Biodegradable nanoparticles of methoxy poly(ethylene glycol)-b-poly( d, l-lactide)/methoxy poly(ethylene glycol)- b-poly(ϵ-caprolactone) blends for drug delivery
© Baimark and Srisuwan; licensee Springer. 2012
Received: 20 April 2012
Accepted: 18 May 2012
Published: 30 May 2012
The effects of blend weight ratio and polyester block length of methoxy poly(ethylene glycol)-b-poly( d, l-lactide) (MPEG- b-PDLL)/methoxy poly(ethylene glycol)- b-poly(ϵ-caprolactone) (MPEG- b-PCL) blends on nanoparticle characteristics and drug release behaviors were evaluated. The blend nanoparticles were prepared by nanoprecipitation method for controlled release of a poorly water-soluble model drug, indomethacin. The drug-loaded nanoparticles were nearly spherical in shape. The particle size and drug loading efficiency slightly decreased with increasing MPEG- b-PCL blend weight ratio. Two distinct thermal decomposition steps from thermogravimetric analysis suggested different blend weight ratios. Thermal transition changes from differential scanning calorimetry revealed miscible blending between MPEG- b-PDLL and MPEG- b-PCL in an amorphous phase. An in vitro drug release study demonstrated that the drug release behaviors depended upon the PDLL block length and the blend weight ratios but not on PCL block length.
KeywordsBiodegradable polymers Polymer blends Diblock copolymers Nanoparticles Nanoprecipitation method Controlled release
In the past few decades, biodegradable and biocompatible nanoparticles of methoxy poly(ethylene glycol)-b-poly( d l-lactide) (MPEG- b-PDLL) and methoxy poly(ethylene glycol)- b-poly(ϵ-caprolactone) (MPEG- b-PCL) amphiphilic diblock copolymers have shown potential as controlled-release drug delivery carriers because of the small size of their nanoparticles, which improves circulation time in the body and decreases the administration frequency when compared to microparticles which are rapidly cleared by the reticuloendothelial tissue [1, 2]. Moreover, for MPEG-b-PDLL and MPEG- b-PCL nanoparticles suspended in water, PDLL and PCL hydrophobic cores are surrounded by hydrophilic MPEG blocks on the nanoparticle surface to solubilize hydrophobic drugs; this increases blood circulation time and decreases uptake by the liver of the nanoparticles [3–6]. The need for surfactants when preparing nanoparticles of amphiphilic diblock copolymer by the nanoprecipitation method can be removed. The protective effect of the hydrophilic MPEG block is adequate for preventing nanoparticle aggregation. The poly(vinyl alcohol), Span series, Tween series, poly(ethylene oxide) (PEO), and poloxamer (PEO-poly(propylene oxide) block copolymer) have been used as surfactants to stabilize emulsion droplets . These surfactants remain at the particle surface and are difficult to remove which affect the biodegradability and drug release profile of the drug-loaded particles. Also, these remaining surfactants can influence the human body, for example, causing an allergy-like reaction.
In previous studies, much attention was paid to the drug-loaded nanoparticles of these amphiphilic diblock copolymers with different types of chemical compositions and lengths of polymer blocks used [8–11]. Drug release profiles of the nanoparticles depended upon these factors. The physical blending of polymers is an alternative method that has been widely used to adjust the properties of biodegradable polyesters [12–15]. Thus unique properties of polymer blends, quite different from the origin polymers, were obtained. The drug release rate from poly(l-lactide)/PCL blend nanoparticles prepared from the nanoprecipitation method using poloxamer 188 as the surfactant has been adjusted by varying the blend weight ratios .
The characteristics and drug release behaviors of the MPEG-b-PCL nanoparticles containing drug prepared by the nanoprecipitation method can be controlled by adjusting the processing parameters, such as the organic/water phase volume ratio, polymer concentration, drug/polymer weight ratio, and stirring speed . However, the effect of MPEG-b-PDLL/MPEG- b-PCL blending on characteristics and drug release of the nanoparticles has not been reported.
In this study, surfactant-free MPEG-b-PDLL/MPEG- b-PCL blend nanoparticles containing a model drug were prepared by the nanoprecipitation method. Indomethacin was selected as the model drug because of its poor water solubility. The effects of different polyester block lengths and blend weight ratios on the nanoparticle characteristics, drug loading efficiency, and drug release profiles were studied and discussed.
Molecular weight characteristics of diblock copolymers
Mn, theoretical (g/mol)a
Mn, GPC (g/mol)b
Preparation of drug-loaded blend nanoparticles
Drug-loaded blend nanoparticles were prepared via a nanoprecipitation method. Briefly, 4 mg of indomethacin and 60 mg of copolymer blend were co-dissolved in 6 mL of acetone. The organic solution was added dropwise into 60 mL of distilled water under magnetic stirring. The nanoparticles were immediately formed after solvent extraction. The organic solvent was then evaporated at room temperature for 6 h in a fume hood. The drug-loaded blend nanoparticles with MPEG-b-PDLL/MPEG- b-PCL blend weight ratios of 100/0, 75/25, 50/50, 25/75, and 0/100 ( w/w) were investigated. The resultant nanoparticle suspensions were centrifuged at 15,000 rpm 4°C for 2 h. The supernatant was carefully discarded and the precipitated nanoparticles were then resuspended in a phosphate buffer solution media (0.1 M, pH 7.4). The dried drug-loaded nanoparticles were obtained by freeze-drying the precipitated nanoparticles for 48 h.
Characterization of drug-loaded blend nanoparticles
where ΔHm is the melting enthalpy of the nanoparticles, and 135.44 J/g is the melting enthalpy for 100% crystalline PCL .
In vitro drug release
In vitro release of indomethacin from the blend nanoparticles was performed by dialysis bag diffusion technique. The drug-loaded nanoparticle suspension (10 mL) was placed in a dialysis bag, tied, and immersed into 100 mL of phosphate buffered saline (0.1 M, pH 7.4). The entire system was kept at 37°C under shaking at 100 rpm.
At predetermined time intervals, 5 mL aliquots of the release medium were withdrawn from the release medium, and the same volume of fresh buffer solution was added to continue the release test. The concentration of indomethacin released was monitored using an UV–vis spectrophotometer at 319 nm. According to a predetermined indomethacin concentration-UV absorbance standard curve, indomethacin concentration of the release medium was obtained. Percentage of indomethacin release was calculated based on the ratio of drug release at each release time and initial drug content in the nanoparticles. The average percentage release was calculated from the three experiments.
Results and discussion
Morphology and size
Thermal decomposition can be clearly observed from differential TG (DTG) thermograms. Figure 3 (bottom) show DTG thermograms of the MPEG-b-PDLL30K/MPEG- b-PCL30K blend nanoparticles as examples. The two-step decomposition process of the blend nanoparticles is clearly illustrated. The peak temperature of the DTG thermogram is the temperature of maximum decomposition rate ( Td, max). The lower and higher Td, max values of the DTG thermograms are attributed to MPEG-b-PDLL and MPEG- b-PCL decompositions, respectively. The Td, max of MPEG-b-PDLL and MPEG- b-PCL decomposition peaks are in the range of 343°C to 354°C and 400°C to 418°C, respectively, which also indicates higher thermal stability of the MPEG- b-PCL matrix. It should be noted that the peak areas of the DTG thermograms strongly depend on the blend weight ratio. It can be clearly seen that the peak area of the lower temperature peak due to MPEG- b-PDLL decomposition decreased steadily as the MPEG- b-PDLL blend weight ratio decreased.
The TG and DTG thermograms of the blend nanoparticles of MPEG-b-PDLL30K/MPEG- b-PCL60K, MPEG- b-PDLL60K/MPEG- b-PCL30K, and MPEG- b-PDLL60K/MPEG- b-PCL60K changed with the blend weight ratio similar to the MPEG- b-PDLL30K/MPEG- b-PCL30K blend nanoparticles. The thermogravimetry results supported the fact that MPEG- b-PDLL/MPEG- b-PCL blend nanoparticles with different blend weight ratios were obtained.
Drug loading efficiency
In vitro drug release
It can be seen that the drug release contents from the nanoparticles are in the order MPEG-b-PCL30K ≈ MPEG- b-PCL60K > MPEG- b-PDLL30K > MPEG- b-PDLL60K. The results may be explained due to the crystallinity of the MPEG- b-PCL component which could lead to formation of a channel structure in the nanoparticle matrix and results in the drug being easily released from the nanoparticles [10, 16]. Zhang et al.  reported that the drug release content from the MPEG-b-P(CL- co-DLL) nanoparticles increased with the CL content. For the blend nanoparticles, with increasing MPEG- b-PCL blend weight ratio, the drug release increased. The higher crystallinity of the blend nanoparticles is due to the larger MPEG- b-PCL blend weight ratio, inducing faster drug release from the nanoparticles. The drug release results indicate that the polyester block type and blend weight ratio were important factors for controlling the drug release content from the blend nanoparticles.
In the present study, drug-loaded MPEG-b-PDLL/MPEG- b-PCL blend nanoparticles with various polyester block lengths and blend weight ratios were prepared by nanoprecipitation method. They were nearly spherical in shape. The average particle size slightly decreased as the MPEG- b-PCL blend weight ratio increased. The thermal decomposition behaviors confirm the difference in MPEG- b-PDLL/MPEG- b-PCL blend weight ratios of the blend nanoparticles. Melting temperature and melting enthalpy depression of MPEG- b-PCL indicate the miscibility between MPEG- b-PDLL and MPEG- b-PCL components in the drug-loaded blend nanoparticle matrix.
The nanoparticles of MPEG-b-PDLL and MPEG- b-PCL showed the slowest and fastest drug releases, respectively. The drug release behaviors of the blend nanoparticles were between the MPEG- b-PCL and MPEG- b-PDLL nanoparticles. The drug release from the blend nanoparticles can be tailored by adjusting the PCL block length and blend weight ratio. These blend nanoparticles without any surfactants added are considered to be promising biodegradable drug carriers for sustained release of poorly water-soluble drugs.
The authors would like to acknowledge financial support from the Research, Development and Engineering (RD&E) fund through The National Nanotechnology Center (NANOTEC), The National Science and Technology Development Agency (NSTDA), Thailand (Project No. NN-B-22-EN4-30-52-11) to Mahasarakham University. The authors also thank the Center of Excellence for Innovation in Chemistry (PERCH-CIC), and the Commission on Higher Education, Ministry of Education, Thailand.
- Stolnik S, Illum L, Davis SS: Long circulating microparticulate drug carriers. Adv Drug Deliv Rev 1995, 16: 195. 10.1016/0169-409X(95)00025-3View ArticleGoogle Scholar
- Stolnik S, Heald CR, Neal J, Garnett MC, Davis SS, Illum L, Purkiss SC, Barlow RJ, Gellert PR: Polylactide-poly(ethylene Glycol) miscellar-like particles as potential drug carriers: production, colloidal properties and biological performance. J Drug Target 2001, 9: 361. 10.3109/10611860108998772View ArticleGoogle Scholar
- Tanodekaew S, Pannu R, Heatley F, Attwood D, Booth C: Association and surface properties of diblock copolymers of ethylene oxide and dl-lactide in aqueous solution. Macromol Chem Phys 1997, 198: 927. 10.1002/macp. 1997.021980402View ArticleGoogle Scholar
- Lemoine D, Francois C, Kedzierewicz F, Preat V, Holman M, Maincent P: Stability study of nanoparticles of poly(ε-caprolactone), poly(d, l-lactide) and poly(d, l-lactide-co-glycolide). Biomaterials 1996, 17: 2191. 10.1016/s0142-9612(96)00049-XView ArticleGoogle Scholar
- Kim SY, Lee YM, Baik DJ, Kang JS: Toxic characteristics of methoxy poly(ethylene glycol)/poly(ϵ-caprolactone) nanospheres; in vitro and in vivo studies in the normal mice. Biomaterials 2003, 24: 55. 10.1016/S0142-9612(02)00248-XView ArticleGoogle Scholar
- Otsuka H, Nagasaki Y, Kataoka K: Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications. Curr Opin Colloid Interface Sci 2001, 6: 3. 10.1016/S1359-0294(00)00082-0View ArticleGoogle Scholar
- Jeon H-J, Jeong Y-I, Jang M-K, Park Y-H, Nah J-W: Effect of solvent on the preparation of surfactant-free poly(dl-lactide-co-glycolide) nanoparticles and norfloxacin release characteristics. Int J Pharm 2000, 207: 99. S0378-5173(00)00537-8View ArticleGoogle Scholar
- Kim SY, Shin IG, Lee YM, Cho CS, Sung YK: Methoxy poly(ethylene glycol) and epsilon-caprolactone amphiphilic block copolymeric micelle containing indomethacin. II. Micelle formation and drug release behaviours. J Control Release 1998, 51: 13. 10.1016/S0168-3659(97)00124-7View ArticleGoogle Scholar
- Shuai X, Ai H, Nasongkla N, Kim S, Gao J: Micellar carriers based on block copolymers of poly(ϵ-caprolactone) and poly(ethylene glycol) for doxorubicin delivery. J Control Release 2004, 98: 415. 10.1016/j.jconrel.2004.06.003View ArticleGoogle Scholar
- Zhang Y, Wang C, Yang W, Shi B, Fu S: Tri-component of diblock polymers of poly(ethylene glycol)-poly(ϵ-caprolactone-co-lactide): synthesis, characterization and loading campothecin. Colloid Polym Sci 2005, 283: 1246. 10.1007/s00396-005-1306-5View ArticleGoogle Scholar
- Zhang Y, Li X, Zhou Y, Wang X, Fan Y, Huang Y, Liu Y: Preparation and evaluation of poly(ethylene glycol)–poly(lactide) micelles as nanocarriers for oral delivery of cyclosporine A. Nanoscale Res Lett 2010, 5: 917. 10.1007/s11671-010-9583-4View ArticleGoogle Scholar
- Lopez-Rodriguez N, Lopez-Arraiza A, Meaurio E, Sarasua JR: Crystallization, morphology, and mechanical behavior of polylactide/poly(ϵ-caprolactone) blends. Polym Eng Sci 2006, 46: 1299. 10.1002/pen.20609View ArticleGoogle Scholar
- Dong Y, Feng SS: Nanoparticles of poly(d, l-lactide)/methoxy poly(ethylene glycol)-poly(d, l-lactide) blends for controlled release of paclitaxel. J Biomed Mater Res 2006, 78A: 12. 10.1002/jbm.a.30684View ArticleGoogle Scholar
- Yao M, Deng H, Mai F, Wang K, Zhang Q, Chen F, Fu Q: Modification of poly(lactic acid)/poly(propylene carbonate) blends through melt compounding with maleic anhydride. Express Polym Lett 2011, 5: 937. 10.3144/expresspolymlett.2011.92View ArticleGoogle Scholar
- Modi S, Koelling K, Vodovotz Y: Miscibility of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with high molecular weight poly(lactic acid) blends determined by thermal analysis. J Appl Polym Sci 2012, 124: 3074. 10.1002/app. 35343View ArticleGoogle Scholar
- Ge H, Hu Y, Yang S, Jiang X, Yang C: Preparation, characterization, and drug release behaviors of drug-loaded ϵ-caprolactone/L-lactide copolymer nanoparticles. J Appl Polym Sci 2000, 75: 874. 10.1002/(SICI)1097-4628(20000214)75View ArticleGoogle Scholar
- Wei XW, Gong CY, Gou ML, Fu SZ, Guo QF, Shi S, Luo F, Guo G, Qiu LY, Qian ZY: Biodegradable poly(ϵ-caprolactone)-poly(ethylene glycol) copolymers as drug delivery system. Int J Pharm 2009, 381: 1. 10.1016/j.ijpharm.2009.07.033View ArticleGoogle Scholar
- Baimark Y, Srisa-ard M, Threeprom J, Srisuwan Y: Preparation of nanoparticle colloids of methoxy poly(ethylene glycol)-b-poly(d, l-lactide): effects of surfactant and organic solvent. Colloid Polym Sci 2007, 285: 1521. 10.1007/s00396-007-1731-8View ArticleGoogle Scholar
- Baimark Y: Surfactant-free nanospheres of methoxy poly (ethylene glycol)-b-poly (ϵ-caprolactone) for controlled release of ibuprofen. J Appl Sci 2009, 9: 2287. 10.3923/jas.2009.2287.2293View ArticleGoogle Scholar
- Bai W, Zhang L-F, Li Q, Chen D-L, Xiong C-D: In vitrohydrolytic degradation of poly(para-dioxanone)/poly(d,l-lactide) blends. Mater Chem Phys 2010, 122: 79. 10.1016/j.matchemphys.2010.02.064View ArticleGoogle Scholar
- Nojima S, Akutsu Y, Washino A, Tanimoto S: Morphology of melt-quenched poly(ϵ-caprolactone)-block-polyethylene copolymers. Polymer 2004, 45: 7317. 10.1016/j.polymer.2004.08.044View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.