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Tailoring structural properties of spray-dried methotrexate-loaded poly (lactic acid)/poloxamer microparticle blends

  • Edilene Gadelha de Oliveira
  • Paula Renata Lima Machado
  • Kleber Juvenal Silva Farias
  • Tiago R. da Costa
  • Dulce Maria Araújo Melo
  • Ariane Ferreira Lacerda
  • Matheus de Freitas Fernandes-Pedrosa
  • Alianda Maira Cornélio
  • Arnóbio Antônio da Silva-JuniorEmail author
Biomaterials Synthesis and Characterization Original Research
Part of the following topical collections:
  1. Biomaterials Synthesis and Characterization

Abstract

Drug delivery systems can overcome cancer drug resistance, improving the efficacy of chemotherapy agents. Poly (lactic acid) (PLA) microparticles are an interesting alternative because their hydrophobic surface and small particle size could facilitate interactions with cells. In this study, two poloxamers (PLX 407 and 188) were applied to modulate the structural features, the drug release behavior and the cell viability from spray-dried microparticles. Five formulations with different PLA: PLX blend ratio (100:0, 75:25, 50:50, 25:50, and 0:100) were well-characterized by SEM, particle size analysis, FTIR spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction analysis (XRD). The spray-dried microparticles showed higher drug loading, spherical-shape, and smaller particle size. The type of poloxamer and blend ratio affected their structural and functional properties such as morphology, crystallinity, blend miscibility, drug release rate, and cell viability. The methotrexate (MTX), a model drug, was loaded in amorphous spray-dried microparticles. Moreover, the drug release studies demonstrated that PLX induced a leaching-effect of MTX from PLA: PLX blends, suggesting the formation of MTX/PLX micelles in aqueous medium. This finding was better established by cell viability assays. Therefore, biocompatible PLA: PLX blends showed promising in vitro results, and further in vivo studies will be performed to evaluate the performance of this chemotherapeutic agent.

Abbreviations

MTX

Methotrexate

PLA

Poly (lactic acid)

PLX 407

Poloxamer 407

PLX 188

Poloxamer 188

PEO

Poly (ethylene oxide)

PPO

Poly (propylene oxide) (PPO)

Blank PLA

Blank PLA microparticles

Blank PLX

Blank PLX microparticles

MTX-PLA

Methotrexate-loaded PLA microparticles

MTX-PLX

Methotrexate-loaded PLX microparticles

PLA: PLX

Blends between PLA and PLX

PLA: PLX 25:75

Blends between PLA and PLX in the ratio 25:75

PLA: PLX 50:50

Blends between PLA and PLX in the ratio 50:50

PLA: PLX 75:25

Blends between PLA and PLX in the ratio 75:25

MTX-PLA: PLX

Methotrexate-loaded PLA: PLX blends

SEM

Scanning Electron Microscopy

SPAN

Polydispersity index

DL

Drug loading

EE

Encapsulation Efficiency

DLS

Dynamic Light Scattering

XRD

X-ray Diffraction Analysis

DSC

Differential Scanning Calorimetry

MTT

3-[4,5-dimethylthiazol-2-yl]−2,5-diphenyltetrazolium bromide

FTIR

Fourier Transform Infrared Spectroscopy

Notes

Acknowledgements

The authors gratefully acknowledge the financial support from CNPQ (grant number: 479195/2008; 483073/2010-5, 481767/2012-6) and CAPES (Scholarship of E.G. Oliveira). The authors also thank the help of Andy Cumming in checking the English text.

Author contributions

E.G. Oliveira performed all experiments and drafted the manuscript. P.R.L. Machado and K.J.S. Farias were responsible for the cell assays. D.M.A. Melo, T.R. da Costa performed DSC analyses. M.F. Fernandes-Pedrosa and A.F. Lacerda suggested improvements in the experimental methodology and revised this part of the paper. A.M. Cornélio helped with discussion about biological activity. A.A. da Silva-Junior suggested the research line as well as wrote and revised the final version of the manuscript before submission.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Carretero G, Puig L, Dehesa L, Carrascosa JM, Ribera M, Sánchez-Regaña M, et al. Guidelines on the use of methotrexate in psoriasis. Actas Dermosifiliogr. 2010;101:600–13.  https://doi.org/10.1016/S1578-2190(10)70682-X.
  2. 2.
    Paci A, Veal G, Bardin C, Levêque D, Widmer N, Beijnen J, et al. Review of therapeutic drug monitoring of anticancer drugs part 1 - Cytotoxics. Eur J Cancer. 2014;50:2010–9.  https://doi.org/10.1016/j.ejca.2014.04.014.
  3. 3.
    Shibayama Y, Takeda Y, Yamada K. Effect of methotrexate treatment on expression levels of organic anion transporter polypeptide 2, P-glycoprotein and bile salt export pump in rats. Biol Pharm Bull. 2009;32:493–6.  https://doi.org/10.1248/bpb.32.493.CrossRefGoogle Scholar
  4. 4.
    Corem-Salkmon E, Ram Z, Daniels D, Perlstein B, Last D, Salomon S, et al. Convection-enhanced delivery of methotrexate-loaded maghemite nanoparticles. Int J Nanomed. 2011;6:1595–602.  https://doi.org/10.2147/IJN.S23025.
  5. 5.
    Lei H, Gao X, Wu WD, Wu Z, Chen XD. Aerosol-assisted fast formulating uniform pharmaceutical polymer microparticles with variable properties toward pH-sensitive controlled drug release. Polym (Basel). 2016;8:1–15.  https://doi.org/10.3390/polym8050195.
  6. 6.
    do Nascimento EG, de Caland LB, de Medeiros ASA, Fernandes-Pedrosa MF, Soares-Sobrinho, Santos KSCR, et al. Tailoring drug release properties by gradual changes in the particle engineering of polysaccharide chitosan based powders. Polym (Basel). 2017;9:1–14.  https://doi.org/10.3390/polym9070253.
  7. 7.
    Paganelli F, Cardillo JA, Melo Jr LAS, Lucena DR, Silva Jr AA, Oliveira AG, et al. A single intraoperative sub-Tenon’s capsule injection of triamcinolone and ciprofloxacin in a controlled-release system for cataract surgery. Investig Ophthalmol Vis Sci. 2009;50:3041–7.  https://doi.org/10.1167/iovs.08-2920.
  8. 8.
    Yang MY, Chan JGY, Chan HK. Pulmonary drug delivery by powder aerosols. J Control Release. 2014;193:228–40.  https://doi.org/10.1016/j.jconrel.2014.04.055.CrossRefGoogle Scholar
  9. 9.
    Mesquita PC, Oliveira AR, Fernandes-Pedrosa MF, Oliveira AG, Silva-Júnior AA. Physicochemical aspects involved in methotrexate release kinetics from biodegradable spray-dried chitosan microparticles. J Phys Chem Solids. 2015;81:27–33.  https://doi.org/10.1016/j.jpcs.2015.01.014.
  10. 10.
    Oliveira AR, Molina EF, Mesquita PC, Fonseca JLC, Rossanezi G, Fernandes-Pedrosa MF, et al. Structural and thermal properties of spray-dried methotrexate-loaded biodegradable microparticles. J Therm Anal Calorim. 2013;112:555–65.  https://doi.org/10.1007/s10973-012-2580-3.
  11. 11.
    Mansour HM, Sohn M, Al-Ghananeem A, DeLuca PP. Materials for pharmaceutical dosage forms: Molecular pharmaceutics and controlled release drug delivery aspects. Int J Mol Sci. 2010;11:3298–322.  https://doi.org/10.3390/ijms11093298.CrossRefGoogle Scholar
  12. 12.
    Kohane DS, Langer R. Polymeric biomaterials in tissue engineering. Pediatr Res. 2008;63:487–91.CrossRefGoogle Scholar
  13. 13.
    Böstman O, Pihlajamäki H. Clinical biocompatibility of biodegradable orthopaedic implants for internal fixation: a review. Biomaterials. 2000;21:2615–21.  https://doi.org/10.1016/S0142-9612(00)00129-0.CrossRefGoogle Scholar
  14. 14.
    Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol. 2008;79:1585–91.  https://doi.org/10.1902/jop.2008.080183.CrossRefGoogle Scholar
  15. 15.
    Goldberg M, Langer R, Jia X. Nanostructured materials for applications in drug delivery and tissue engineering. J Biomater Sci Polym. 2008;6:2166–71.  https://doi.org/10.1021/nl061786n.Core-Shell.CrossRefGoogle Scholar
  16. 16.
    Chung HJ, Park TG. Surface engineered and drug releasing pre-fabricated scaffolds for tissue engineering. Adv Drug Deliv Rev. 2007;59:249–62.  https://doi.org/10.1016/j.addr.2007.03.015.CrossRefGoogle Scholar
  17. 17.
    Ma Z, Mao Z, Gao C. Surface modification and property analysis of biomedical polymers used for tissue engineering. Colloids Surf B Biointerfaces. 2007;60:137–57.  https://doi.org/10.1016/j.colsurfb.2007.06.019.CrossRefGoogle Scholar
  18. 18.
    Santos-Silva AM, De Caland LB, Oliveira ALCSL, Araújo-Júnior RF, Fernandes-Pedrosa MF, Cornélio AM, et al. Designing structural features of novel benznidazole-loaded cationic nanoparticles for inducing slow drug release and improvement of biological efficacy. Mater Sci Eng C. 2017;78:978–87.  https://doi.org/10.1016/j.msec.2017.04.053.
  19. 19.
    Leo E, Ruozi B, Tosi G, Vandelli MA. PLA-microparticles formulated by means a thermoreversible gel able to modify protein encapsulation and release without being co-encapsulated. Int J Pharm. 2006;323:131–8.  https://doi.org/10.1016/j.ijpharm.2006.05.047.CrossRefGoogle Scholar
  20. 20.
    Gou M, Li X, Dai M, Gong CY, Wang XH, Xie Y, et al. A novel injectable local hydrophobic drug delivery system: Biodegradable nanoparticles in thermo-sensitive hydrogel. Int J Pharm. 2008;359:228–33.  https://doi.org/10.1016/j.ijpharm.2008.03.023.
  21. 21.
    Barwal I, Sood A, Sharma M, Singh B, Yadav SC. Development of stevioside Pluronic-F-68 copolymer based PLA-nanoparticles as an antidiabetic nanomedicine. Colloids Surf B Biointerfaces. 2013;101:510–6.  https://doi.org/10.1016/j.colsurfb.2012.07.005.
  22. 22.
    Chen L, Sha X, Jiang X, Chen Y, Ren Q, Fang X. Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: Optimization and in vitro, in vivo evaluation. Int J Nanomed. 2013;8:73–84.  https://doi.org/10.2147/IJN.S38221.
  23. 23.
    Jackson JK, Hung T, Letchford K, Burt HM. The characterization of paclitaxel-loaded microspheres manufactured from blends of poly(lactic-co-glycolic acid) (PLGA) and low molecular weight diblock copolymers. Int J Pharm. 2007;342:6–17.  https://doi.org/10.1016/j.ijpharm.2007.04.022.CrossRefGoogle Scholar
  24. 24.
    Bonacucina G, Cespi M, Mencarelli G, Giorgioni G, Palmieri GF. Thermosensitive self-assembling block copolymers as drug delivery systems. Polym (Basel). 2011;3:779–811.  https://doi.org/10.3390/polym3020779.
  25. 25.
    Batrakova EV, Kabanov AV. Pluronic block copolymers: Evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J Control Release. 2008;130:98–106.  https://doi.org/10.1016/j.jconrel.2008.04.013.CrossRefGoogle Scholar
  26. 26.
    Cambón A, Rey-Rico A, Barbosa S, Soltero JFA, Yeates SG, Brea J, et al. Poly(styrene oxide)-poly(ethylene oxide) block copolymers: From “classical” chemotherapeutic nanocarriers to active cell-response inducers. J Control Release. 2013;167:68–75.  https://doi.org/10.1016/j.jconrel.2013.01.010.
  27. 27.
    Gong J, Jaiswal R, Mathys J-M, Combes V, Grau GER, Bebawy M. Microparticles and their emerging role in cancer multidrug resistance. Cancer Treat Rev. 2012;38:226–34.  https://doi.org/10.1016/j.ctrv.2011.06.005.
  28. 28.
    Oliveira EG, De Caland LB, Oliveira AR, Machado PRL, Farias KJS, Da Costa TR, et al. Monitoring thermal, structural properties, methotrexate release and biological activity from biocompatible spray dried microparticles. J Therm Anal Calorim. 2017;130:1481–90.  https://doi.org/10.1007/s10973-017-6547-2.
  29. 29.
    Oliveira AR, Caland LB, Oliveira EG, Egito EST, Pedrosa, MFF, Silva-Júnior AA. HPLC-DAD and UV-vis spectrophotometric methods for methotrexate assay in different biodegradable Microparticles. J Braz Chem Soc. 2015;26:649–59.  https://doi.org/10.5935/0103-5053.20150022.
  30. 30.
    Segal L, Creely JJ Jr, Martin AE, Conrad CM. An empirical method for estimating the degree of crystallinity of native cellulose using the x-ray diffractometer. Text Res J. 1959;29:786–94.CrossRefGoogle Scholar
  31. 31.
    Chadha R, Arora P, Kaur R, Saini A, Singla ML, Jain DS. Characterization of solvatomorphs of methotrexate using thermoanalytical and other techniques. Acta Pharm. 2009;59:245–57.  https://doi.org/10.2478/v10007-009-0024-9.
  32. 32.
    Fu Y, Shyu S, Su F, Yu P. Development of biodegradable co-poly (D,L-lactic/glycolic acid) microspheres for the controlled release of 5-FU by the spray drying method. Colloids Surf B Biointerfaces. 2002;25:269–79.CrossRefGoogle Scholar
  33. 33.
    Gavini E, Manunta L, Giua S, Achenza G, Giunchedi P. Spray-dried poly(D,L-lactide) microspheres containing carboplatin for veterinary use: in vitro and in vivo studies. AAPS PharmSciTech. 2005;6:E108–14.  https://doi.org/10.1208/pt060117.
  34. 34.
    Silva-Júnior AA, Scarpa MV, Pestana KC, Mercuri LP, Matos JR, Oliveira AG. Thermal analysis of biodegradable microparticles containing ciprofloxacin hydrochloride obtained by spray drying technique. Thermochim Acta. 2008;467:91–98.  https://doi.org/10.1016/j.tca.2007.10.018.
  35. 35.
    Iskandar F, Gradon L, Okuyama K. Control of the morphology of nanostructured particles prepared by the spray drying of a nanoparticle sol. J Colloid Interface Sci. 2003;265:296–303.  https://doi.org/10.1016/S0021-9797(03)00519-8.CrossRefGoogle Scholar
  36. 36.
    Nandiyanto ABD, Okuyama K. Progress in developing spray-drying methods for the production of controlled morphology particles: From the nanometer to submicrometer size ranges. Adv Powder Technol. 2011;22:1–19.  https://doi.org/10.1016/j.apt.2010.09.011.CrossRefGoogle Scholar
  37. 37.
    Saini P, Arora M, Kumar MNVR. Poly (lactic acid) blends in biomedical applications. Adv Drug Deliv Rev. 2016;107:47–59.  https://doi.org/10.1016/j.addr.2016.06.014.CrossRefGoogle Scholar
  38. 38.
    Blasi P, D’Souza SS, Selmin F, DeLuca PP. Plasticizing effect of water on poly(lactide-co-glycolide). J Control Release. 2005;108:1–9.  https://doi.org/10.1016/j.jconrel.2005.07.009.CrossRefGoogle Scholar
  39. 39.
    Park TG, Cohen S, Langer R. Poly(L-lactic acid)/Pluronic blends: characterization of phase separation behavior, degradation, and morphology and use as protein-releasing matrixes. Macromolecules. 1992;25:116–22.  https://doi.org/10.1021/ma00027a019.CrossRefGoogle Scholar
  40. 40.
    Can E, Udenir G, Kanneci AI, Kose G, Bucak S. Investigation of PLLA/PCL blends and paclitaxel release profiles. AAPS PharmSciTech. 2011;12:1442–53.  https://doi.org/10.1208/s12249-011-9714-y.
  41. 41.
    Kiss E, Bertóti I, Vargha-Butler EI. XPS and wettability characterization of modified poly(lactic acid) and poly(lactic/glycolic acid) films. J Colloid Interface Sci. 2002;245:91–8.  https://doi.org/10.1006/jcis.2001.7954.CrossRefGoogle Scholar
  42. 42.
    Chen Y, Zhang W, Gu J, Ren Q, Fan Z, Zhong W. Enhanced antitumor efficacy by methotrexate conjugated Pluronic mixed micelles against KBv multidrug resistant cancer. Int J Pharm. 2013;452:421–33.  https://doi.org/10.1016/j.ijpharm.2013.05.015.
  43. 43.
    Lim JS, Park KIl, Chung GS, Kim JH. Effect of composition ratio on the thermal and physical properties of semicrystalline PLA/PHB-HHx composites. Mater Sci Eng C. 2013;33:2131–7.  https://doi.org/10.1016/j.msec.2013.01.030.CrossRefGoogle Scholar
  44. 44.
    Pillin I, Montrelay N, Grohens Y. Thermo-mechanical characterization of plasticized PLA: is the miscibility the only significant factor? Polym (Guildf). 2006;47:4676–82.  https://doi.org/10.1016/j.polymer.2006.04.013.CrossRefGoogle Scholar
  45. 45.
    Loh CH, Wang R, Shi L, Fane AG. Fabrication of high performance polyethersulfone UF hollow fiber membranes using amphiphilic Pluronic block copolymers as pore-forming additives. J Memb Sci. 2011;380:114–23.  https://doi.org/10.1016/j.memsci.2011.06.041.CrossRefGoogle Scholar
  46. 46.
    Xiong XY, Li YP, Li ZL, Zhou CH, Tam KC, Liu ZH, et al. Vesicles from Pluronic/poly(lactic acid) block copolymers as new carriers for oral insulin delivery. J Control Release. 2007;120:11–17.  https://doi.org/10.1016/j.jconrel.2007.04.004.
  47. 47.
    Yan F, Zhang C, Zheng Y, Mei L, Tang L, Song C, et al. The effect of poloxamer 188 on nanoparticle morphology, size, cancer cell uptake, and cytotoxicity. Nanomedicine Nanotechnology, Biol Med. 2010;6:170–8.  https://doi.org/10.1016/j.nano.2009.05.004.
  48. 48.
    de Oliveira AR, Mesquita PC, Machado PRL, Farias KJS, Almeida YMB, Fernandes-Pedrosa MF, et al. Monitoring structural features, biocompatibility and biological efficacy of gamma-irradiated methotrexate-loaded spray-dried microparticles. Mater Sci Eng C. 2017;80:438–48.  https://doi.org/10.1016/j.msec.2017.06.013.
  49. 49.
    Zhang Y, Lam YM. Study of mixed micelles and interaction parameters for polymeric nonionic and normal surfactants. J Nanosci Nanotechnol. 2006;6:1–5.  https://doi.org/10.1166/jnn.2006.673.CrossRefGoogle Scholar
  50. 50.
    Hu M, Chen M, Li G, Pang Y, Wang D, Wu J, et al. Biodegradable hyperbranched polyglycerol with ester linkages for drug delivery. Biomacromolecules. 2012;13:3552–61.  https://doi.org/10.1021/bm300966d.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Edilene Gadelha de Oliveira
    • 1
  • Paula Renata Lima Machado
    • 2
  • Kleber Juvenal Silva Farias
    • 2
  • Tiago R. da Costa
    • 3
  • Dulce Maria Araújo Melo
    • 3
  • Ariane Ferreira Lacerda
    • 1
  • Matheus de Freitas Fernandes-Pedrosa
    • 1
  • Alianda Maira Cornélio
    • 4
  • Arnóbio Antônio da Silva-Junior
    • 1
    Email author
  1. 1.Laboratory of Pharmaceutical Technology and Biotechnology, Department of PharmacyFederal University of Rio Grande do Norte, UFRN, Gal. Gustavo Cordeiro de FariasNatalBrazil
  2. 2.Department of Clinical AnalysisFederal University of Rio Grande do Norte, UFRN, Av. Gal. Gustavo Cordeiro de Farias s/n, PetropolisNatalBrazil
  3. 3.Institute of ChemistryFederal University of Rio Grande do Norte, UFRNNatalBrazil
  4. 4.Department of MorphologyFederal University of Rio Grande do Norte, UFRNNatalBrazil

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