Article Journal of Biomedical Nanotechnology

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Vol. 9, 1286–1292, 2013 www.aspbs.com/jbn

PAMAM Dendrimer Generation 5–Pluronic F127 Nanofilm as a Matrix for Local Metronidazole Release Tran Huu Dung2 , Le Thanh Do1 , and Hoon Yoo1 ∗ 1 2

Department of Pharmacology and Dental Therapeutics, College of Dentistry, Chosun University, Gwangju, 501-759, Korea Department of Analysis, Faculty of Pharmacy, Hue Medicine and Pharmacy University, Hue City, 47000, Vietnam

A series of dendrimer G5-pluronic F127 nanofilms (at 1:10, 1:20 and 1:30 mole ratios), loaded with various percent of metronidazole hydrochloride, were prepared by the drug deposition with/without gelatin coating. The nanostructural feature of dendrimer G5-pluronic F127 as a matrix for a sustained drug release was investigated by choosing metronidazole, an antibacterial and antiprotozoal drug as a model drug. The studies on surface morphology, polymer erosion and metronidazole release of the prepared nanofilms revealed unique surface morphology, low film erosion rate and long drug release time. The drug release and the erosion rate of nanofilm were slowed in acidic pH condition and the presence of saliva in medium. The nanofilm of G5-PF127 (1:30 mole ratio) coated with gelatin further prolonged metronidazole release showing G5-PF127 coated with 20% gelatin to be the best suited for a metronidazole release. The nanofilms were stable for up to 9 months at dried condition, while those stored at room temperature with 30% relative humidity were Delivered by Publishing Technology to: SUNY Upstate Medical University less stable. Our results show that PAMAM dendrimer G5–pluronic F127 nanofilm has a potential to serve as a matrix for IP: 199.20.44.120 On: Thu, 15 Oct 2015 08:28:12 the local drug delivery.

Copyright: American Scientific Publishers KEYWORDS: PAMAM Dendrimer G5-Pluronic F127, Release, Erosion, Nanofilm, Metronidazole.

INTRODUCTION Delivering drugs to a targeted site and maintaining their therapeutic level in a suitable time are essential for the disease treatment.1 2 To achieve a therapeutic effect, a drug after administration has to pass through certain physiologic barriers and/or pathways, reaching to a target site with effective concentration. Numerous efforts were made for the development of a specific drug carrier/delivery system, which maintains continuous drug levels and reduces side effects by modulating the release of drug and improving tissue or organ specificity.3 4 These include polymeric drug delivery systems such as polylactides (PLA), polyglycolides (PGA), poly(lactide-co-glycolides) (PLGA), polyanhydrides, polyorthoesters, poly(ethylene oxide) modified poly(-caprolactone), polyethylene glycol, polyvinylpyrrolidone K30 and dendrimers.5–8 In these systems, drugs or other active agents were released from the polymeric carrier at a disease site (e.g., an ∗

Author to whom correspondence should be addressed. Email: [email protected] Received: 28 November 2011 Accepted: 4 April 2012

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infected organism), generally by diffusion, degradation and swelling followed by diffusion.9 Poly(amidoamine) (PAMAM) dendrimers is a polymer of spherical shape, whose molecular structure consists of an initiator core, repeating units with branches and terminal functional groups.2 10 Recently dendrimers have been extensively investigated as a drug delivery vehicle or gene/oligonucleotide carrier due to its unique properties such as water solubility and well-defined molecular architecture.11 The nanostructure of dendrimer was used as a cargo for the delivery/release of water insoluble drugs such as flurbiprofen and acidic antiinflammatory drug.12 However, positive surface charge of dendrimer in physiological condition caused the cytotoxic effect and limited its biocompatability as drug delivery system.13 14 In this study, we prepared PAMAM dendrimer generation 5 (G5)–pluronic F127 loaded with various percent of a drug. Pluronic polymers (poloxamers) which have chemical structure of triblock copolymer poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) was covalently bonded with surface amino groups of dendrimer by various mole ratio reactions.15 16 Bond formation between PAMAM dendrimer G5 and pluronic 1550-7033/2013/9/1286/007

doi:10.1166/jbn.2013.1534

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PAMAM Dendrimer Generation 5–Pluronic F127 Nanofilm as a Matrix for Local Metronidazole Release

F127 polymer generates a hybrid (graft) form of dendritic polymer with long hydrocarbon branches containing hydrophobic poly(propylene oxide) and hydrophilic poly(ethylene oxide), which increases the outer shell space of dendrimer and partially shields cationic charge on dendrimer surface.17 Thus, we hypothesized that the structural feature of dendrimer G5-pluronic F127 would increase the nanostructural volume to entrap drugs and might be suited for a sustained drug release.18–20 To test this hypothesis metronidazole, an antibacterial and antiprotozoal drug,21 was chosen as a model drug. Metronidazole is a known effective drug in the topical treatment against rosacea (a chronic multifactorial vascular skin disorder), trichomonas vaginalis, Crohn’s disease, anaerobic infection as well as periodontal diseases (e.g., acute ulcerative gingivitis, pericoronitis, certain periapical infections) where anaerobes are implicated as pathogens.22 Here we prepared a series of metronidazole loaded nanofilms and evaluated the release behavior and the stability of metronidazole.

images provided characteristic morphology property and three dimensional structure on the surface of G5-pluronic F127 nanofilm, which was obtained by the HITACHI S5000 scanning electron microscopy (Hitachi Ltd., Tokyo, Japan). Nanofilm Erosion Study The polymeric erosion rate was determined by using a modified rotating-basket apparatus. A 40 mesh stainless steel basket apparatus dipped into a cuvette containing 3.5 ml of PBS solution (pH 7.0), was set under a magnetic stirring condition at 37  C. The prepared nanofilm was put into basket and the outer phase was continuously stirred. As the nanofilm erodes, the dissolved polymer partly diffused into the outer phase. The remaining nanofilms were taken out at appropriate time, dried in the room temperature for 12 h, and then further dried in a vacuum oven for 24 h for the gravimetric analysis.

In Vitro Drug Release From Nanofilm of Dendrimer G5-Pluronic F127 EXPERIMENTAL DETAILS In vitro release study of metronidazole from the prepared Materials nanofilms was carried out in a UV-cell release apparatus. PAMAM dendrimers and pluronics were purchased from Dendrimer G5-pluronic F127 nanofilms loaded with 10% Aldrich (Milwaukee, WI, USA). All other chemicals were metronidazole hydrochloride were placed in mini-dialysis from Sigma Chemical (St. Louis, MO, USA). Vinyl tubes (molecular weight cutoff: 30000 Da) containing polysiloxane impression material was obtained from GC Delivered by Publishing Technology to: Medical 100SUNY l of Upstate PBS solution, pH University 7.0. In this molecular weight Co. (Tokyo, Japan). IP: 199.20.44.120 On: Thu, 15 Oct 2015 08:28:12 cutoff, dendrimer G5-pluronic F127 of higher molecuCopyright: American Scientific Publishers lar weights stayed inside the dialysis membrane while Preparation of the Nanofilm of Dendrimer the released metronidazole diffused out of the dialysis G5–Pluronic F127 Loaded with Metronidazole tube. The dialysis tube was placed in a UV-cell containThe film of metronidazole loaded dendrimer G5–pluronic ing 3.5 ml of PBS at 37  C while the outer phase was F127 was prepared in aluminum disc (1.0 mm in thickness stirred continuously. The released metronidazole in the and 5 mm in diameter) which was sterilized. Dendrimer outer phase was monitored by UV spectrophotometer at G5-pluronic F127 (1/10, 1/20 and 1/30 mole ratio) were 320 nm. Triplicate runs were carried out for each sample. dissolved in deionized water to form 20% (w/v) solution. The effect of metronidazole concentration, pH and saliva To produce metronidazole loaded dendrimer G5-PF127 on the drug release was also carried out by following the nanofilm, appropriate amount of metronidazole hydrochlosimilar procedure. ride was dissolved in casting solution to prepare final con centrations of 10 and 15% (w/w) at 4 C. A 150 l of Coating Nanofilm of Dendrimer dendrimer G5-pluronic F127 solution in the presence of G5-Pluronic F127 metronidazole was deposited gradually in the disc for 6 h. Three different concentrations of gelatin solutions (5, 10 The water was evaporated at room temperature for 24 h, and 20% of gelatin) were prepared in distilled water and further dried under the vacuum for 24 h. Finally, the at 37  C. The nanofilm of dendrimer G5-pluronic casting discs were placed in a desiccator to avoid the F127 (1:30 mole ratio) loaded with 10% metronidazole moisture in the air. The prepared nanofilm was carefully hydrochloride was dipped in gelatin solution, and then separated from the aluminum disc and stored at room dried in a vacuum oven for 24 h before investigating the temperature in a light protected desiccator. Dendrimer G5 drug release profile. or G5-pluronic F68 (mole ratio of 1:10, 1:20 or 1:30) nanofilms loaded with metronidazole hydrochloride were also prepared by the same method. Effect of Humidity The nanofilm of dendrimer G5-pluronic F127 (1:30 mole Morphology of Dendrimer G5–Pluronic ratio) loaded with 10% metronidazole hydrochloride were F127 Nanofilm stored in desiccators containing dried silica gel (approximately zero relative humidity) or stored at room temThe scanning electron microscope (SEM) was used to properature under 30% humidity over a period of 1, 6 and duce high-resolution image of a nanofilm surface. SEM J. Biomed. Nanotechnol. 9, 1286–1292, 2013

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9 months. The prepared samples were evaluated with respect to the drug release profile and the degree of drug decomposition on capillary zone electrophoresis. Capillary Zone Electrophoresis (CZE) Capillary zone electrophoresis was carried out with a constant voltage at 20  C using a P/ACE MDQ Capillary Electrophoresis System (BECKMAN COULTER) equipped with a standard cassette containing an uncoated fused-silica capillary (50 m I.D. ×725 cm long; effective length = 600 cm) and a photodiode array detector. The capillary was conditioned before injection by washing with 0.1 M sodium hydroxide, then ultra pure water. The running buffer used for analysis was 100 mM borate, pH 9.2. In Vivo Study on Nanofilm Erosion and Metronidazole Release Implant stick of dendrimer G5-pluronic F127 (1:30) nanofilm loaded with 10% metronidazol was prepared in the average weight of 6.6 mg ±05 (diameter: 1.2–1.5 mm length: 2–2.5 mm). Male Sprague Dawley rats at 8 weeks of age (average weight of 250 g) were obtained from the animal facility of Chosun University. All the rats were

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maintained under pathogen-free condition in the animal facility. Prior to the anesthesia with diethyl ether the dorsal torso of rat was shaved and disinfected with 70% ethanol. After dermis was cut out by surgery knife, the prepared implant stick was subcutaneously inserted and followed by sealing the wound site with the gum of vinyl polysiloxane impression material. The inserted sticks were taken out at a certain time period by reopening the wound after anesthetizing the rat with diethyl ether. The sticks, after carefully removing blood and tissue, were dried in vacuum oven at 40  C and weighed to determine the degree of film erosion. The amount of the remaining metronidazole was determined by dissolving the retrieved implant stick in 10 ml of 0.1 N HCl and then measuring the absorbance at a wavelength of 350 nm using UV/Visible spectrophotometer.

RESULTS AND DISCUSSION Preparation and Morphology of Dendrimer G5-Pluronic F127 Nanofilm The nanofilms of dendrimer G5–pluronic F127 loaded with metronidazole hydrochloride were prepared as a thin and

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Figure 1. SEM image of dendrimer G5-pluronic F127 nanofilm at magnification of 50 K. (A) dendrimer G5 nanofilm, (B) dendrimer G5-pluronic F127 (1:10 mole ratio), (C) dendrimer G5-pluronic F127 (1:20 mole ratio), (D) dendrimer G5-pluronic F127 (1:30 mole ratio).

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PAMAM Dendrimer Generation 5–Pluronic F127 Nanofilm as a Matrix for Local Metronidazole Release

round shape in weight range of 270 ± 15 mg (5 mm in diameter and 0.5 mm in thickness) and stored at room temperature in light protected desiccators. The dried nanofilms were opaque and homogeneous with yellowish color on surface. The nanofilm loaded with 15% metronidazole hydrochloride (w/w) showed visible crystalline on the film surface due to the presence of undissolved drugs. The surface of nanofilms became heterogeneous and rough as the mole ratio increases. Especially, the film surface at the mole ratio of 1:30 became spongy-like and highly adsorptive (Fig. 1).

(A) 100 Percent erossion (%)

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80 60

43 40 20 0 G5

G5-PF68 (1/10)

G5-PF127 (1/10)

Released time (60 min)

Percent erosion (%)

Nanofilm Erosion Study The erosion rate of nanofilm was dependent on the num99 99 98 (B) 100 ber of pluronic units and the mole ratio of pluronic on dendrimer surface reducing the erosion rate when 79 78 76 80 hydrophilic amine groups of dendrimer G5 were replaced with hydrophobic PPO units on pluronic moieties. As 58 60 shown in Figure 2(A), the nanofilm of dendrimer G544 43 pluronic F127 was evaluated on its erosion by compar35 40 32 ing with the percent erosion of dendrimer G5 nanofilm or dendrimer G5-pluronic F68 nanofilm. The erosion rate of 14 20 dendrimer G5-pluronic F127 (mole ratio of 1:10) nanofilm was much slower than the one of dendrimer G5-pluronic 0 F68 (1:10), which has less number of pluronic units com60 120 180 240 pared to pluronic F127, with the percent erosion of 43% released times (minutes) at 60 min (Fig. 2(A)).Delivered Similarly,bythe nanofilm with high to: SUNY Upstate Medical University Publishing Technology 199.20.44.120 On: Thu, 15 Oct 2015 08:28:12 Figure 2. Erosion profile of PAMAM dendrimer G5–pluronic mole ratio of pluronic to dendrimerIP: showed slower erosion Copyright: American Scientific Publishers F127 nanofilm. (A) Comparison of percent erosion of denrate than the nanofilm at low mole ratio indicating that drimer pluronic nanofilms. Pluronic F127 has 99 units the increased hydrophobicity by the grafted pluronic F127 of poly(ethylene oxide) and 69 units of poly(propylene suppresses the erosion of the nanofilm (Fig. 2(B)). oxide) groups. Pluronic F68 has 30 units of poly(propylene Drug Release From the Nanofilms of Dendrimer G5-Pluronic F127 In order to predict the release rate of metronidazole from the nanofilm of dendrimer G5-pluronic F127, we applied the diffusion of metronidazole from the nanofilms to Higuchi’s model (Eq. (1))  √ (1) Qt = 2DSA − 05S × t = kH t where Qt is the amount of metronidazole released in time t, D and S are the diffusion and solubility coefficient of the metronidazole in the medium, A is the metronidazole content per cubic millimeter of nanofilm and KH is the release rate constant for the Higuchi model.23 24 According to Higuchi’s equation applied to Qt versus t 1/2 , the release rate constant (KH ) of metronidazole decreased in the order of mole ratio of dendrimer to pluronic F127, 1  10 > 1  20 > 1  30 (Table I). The release rate of metronidazole from the nanofilm prepared with 1:30 mole ratio of dendrimer to pluronic F127 was slower with less burst effect compared to the one of nanofilm with low mole ratio, which is consistent with the predicted release constants based on Higuchi’s model (Fig. 3(A)). Namely, the mole ratio of dendrimer to pluronic F127 played an J. Biomed. Nanotechnol. 9, 1286–1292, 2013

oxide) groups and 75 units of poly(ethylene oxide) in structure. (B) Comparison of percent erosion of dendrimer G5pluronic F127 nanofilms at different mole ratios. Light blue, dendrimer G5-pluronic F127 (1:10 mole ratio); purple, dendrimer G5-pluronic F127 (1:20 mole ratio); light yellow, dendrimer G5-pluronic F127 (1:30 mole ratio). Data represent the means ± SD of triplicate experiments.

important role in the determination of release rate constants (KH  of metronidazole. This indicates that the bulky nanostructures of dendrimer G5-PF127 surface at high mole ratio must have steric hindrance and limit the release of metronidazole entrapped in the nanofilm. The release profile of metronidazole from nanofilm was altered by Table I. Release rate constants (K) of metronidazole from dendrimer G5-pluronic F127 nanofilms based on Higuchi’s model. Nanofilm (mole ratio) 1:10 1:20 1:30

Release rate constant K (mg/hr1/2 × mm2 )

Correlative coefficient (R2 )

0.1531 0.1068 0.1042

0.9952 0.9978 0.9922

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(B)

(C)

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Figure 3. Drug release profiles of dendrimer G5-pluronic F127 nanofilms loaded with 10% metronidazole hydrochloride. (A) At IP: 199.20.44.120 On: Thu, 15 Oct 2015 08:28:12 the conditions of different mole ratios of dendrimer to pluronic F127: () free drug; () dendrimer G5-pluronic F127 (1:10 mole Copyright: American Scientific Publishers ratio); () dendrimer G5-pluronic F127 (1:20 mole ratio); () dendrimer G5-pluronic F127 (1:30 mole ratio). (B) At various pH conditions in PBS: () pH 10.0; () pH 7.0; () pH 5.0. (C) Under saliva medium: () PBS pH 7.0; () 20% saliva; () 50% saliva. (D) The nanofilms of dendrimer G5-pluronic F127 (1:30 mole ratio) loaded with 10% metronidazole hydrochloride were coated with 5, 10 and 20% of gelatin in PBS, pH 7.0: () without gelatin coating; () 5% gelatin; () 10% gelatin; () 20% gelatin. Measurements were made in triplicate and averaged.

pH of release media. The release of metronidazole was slowed under the acidic condition of pH 5 compared to the ones of neutral or basic pH condition (Fig. 3(B)). Also the presence of saliva in medium altered the release rate retarding metronidazole release as the percent of saliva increases (Fig. 3(C)). The release of metronidazole was further retarded when the nanofilm surface was coated with extra thin layer of gelatin (Fig. 3(D)). Noticeably the amount of metronidazole released was less than the total amount of the metronidazole loaded into nanofilms. This suggests that a small partition of metronidazole remains inside polymeric nanofilm even after reaching the maximum release of metronidazole. In addition, burst effect was observed in most of metronidazole release profiles, probably due to the large ratio of surface area to nanostructural volume. However, the release profile of nanofilm loaded with 10% metronidazole coated with 20% gelatin showed much less burst effect. Instead, a sigmoid shape of drug release profile was observed with prolonged drug release indicating that metronidazole was initially diffused out by the swelling of gelatin coat and then, after gelatin 1290

coat completely dissolved, subsequently released by the polymeric erosion in nanofilm. Effect of Humidity on the Nanofilm of Metronidazole Loaded Dendrimer G5-pluronic F127 The effect of humidity on the metronidazole release was examined from the dendrimer G5-pluronic F127 (1:30 mole ratio) nanofilm loaded with 10% metronidazole hydrochloride after keeping the film for 1, 6 or 9 months at low humidity condition (Fig. 4). Interestingly, the drug release profiles from the nanofilms kept for 6 and 9 months showed no significant difference (Fig. 4(A)). However, the nanofilms stored at 30% humidity over a period of 6 and 9 months showed polymeric erosion with high drug release profile. The surface film layer became sticky with moisture due to a decomposition of drug. CZE analysis with the metronidazole loaded nanofilm, stored for 6 to 9 months under the humid condition, revealed the decomposition of metronidazole (Fig. 4(B)). The absorbance of metronidazole peak in the electropherogram was significantly J. Biomed. Nanotechnol. 9, 1286–1292, 2013

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PAMAM Dendrimer Generation 5–Pluronic F127 Nanofilm as a Matrix for Local Metronidazole Release (A)

(A)

(B) (B)

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Figure 5. The erosion and metronidazole (MTZ) release profiles of dendrimer G5-pluronic F127 (1:30 mole ratio) nanofilm in vivo. (A) Percent erosion of dendrimer G5-pluronic F127 by Publishing Technology to: SUNY Upstate Medical University nanofilm. (B) Percent drug release profile of dendrimer G5IP: 199.20.44.120 On: Thu, 15 Oct 2015 08:28:12 pluronic F127 nanofilm. Data represent the means ± SD of Copyright: American Scientific Publishers triplicate experiments.

reduced and instead a broaden peak was newly appeared nearby the peak of metronidazole.

Figure 4. Drug release profile and stability in the dendrimer G5-pluronic F127 nanofilm. Metronidazole crystallization and the color change of nanofilm surface were observed when nanofilm containing metronidazole was exposed to humid condition at room temperature. (A) Drug release profiles from nanofilm of dendrimer G5-pluronic F127 (1:30 mole ratio) loaded with 10% metronidazole in PBS (pH 7.0) after certain storage period at room temperature. () 1 month storage; () 6 month storage; () 9 month storage (B) The detection of decomposed metronidazole was carried out by CZE with the running buffer of 100 mM sodium borate, pH 9.2. (a), one month storage of dendrimer G5-pluronic F127 (1:30 mole ratio) film loaded with 10% metronidazole; (b), after 6 month; (c), after 9 month. The nanofilm samples were stored at room temperature in 30% humidity over a period of 1, 6 and 9 months. Peaks were detected at 220 nm. Data in (A) represent the means of triplicate experiments. J. Biomed. Nanotechnol. 9, 1286–1292, 2013

Nanofilm Erosion and Metronidazole Release In Vivo The release of metronidazole from the dendrimer G5pluronic F127 nanofilm was further examined in a rat dorsal implant model. Implant sticks containing 10 % metronidazole entrapped dendrimer G5-pluronic F127 (1:30) nanofim were subcutaneously inserted into the dorsal torso of rat as described in Experimental details. The polymer erosion and the release profile of metronidazole were examined by determining the weights and the concentration of metronidazole remained in the retrieved implant stick. Similar to in vitro results, both the rates of polymer erosion and metronidazole release were moderately reduced. The erosion of copolymer film was time-dependent with the duration time over 50 hours (Fig. 5(A)). Also the in vivo release profile of metronidazole showed the slow release rate of metronidazole for the extended period of time (Fig. 5(B)).

CONCLUSION The nanofilms of dendrimer G5-pluronic F127 loaded with metronidazole showed characteristic properties on 1291

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surface morphology, polymer erosion and metronidazole release profiles supporting that nanofilm of dendrimer G5– pluronic F127 may have a function to serve as a matrix for the local release of drug.

conjugated drug and noncovalent drug inclusion complex. J. Drug Target 18, 389 (2010). 12. A. Asthana, A. S. Chauhan, P. V. Diwan, and N. K. Jain, Poly(amidoamine) (PAMAM) dendritic nanostructures for controlled site-specific delivery of acidic anti-inflammatory active ingredient. AAPS PharmSciTech 6, E536 (2005). Acknowledgment: This work was supported by the 13. G. Pan, Y. Lemmouchi, E. O. Akala, and O. Bakare, Studies on National Research Foundation of Korea (NRF) funded PEGylated and drug-loaded PAMAM dendrimers. J. Bioactive Compatible Polym. 20, 113 (2005). by the Ministry of Education, Science and Technology 14. W. Wang, W. Xiong, J. Wan, X. Sun, H. Xu, and X. Yang, The (No. 2009-0076328). decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress. Nanotechnology 20, 105103 (2009). REFERENCES 15. J. C. Ha, S. Y. Kim, and Y. M. Lee, Poly(ethylene oxide)1. L. Shultz and S. Zimmerman, Dendrimers: Potential drugs and drug poly(propylene oxide)-poly(ethylene oxide) (Pluronic)/poly(epsilondelivery agents. Pharmacol. News 6, 25 (1999). caprolactone) (PCL) amphiphilic block copolymeric nanospheres. I. 2. P. Kolhe, E. Misra, R. M. Kannan, S. Kannan, and M. Lieh-Lai, Preparation and characterization. J. Control Release 62, 381 (1999). Drug complexation, in vitro release and cellular entry of den16. R. L. Rill, Y. Liu, D. H. Van Winkle, and B. R. Locke, Pluronic drimers and hyperbranched polymers. Int. J. Pharm. 259, 143 copolymer liquid crystals: Unique, replaceable media for capillary (2003). gel electrophoresis. J. Chromatogr. A 817, 287 (1998). 3. J. Lindhe, L. Heijl, J. M. Goodson, and S. S. Socransky, Local tetra17. W. Zhang, G. Dong, H. Yang, J. Sun, J. Zhou, and J. Wang, Syncycline delivery using hollow fiber devices in periodontal therapy. thesis, surface and aggregation properties of a series of amphiphilic J. Clin. Periodontol. 6, 141 (1979). dendritic copolymers. Colloids Surf. A: Physicochem. Eng. Aspects 4. B. Arica, P. Aksungur, S. Senel, ¸ H. S. Ka¸s, M. F. Sargon, and A. A. 348, 45 (2009). Hincal, Natamycin loaded chitosan micropheres for periodontal ther18. A. Quintana, E. Raczka, L. Piehler, I. Lee, A. Myc, I. Majoros, A. K. apy, J. Faculty Pharm. 23, 77 (2003). Patri, T. Thomas, J. Mule, and J. R. Baker, Design and function 5. R. Langer, Drug delivery and targeting, Nature 392, 5 (1998). of a dendrimer-based therapeutic nanodevice targeted to tumor cells 6. E. S. Park, M. Maniar, and J. C. Shah, Biodegradable polyanhydride through the folate receptor. Pharm. Res. 19, 1310 (2002). devices of cefazolin sodium, bupivacaine, and taxol for local drug 19. J. Jiang, C. Li, M. Rafailovich, and J. Sokolov, Rheological and mordelivery: Preparation, and kinetics and mechanism of in vitro release. phological characterization of triblock copolymer (PEO-PPO-PEO)J. Control Release 52, 179 (1998). clay gel in aqueous solution. Mater. Res. Soc. Sympos. Proc. 898, 55 7. S. C. Yang, H. X. Ge, Y. Hu, X. Q. Jiang, and C. Z. (2005). Yang, Doxorubicin-loaded poly(butylcyanoacrylate) nanoparticles to: SUNY Delivered by Publishing Technology Upstate Medical University 20. Oct M. J.2015 Santander-Ortega, produced by emulsifier-free emulsion polymerization. J.On: Appl. IP: 199.20.44.120 Thu, 15 08:28:12 A. B. Jodar-Reyes, N. Csaba, D. BastosGonzalez, and J. L. Ortega-Vinuesa, Colloidal stability of pluronic Polym. Sci. 78, 517 (2000). Copyright: American Scientific Publishers F68-coated PLGA nanoparticles: A variety of stabilisation mecha8. S. H. Choi, S. H. Lee, and T. G. Park, Temperature-sensitive nisms. J. Colloid Interf. Sci. 302, 522 (2006). pluronic/poly(ethylenimine) nanocapsules for thermally triggered 21. D. A. Mitchell, Metronidazole: Its use in clinical dentistry. J. Clin. disruption of intracellular endosomal compartment. BiomacroPeriodontol 11, 145 (1984). molecules 7, 1864 (2006). 22. S. Sato, M. J. Fonseca, J. O. Ciampo, J. R. Jabor, and V. Pedrazzi, 9. J. Heller, R. W. Baker, and J. O. Rodin, Controlled drug release Metronidazole-containing gel for the treatment of periodontitis: An by polymer dissolution. I. Partial esters of maleic anhydride in vivo evaluation. Braz. Oral Res. 22, 145 (2008). copolymers—properties and theory. J. Appl. Polym. Sci. 22, 1991 23. K. Higashi, M. Matsushita, K. Morisaki, S. Hayashi, and T. Mayumi, (2003). Local drug delivery systems for the treatment of periodontal disease. 10. J. Peterson, A. Ebber, V. Allikmaa, and M. Lopp, Synthesis and CZE J. Pharmacobiodyn. 4, 72 (1991). analysis of Pamam dendrimers with an ethylenediamine core. Proc. 24. E. Pinon-Segundo, A. Ganem-Quintanar, V. Alonso-Perez, and Estonian Acad. Sci. Chem. 50, 156 (2001). D. Quintanar-Guerrero, Preparation and characterization of triclosan 11. Y. Y. Jiang, G. T. Tang, L. H. Zhang, S. Y. Kong, S. J. Zhu, and Y. Y. nanoparticles for periodontal treatment. Int. J. Pharm. 294, 217 Pei, PEGylated PAMAM dendrimers as a potential drug delivery (2005). carrier: In vitro and in vivo comparative evaluation of covalently

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PAMAM dendrimer generation 5-pluronic F127 nanofilm as a matrix for local metronidazole release.

A series of dendrimer G5-pluronic F127 nanofilms (at 1:10, 1:20 and 1:30 mole ratios), loaded with various percent of metronidazole hydrochloride, wer...
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