQ10-NE-TPGS had a higher systemic exposure and more effectively targeted CoQ10 to the heart than CoQ10-NE-LC. Coating nanoparticles with polyethylene glycol 1000 reduces their uptake and clearance by the reticuloendothelial system, prolongs their residence time in the circulation, and results in higher plasma levels [13]. Additionally, myocardial tissue is rich in developed vasculature physiologically, the spontaneous accumulation in heart tissue via penetrating through vasculature effect is higher the other tissue [14]. Furthermore, the fact that TPGS inhibits P-glycoprotein may partially explain its ability to deliver higher concentrations of therapeutics [15]. To date, the slow accumulation of CoQ10 in heart tissue after oral administration has hampered its clinical application for treating acute heart disease. Our data suggest that CoQ10NE-TPGS administered intravenously may meet the clinical need to rapidly raise heart levels of CoQ10 to effectively treat acute cardiac events. 4. Conclusions CoQ10-containing nanoemulsions were prepared by hot HPH to yield particles with an approximate diameter of 50 nm. CoQ10-NETPGS more effectively delivered CoQ10 to heart tissue than CoQ10NE-LC after intravenous administration; higher tissue levels were
maintained for 90 min after injection. These data suggest that CoQ10-NE-TPGS might be a potential vehicle to deliver CoQ10 with great clinical benefit to treat acute heart disease.
Acknowledgment This research was funded by the International Scientific Cooperation Project from Ministry of Science and Technology of China (2008DFB50060) and Suzhou International Science and Technology Cooperation Program (SH201204). References [1] Pepe S, Marasco SF, HaAs SJ, Sheran FL, Krum H, Rosenfeldt FL. Mitochondrion 2007;7:S154–67. [2] Singh U, Devaraj S, Jialal I. Nutrition Reviews 2007;65:286–93. [3] Singh RB, Wander GS, Rastogi A, Shukla PK, Mittal A, Sharma JP, et al. Cardiovascular Drugs and Therapy 1998;12:347–53. [4] Verma DD, Hartner WC, Thakkar V, Levchenko TS, Torchilin VP. Pharmaceutical Research 2007;24:2131–7. [5] Takada M, Yuzuriha T, Katayama K, Yamato C, Koyama N. Journal of Nutritional Science and Vitaminology 1985;31:115–20. [6] Zhang Z, Tan S, Feng SS. Biomaterials 2012;33:4889–906. [7] Zhang Z, Mei L, Feng SS. Nanomedicine 2012;7:1645–7. [8] Feng SS, Zhao LY, Zhang ZP, Bhakta G, Win KY, Dong YC, et al. Chemical Engineering Science 2007;62:664–8. [9] Ma Y, Huang L, Song C. Polymer 2010;51:5952–9. [10] Huang L, Chen H, Zheng Y, Song X, Liu R, Liu K, et al. Integrative Biology 2011;3:993–1002. [11] Ruiz-Jiménez J, Priego-Capote F, Quesada JM. Journal of Chromatography A 2007;1175:242–8. [12] Kuntsche J, Koch MHJ, Fahr A, Bunjes H. European Journal of Pharmaceutical Sciences 2009;38:238–48. [13] Takahama H, Minamino T, Asanuma H, Fujita M, Asai T, Wakeno M, et al. Journal of the American College of Cardiology 2009;53:709–17. [14] Lukyanov AN, Hartner WC, Torchilin VP. Journal of Controlled Release 2004;94:187–93. [15] Parhi P, Mohanty C, Sahoo SK. Acta Biomaterialia 2011;7:3656–69.