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Layer by layer surface engineering of poly (lactide-co-glycolide) nanoparticles: A versatile tool for nanoparticle engineering for targeted drug delivery


Recent work regarding the Layer by Layer (LbL) engineering of poly(lactide-co-glycolide) nanoparticles (PLGA NPs) is reviewed here. The LbL engineering of PLGA NPs is applied as a means of generating advanced drug delivery devices with tailored recognition, protection, cargo and release properties. LbL in combination with covalent chemistry is used to attach PEG and folic acid to control cell uptake and direct it towards cancer cells. LbL coatings composed of chitosan and alginate show low protein interactions and can be used as an alternative to Pegylation. The assembly on top of LbL coatings of lipid layers composed of variable percentages of 1,2-dioleoyl-sn-glycero-3-choline (DOPC) and 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS) increases NP uptake and directs the NPs towards the endoplasmic reticulum. The antibody anti-TNF-α is encapsulated forming a complex with alginate that is assembled LbL on top of PLGA NPs. The antibody is released in cell culture following first order kinetics. The release kinetics of encapsulated molecules inside PLGA NPs are studied when the PLGA NPs are coated via LbL with different polyelectrolytes. The intracellular release of encapsulated Doxorubicin is studied in the HepG2 cell line by means of Fluorescence Lifetime Imaging.

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  1. 1

    Hans ML, Lowman AM. Biodegradable nanoparticles for drug delivery and targeting. Curr Opin Solid State Mater Sci, 2002, 6: 319–327

    Article  CAS  Google Scholar 

  2. 2

    Langer R. New methods of drug delivery. Science, 1990, 249: 1527–1533

    Article  CAS  Google Scholar 

  3. 3

    Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev, 1999, 99: 3181–3198

    Article  CAS  Google Scholar 

  4. 4

    Ishihara T, Mizushima T. Techniques for efficient entrapment of pharmaceuticals in biodegradable solid micro/nanoparticles. Exp Opin Drug Deliv, 2010, 7: 565–575

    Article  CAS  Google Scholar 

  5. 5

    Patil YB, Swaminathan SK, Sadhukha T, Ma L, Panyam J. The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials, 2010, 31: 358–365

    Article  CAS  Google Scholar 

  6. 6

    Yuan XD, Rathinavelu A, Hao JS, Narasimhan M, He M, Heitlage V, Tam L, Viqar S, Salehi M, Li L. siRNA drug delivery by biodegradable polymeric nanoparticles. J Nanosci Nanotech, 2006, 6: 2821–2828

    Article  CAS  Google Scholar 

  7. 7

    Hirsjärvi S, Peltonen L, Hirvonen J. Layer-by-layer polyelectrolyte coating of low molecular weight poly(lactic acid) nanoparticles. Colloids Surf B, 2006, 49: 93–99

    Article  Google Scholar 

  8. 8

    Yang Y, Yueh-Hen Hsu P. The effect of poly(d,l-lactide-co-glycolide) microparticles with polyelectrolyte self-assembled multilayer surfaces on the cross-presentation of exogenous antigens. Biomaterials, 2008, 29: 2516–2526

    Article  CAS  Google Scholar 

  9. 9

    Yu D, Zhang Y, Zhou X, Mao Z, Gao C. Influence of surface coating of PLGA particles on the internalization and functions of human endothelial cells. Biomacromolcules, 2012, 13: 3272–3282

    Article  CAS  Google Scholar 

  10. 10

    Cohen H, Gao J, Fishbein I, Kousaev V, Sosnowski S, Slomkowski S, Golomb G. Levy RJ. Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Therapy, 2000, 7: 1896–1905

    Article  CAS  Google Scholar 

  11. 11

    Allémann E, Leroux JC, Gurny R, Doelker E. In vitro extended-release properties of drug-loaded poly(dl-lactic acid) nanoparticles produced by a salting-out procedure. Pharm Res, 1993, 10: 1732–1737

    Article  Google Scholar 

  12. 12

    Zambaux MF, Bonneaux F, Gref R, Maincent P, Dellacherie E, Alonso MJ, Labrude P, Vigneron C. Influence of experimental parameters on the characteristics of poly(lactic acid) nanoparticles prepared by a double emulsion method. J Controlled Release, 1998, 50: 31–40

    Article  CAS  Google Scholar 

  13. 13

    Crotts G, Sah H, Park TG. Adsorption determines in-vitro protein release rate from biodegradable microspheres: Quantitative analysis of surface area during degradation. J Controlled Release, 1997, 47: 101–111

    Article  CAS  Google Scholar 

  14. 14

    Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev, 2003, 55: 329–347

    Article  CAS  Google Scholar 

  15. 15

    Scholes PD, Coombes AGA, Illum L, Davis SS, Vert M, Davies MC. The preparation of sub-200 nm poly(lactide-co-glycolide) microspheres for site-specific drug delivery. J Controlled Release, 1993, 25: 145–153

    Article  CAS  Google Scholar 

  16. 16

    Weiss B, Schneider M, Muys L, Taetz S, Neumann D, Schaefer UF, Lehr CM. Coupling of biotin-(poly(ethylene glycol))amine to poly(d,l-lactide-co-glycolide) nanoparticles for versatile surface modification. Bioconjugate Chem, 2007, 18: 1087–1094

    Article  CAS  Google Scholar 

  17. 17

    Mundargi RC, Babu VR, Rangaswamy V, Patel P, Aminabhavi TM. Nano/micro technologies for delivering macromolecular Ttherapeutics using poly(d,l-lactide-co-glycolide) and its derivatives. J Controlled Release, 2008, 125: 193–209

    Article  CAS  Google Scholar 

  18. 18

    Bala I, Hariharan S, Kumar MNVR. PLGA nanoparticles in drug delivery: The state of the art. Crit Rev Ther Drug, 2004, 21: 387–422

    Article  CAS  Google Scholar 

  19. 19

    Yang YY, Chia HH, Chung TS. Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method. J Controlled Release, 2000, 69: 81–96

    Article  CAS  Google Scholar 

  20. 20

    Hornig S, Heinze T, Becer CR, Schubert US. Synthetic polymeric nanoparticles by nanoprecipitation. J Mater Chem, 2009, 19: 3838–3840

    Article  CAS  Google Scholar 

  21. 21

    Bilati U, Allémann E, Doelker E. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci, 2005, 24: 67–75

    Article  CAS  Google Scholar 

  22. 22

    Jensen DMK, Cun D, Maltesen MJ, Frokjaer S, Nielsen HM, Foged C. Spray drying of siRNA-containing PLGA nanoparticles intended for inhalation. J Controlled Release, 2010, 142: 138–145

    Article  Google Scholar 

  23. 23

    Fessi H, Piusieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm, 1989, 55: R1–R4

    Article  CAS  Google Scholar 

  24. 24

    O’Donnell PB, McGinity JW. Preparation of microspheres by the solvent evaporation technique. Adv Drug Deliv Rev, 1997, 28: 25–42

    Article  Google Scholar 

  25. 25

    Zambaux MF, Bonneaux F, Gref R, Dellacherie E, Vigneron C. Preparation and characterization of protein c-loaded PLA nanoparticles. J Controlled Release, 1999, 60: 179–188

    Article  CAS  Google Scholar 

  26. 26

    Doiron AL, Homan KA, Emelianov S, Brannon-Peppas L. Poly(lactic-co-glycolic) acid as a carrier for imaging contrast agents. Pharm Res, 2009, 26: 674–682

    Article  CAS  Google Scholar 

  27. 27

    Decher G, Hong JD, Schmitt J. Buildup of ultrathin multilayer films by a self-assembly process: III. Consecutively alternating adsorption of anionic and cationic polyelectrolytes on charged surfaces. Thin Solid Films, 1992, 210–211: 831–835

    Article  Google Scholar 

  28. 28

    Decher G. Fuzzy nanoassemblies: toward layered polymeric multicomposites. Science, 1997, 277: 1232–1237

    Article  CAS  Google Scholar 

  29. 29

    Sukhorukov GB, Donath E, Lichtenfeld H, Knippel E, Knippel M, Budde A Möhwald H. Layer-by-layer self assembly of polyelectrolytes on colloidal particles. Colloid Surf A-Physicochem Eng Asp, 1998, 137: 253–266

    Article  Google Scholar 

  30. 30

    Dubas ST, Schlenoff JB. Factors controlling the growth of polyelectrolyte multilayers. Macromolecules, 1999, 32: 8153–8160

    Article  CAS  Google Scholar 

  31. 31

    Donath E, Sukhorukov GB, Caruso F, Davis SA, Möhwald H. Novel hollow polymer shells by colloid-templated assembly of polyelectrolytes. Angew Chem Int Edi, 1998, 37: 2202–2205

    CAS  Google Scholar 

  32. 32

    Donath E, Moya S, Neu B, Sukhorukov GB, Georgieva R, Voigt A, Baumler H, Kiesewetter H, Mohwald H. Hollow polymer shells from biological templates: fabrication and potential applications. Chem-A Euro J, 2002, 8: 5481–5485

    Article  CAS  Google Scholar 

  33. 33

    Wang B, Zhang Y, Mao Z, Gao C. Cellular uptake of covalent poly(allylamine hydrochloride) microcapsules and its influences on cell functions. Macromol biosci, 2012, 12: 1534–45

    Article  CAS  Google Scholar 

  34. 34

    Kiryukhin MV, Gorelik SR, Man SM, Subramanian GS, Antipina MN, Low HY, Sukhorukov GB. Individually addressable patterned multilayer microchambers for site-specific release-on-demand. Macromol rapid commun, 2013, 34: 87–93

    Article  CAS  Google Scholar 

  35. 35

    Zhou J, Romero G, Rojas E, Moya S, Ma L, Gao C. Folic acid modified poly(lactide-co-glycolide) nanoparticles, layer-by-layer surface engineered for targeted delivery. Macromol Chem Phys, 2010, 211: 404–411

    Article  CAS  Google Scholar 

  36. 36

    Zhou J, Ma L, Gao C, Shen J, Moya S. Polyelectrolyte coated PLGA nanoparticles: templation and release behavior. Macromol Biosci, 2009, 9: 326–335

    Article  CAS  Google Scholar 

  37. 37

    Zhou J, Romero G, Rojas E, Ma L, Moya S, Gao C. Layer by layer chitosan/alginate coatings on poly(lactide-co-glycolide) nanoparticles for antifouling protection and folic acid binding to achieve selective cell targeting. J colloid interf sci, 2010, 345: 241–247

    Article  CAS  Google Scholar 

  38. 38

    Romero G, Sanz DJ, Qiu Y, Yu D Mao Z, Gao C, Moya S. E. Lipid layer engineering of poly(lactide-co-glycolide) nanoparticles to control their uptake and intracellular co-localisation. J Mater Chem B, 2013, 1: 2252–2259

    Article  CAS  Google Scholar 

  39. 39

    Moya S, Donath E, Sukhorukov GB, Auch M, Baumler H, Lichtenfeld H, Mohwald H. Lipid coating on polyelectrolyte surface modified colloidal particles and polyelectrolyte capsules. Macromolecules, 2000, 33: 4538–4544

    Article  CAS  Google Scholar 

  40. 40

    Fischlechner M, Zaulig M, Meyer S, Estrela-Lopis I, Cuéllar L, Irigoyen J, Pescador P, Brumen M, Messner P, Moya S. Lipid layers on polyelectrolyte multilayer supports. Soft Matter, 2008, 4: 2245–2258

    Article  CAS  Google Scholar 

  41. 41

    Romero G, Zhou J, Rojas E, Franco A, Sanchez Espinal C, González Fernández A, Gao C, Donath E, Moya S, Estrela-Lopis I. Surface engineered poly(lactide-co-glycolide) nanoparticles for intracellular delivery: Uptake and cytotoxicity-A confocal raman microscopic study. Biomacromolecules, 2010, 11: 2993–2999

    Article  CAS  Google Scholar 

  42. 42

    Kempeni J. Preliminary results of early clinical trials with the fully human anti-TNF monoclonal antibody. Ann Rheum Dis, 1999, 58(suppl I): 70–73

    Article  Google Scholar 

  43. 43

    Zhou J, Moya S, Ma L, Gao C, Shen J. Polyelectrolyte coated PLGA nanoparticles: templation and release behavior. Macromol biosci, 2009, 9: 326–35

    Article  CAS  Google Scholar 

  44. 44

    Siepmann J, Faisant N, Akiki J, Richard J, Benoit JP. Effect of the size of biodegradable microparticles on drug release: Experiment and theory. J Controlled Release, 2004, 96: 123–134

    Article  CAS  Google Scholar 

  45. 45

    Aso Y, Yoshioka S, Li Wan Po A, Terao T. Effect of temperature on mechanisms of drug release and matrix degradation of poly (d,l-lactide) microspheres. J Controlled Release, 1994, 31: 33–39

    Article  CAS  Google Scholar 

  46. 46

    Dai X, Yue Z, Eccleston ME, Swartling J, Slater NKH, Kaminski CF. Fluorescence intensity and lifetime imaging of free and micellar-encapsulated doxorubicin in living cells. Nanomed nanotech bio med, 2008, 4: 49–56

    Article  CAS  Google Scholar 

  47. 47

    Romero G, Qiu Y, Murray RA, Moya S. Study of intracellular delivery of doxorubicin from poly(lactide-co-glycolide) nanoparticles by means of fluorescence lifetime imaging and confocal raman microscopy. Macromol biosci, 2013, 13: 234–241

    Article  CAS  Google Scholar 

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Corresponding author

Correspondence to Sergio E. Moya.

Additional information

Recommended by Prof. GAO Changyou (Zhejiang University)

MOYA Sergio E. (left) studied chemistry at the National University of the South, Argentina and received his Ph.D. in Physical Chemistry from the University of Potsdam, Germany, working at the Max Planck Institute of Colloids and Interfaces. After post doctoral stages at the College de France, Paris, and at the University of Cambridge, UK, he worked for a year and a half at CIQA, Mexico as an independent researcher. After that he joined the Cooperative Centre of Biomaterials in San Sebastian, Spain, as a research group leader. He is also a visiting professor at Zhejiang University, China. His research interests focus on physical chemistry at the nanoscale, soft matter nanotechnology, polyelectrolytes, nanomedicine and nanotoxicology. He is the author of around 75 articles in material science, chemistry, and polymer science.

ROMERO Gabriela (right) received her B.S. in Chemical Engineering from the Autonomous University of San Luis Potosí, Mexico, in 2007. She joined the group of Dr. MOYA at CIC biomaGUNE in 2008 and under her supervision she received a Masters degree in Advanced Materials Engineering from the University of the Basque Country, Spain, in 2009. In the same group she carried out her doctorate studies and she received her Ph.D. degree in Applied Chemistry and Polymer Science from the University of the Basque Country, Spain, in 2012. In October 2012 she joined the group of Dr. Brad Berron as a postdoctoral research associate from the University of Colorado and the University of Kentucky in the USA.

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Romero, G., Murray, R.A., Qiu, Y. et al. Layer by layer surface engineering of poly (lactide-co-glycolide) nanoparticles: A versatile tool for nanoparticle engineering for targeted drug delivery. Sci. China Chem. 56, 1029–1039 (2013).

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  • layer by layer
  • PLGA NPs
  • cell uptake
  • antibody delivery
  • lipid layers
  • intracellular release