Nanomedicine: Size-Related Drug Delivery Applications, Including Periodontics and Endodontics

  • Xu Wen Ng
  • Raghavendra C. Mundargi
  • Subbu S. VenkatramanEmail author


In this chapter, we discuss polymer- and liposome-based nanocarriers used in the delivery of bioactive molecules, from drugs to proteins. The focus is on the enhancements in efficacy of bioactive molecules when nanotechnology is used for delivering them. The perspective centres around commercial and clinical successes and a rationalization of these successes. Microparticulate systems are also discussed in relation to their nano-counterparts, and the advantages of nano size are emphasized in relevant applications. In general, the main application of nanocarriers is in cancer therapy; however, with the ability to programme sustained release of bioactive molecules from certain types of nanoparticles, other applications in ocular, cardiovascular and periodontic/endodontic therapy may be possible.


Nanotherapeutics Liposomes Nanoparticles Sustained release Local delivery Periodontic and endodontic 



Critical micellar concentration


Deoxyribonucleic acid










Extracellular polymeric matrix


Enhanced Permeation and Retention


Food and Drug Administration


Gingival index


Harungana madagascariensis Lam. Ex Poir.


Intraocular pressure








Poly (caprolactone)


Probing depth


Photodynamic therapy


Poly(ethylene glycol)




(Poly l-lactide)


(Poly (d,l-lactic acid and Glycolic acid copolymer)




(Poly vinyl Alcohol)


Poly(vinyl pyrrolidone)


Reticulo-endothelial system


Retinal pigmented epithelium

S. oralis

Streptococcus oralis

S. sanguis

Streptococuss sanguis




Spontaneous emulsification solvent diffusion






Transmission electron microscopy


Glass transition temperatures


Melting points




Tissue-specific antigen


Uni lamellar vesicle



We acknowledge support from the School of Materials Science and Engineering, Nanyang Technological University for part of this work.


  1. 1.
    Rapamune®, an immunosuppressant, approved in 1999; Emend®, an anti-emetic, approved in 2003.Google Scholar
  2. 2.
    Abraxane®, albumin-bound paclitaxel, approved 2005; IT-101, a camptothecin bound cyclodextrin polymer, in clinical trials currently.Google Scholar
  3. 3.
    Ambisome®, approved in 1997, for fungal infections; Diprivan®, an anaesthetic approved in 1989; and Doxil® approved in 1995 for ovarian cancer.Google Scholar
  4. 4.
    Wagner V, et al. The emerging nanomedicine landscape. Nat Biotech. 2006;24(10):1211–7.CrossRefGoogle Scholar
  5. 5.
    Etheridge ML, et al. The big picture on nanomedicine: the state of investigational and approved nanomedicine products. Nanomedicine: Nanotechnol Biology Med. 2013;9(1):1–14.CrossRefGoogle Scholar
  6. 6.
    Venkatraman SS, et al. Polymer- and liposome-based nanoparticles in targeted drug delivery. Front Biosci (Schol Ed). 2010;2:801–14.CrossRefGoogle Scholar
  7. 7.
    Cegnar M, Kos J, Kristl J. Cystatin incorporated in poly(lactide-co-glycolide) nanoparticles: development and fundamental studies on preservation of its activity. Eur J Pharm Sci. 2004;22(5):357–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Quintanar-Guerrero D, et al. Preparation and characterization of nanocapsules from preformed polymers by a new process based on emulsification-diffusion technique. Pharm Res. 1998;15(7):1056–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Olson F, et al. Preparation of liposomes of defined size distribution by extrusion through polycarbonate membranes. Biochim Biophys Acta Biomembr. 1979;​557(1):9–23.CrossRefGoogle Scholar
  10. 10.
    Mayer LD, Bally MB, Cullis PR. Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient. Biochim Biophys Acta Biomembr. 1986;​857(1):​123–6.CrossRefGoogle Scholar
  11. 11.
    Clerc S, Barenholz Y. Loading of amphipathic weak acids into liposomes in response to transmembrane calcium acetate gradients. Biochim Biophys Acta Biomembr. 1995;1240(2):257–65.CrossRefGoogle Scholar
  12. 12.
    Haran G, et al. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta Biomembr. 1993;1151(2):201–15.CrossRefGoogle Scholar
  13. 13.
    Patri AK, Majoros IJ, Baker Jr JR. Dendritic polymer macromolecular carriers for drug delivery. Curr Opin Chem Biol. 2002;6(4):466–71.CrossRefPubMedGoogle Scholar
  14. 14.
    Barenholz Y. Doxil® — the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;​160(2):117–34.CrossRefPubMedGoogle Scholar
  15. 15.
    Vaage J, et al. Therapy of human ovarian carcinoma xenografts using doxorubicin encapsulated in sterically stabilized liposomes. Cancer. 1993;72(12):​3671–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Papahadjopoulos D, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci. 1991;​88(24):​11460–4.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Myocet. Wikipedia; 2014. [cited 2014 Jan 30].
  18. 18.
    Ramesh R, et al. Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector. Mol Ther. 2001;3(3):337–50.CrossRefPubMedGoogle Scholar
  19. 19.
    10Q Detective. Introgen therapeutics: empty promises for cancer patients and shareholders. Seeking alpha April 2007. [cited 2014 Jan 30].
  20. 20.
    Xu L, et al. Fragment-targeted immunoliposomes for systemic gene delivery, U.S. Patent, Editor; 2009.Google Scholar
  21. 21.
    Venkatraman SS, et al. Micelle-like nanoparticles of PLA–PEG–PLA triblock copolymer as chemotherapeutic carrier. Int J Pharm. 2005;298(1):219–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Jie P, et al. Micelle-like nanoparticles of star-branched PEO–PLA copolymers as chemotherapeutic carrier. J Control Release. 2005;110(1):20–33.CrossRefPubMedGoogle Scholar
  23. 23.
    Critical micelle concentration. Wikipedia; 2014. [cited 2014 30 January].
  24. 24.
    Hamaguchi T, et al. NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel. Br J Cancer. 2005;92(7):1240–6.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med. 1995;332(15):1004–14.CrossRefPubMedGoogle Scholar
  26. 26.
    Hamaguchi T, et al. A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation. Br J Cancer. 2007;97(2):​170–6.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    A phase III study of NK105 in patients with breast cancer.; 2012 [cited 2014 Jan 30].
  28. 28.
    Kataoka K, et al. Polymeric micelle containing cisplatin enclosed therein and use thereof. 2003; US 2003/0170201 A1.Google Scholar
  29. 29.
    Pinzani V, et al. Cisplatin-induced renal toxicity and toxicity-modulating strategies: a review. Cancer Chemother Pharmacol. 1994;35(1):1–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Nishiyama N, et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res. 2003;63(24):8977–83.PubMedGoogle Scholar
  31. 31.
    NC-6004 Nanoplatin™. NanoCarrier; 2013. [cited 2014 Jan 30].
  32. 32.
    Nakanishi T, et al. Development of the polymer micelle carrier system for doxorubicin. J Control Release. 2001;74(1–3):295–302.CrossRefPubMedGoogle Scholar
  33. 33.
    Matsumura Y, et al. Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. Br J Cancer. 2004;91(10):1775–81.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Tsukioka Y, et al. Pharmaceutical and biomedical differences between micellar doxorubicin (NK911) and liposomal doxorubicin (Doxil). Jpn J Cancer Res. 2002;93(10):1145–53.CrossRefPubMedGoogle Scholar
  35. 35.
    Torchilin VP. Micellar nanocarriers: pharmaceutical perspectives. Pharm Res. 2007;24(1):1–16.CrossRefPubMedGoogle Scholar
  36. 36.
    Allen C, et al. Polycaprolactone-b-poly(ethylene Oxide) block copolymer micelles as a novel drug delivery vehicle for neurotrophic agents FK506 and L-685,818. Bioconjug Chem. 1998;9(5):564–72.CrossRefPubMedGoogle Scholar
  37. 37.
    Kim SY, et al. Methoxy poly(ethylene glycol) and ϵ-caprolactone amphiphilic block copolymeric micelle containing indomethacin: II. Micelle formation and drug release behaviours. J Control Release. 1998;51(1):13–22.CrossRefPubMedGoogle Scholar
  38. 38.
    Gref R, et al. ‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B Biointerfaces. 2000;18(3–4):301–13.CrossRefPubMedGoogle Scholar
  39. 39.
    Ma LL, Jie P, Venkatraman SS. Block copolymer ‘stealth’ nanoparticles for chemotherapy: interactions with blood cells in vitro. Adv Funct Mater. 2008;​18(5):716–25.CrossRefGoogle Scholar
  40. 40.
    Xu P, et al. Highly stable core-surface-crosslinked nanoparticles as cisplatin carriers for cancer chemotherapy. Colloids Surf B Biointerfaces. 2006;48(1):​50–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Murakami H, et al. Preparation of poly(dl-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method. Int J Pharm. 1999;187(2):143–52.CrossRefPubMedGoogle Scholar
  42. 42.
    Beletsi A, et al. Simultaneous optimization of cisplatin-loaded PLGA-mPEG nanoparticles with regard to their size and drug encapsulation. Curr Nanosci. 2008;4(2):173–8.CrossRefGoogle Scholar
  43. 43.
    Desai MP, et al. Immune response with biodegradable nanospheres and alum: studies in rabbits using staphylococcal enterotoxin B-toxoid. J Microencapsul. 2000;17(2):215–25.CrossRefPubMedGoogle Scholar
  44. 44.
    Cohen H, et al. Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Ther. 2000;7(22):1896–905.CrossRefPubMedGoogle Scholar
  45. 45.
    Dunn SE, et al. In vitro cell interaction and in vivo biodistribution of poly(lactide-co-glycolide) nanospheres surface modified by poloxamer and poloxamine copolymers. J Control Release. 1997;44(1):​65–76.CrossRefGoogle Scholar
  46. 46.
    De Jaeghere F, et al. Formulation and lyoprotection of poly(lactic acid-co-ethylene oxide) nanoparticles: influence on physical stability and in vitro cell uptake. Pharm Res. 1999;16(6):859–66.CrossRefPubMedGoogle Scholar
  47. 47.
    Gref R, et al. Biodegradable long-circulating polymeric nanospheres. Science. 1994;263(5153):​1600–3.CrossRefPubMedGoogle Scholar
  48. 48.
    Peracchia MT, et al. Complement consumption by poly(ethylene glycol) in different conformations chemically coupled to poly(isobutyl 2-cyanoacrylate) nanoparticles. Life Sci. 1997;61(7):749–61.CrossRefPubMedGoogle Scholar
  49. 49.
    Liang C, et al. Improved therapeutic effect of folate-decorated PLGA-PEG nanoparticles for endometrial carcinoma. Bioorg Med Chem. 2011;19(13):​4057–66.CrossRefPubMedGoogle Scholar
  50. 50.
    Lasic DD. On the thermodynamic stability of liposomes. J Colloid Interface Sci. 1990;140(1):302–4.CrossRefGoogle Scholar
  51. 51.
    QLT shows positive efficacy trends from data in plug combinations in phase II studies for glaucoma using latanoprost punctual plug delivery system. QLT, Inc. [cited 2014 Jan 30].
  52. 52.
    Michael Möller. In vitro and in vivo studies of polymeric micelles for ophthalmic applications. Universite de Geneve. [cited 2014 Jan 30].
  53. 53.
    Natarajan JV, et al. Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye. Int J Nanomedicine. 2012;7:123–31.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Natarajan JV, et al. Sustained drug release in nanomedicine: a long-acting nanocarrier-based formulation for glaucoma. ACS Nano. 2014;8(1):419–29.CrossRefPubMedGoogle Scholar
  55. 55.
    Bourges JL, et al. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci. 2003;​44(8):3562–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Bochot A, Fattal E. Liposomes for intravitreal drug delivery: a state of the art. J Control Release. 2012;​161(2):628–34.CrossRefPubMedGoogle Scholar
  57. 57.
    Petersen PE, et al. The global burden of oral diseases and risks to oral health. Bull World Health Organ. 2005;83(9):661–9.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Difference Between Periodontist & Endodontist. Intelligent Dental. [cited 2014 Jan 30].
  59. 59.
    del Pozo JL, Patel R. The challenge of treating biofilm-associated bacterial infections. Clin Pharmacol Ther. 2007;82(2):204–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Álvarez AL, Espinar FO, Méndez JB. The application of microencapsulation techniques in the treatment of endodontic and periodontal diseases. Pharmaceutics. 2011;3(3):538–71.CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Mundargi RC, et al. Nano/micro technologies for delivering macromolecular therapeutics using poly(D, L-lactide-co-glycolide) and its derivatives. J Control Release. 2008;125(3):193–209.CrossRefPubMedGoogle Scholar
  62. 62.
    Srirangarajan S, et al. Randomized, controlled, single-masked, clinical study to compare and evaluate the efficacy of microspheres and gel in periodontal pocket therapy. J Periodontol. 2011;82(1):114–21.CrossRefPubMedGoogle Scholar
  63. 63.
    Patel P, et al. Microencapsulation of doxycycline into poly(lactide-co-glycolide) by spray drying technique: Effect of polymer molecular weight on process parameters. J Appl Polym Sci. 2008;108(6):4038–46.CrossRefGoogle Scholar
  64. 64.
    Strom TA, et al. Endodontic release system for apexification with calcium hydroxide microspheres. J Dent Res. 2012;91(11):1055–9.CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Socialstyrelsen, Editor. Release of nanoparticles from dental materials. Ministry of Health and Social Affair (Sweden): Stockholm; 2013. p. 14–5.Google Scholar
  66. 66.
    Chogle SM, et al. Preliminary evaluation of a novel polymer nanocomposite as a root-end filling material. Int Endod J. 2011;44(11):1055–60.CrossRefPubMedGoogle Scholar
  67. 67.
    Kong M, et al. Antimicrobial properties of chitosan and mode of action: a state of the art review. Int J Food Microbiol. 2010;144(1):51–63.CrossRefPubMedGoogle Scholar
  68. 68.
    Dung TH, et al. Chitosan-TPP nanoparticle as a release system of antisense oligonucleotide in the oral environment. J Nanosci Nanotechnol. 2007;7(11):​3695–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Moulari B, et al. Potentiation of the bactericidal activity of Harungana madagascariensis Lam. ex Poir. (Hypericaceae) leaf extract against oral bacteria using poly (D, L-lactide-co-glycolide) nanoparticles: in vitro study. Acta Odontol Scand. 2006;64(3):​153–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Pinon-Segundo E, et al. Preparation and characterization of triclosan nanoparticles for periodontal treatment. Int J Pharm. 2005;294(1–2):217–32.CrossRefPubMedGoogle Scholar
  71. 71.
    Wilson M. Lethal photosensitisation of oral bacteria and its potential application in the photodynamic therapy of oral infections. Photochem Photobiol Sci. 2004;3(5):412–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Patel NB. Targeted methylene blue-containing polymeric nanoparticle formulations for oral antimicrobial photodynamic therapy. In: Bouvé College of Health Sciences. Department of Pharmaceutical Sciences. Northeastern University; 2009. p. 11.Google Scholar
  73. 73.
    Wilson M, Burns T, Pratten J. Killing of Streptococcus sanguis in biofilms using a light-activated antimicrobial agent. J Antimicrob Chemother. 1996;37(2):​377–81.CrossRefPubMedGoogle Scholar
  74. 74.
    Dunne Jr WM, Mason Jr EO, Kaplan SL. Diffusion of rifampin and vancomycin through a Staphylococcus epidermidis biofilm. Antimicrob Agents Chemother. 1993;37(12):2522–6.CrossRefPubMedCentralPubMedGoogle Scholar
  75. 75.
    Jung B-O, et al. Preparation of amphiphilic chitosan and their antimicrobial activities. J Appl Polym Sci. 1999;72(13):1713–9.CrossRefGoogle Scholar
  76. 76.
    Rabea EI, et al. Chitosan as antimicrobial agent: applications and mode of action. Biomacromolecules. 2003;4(6):1457–65.CrossRefPubMedGoogle Scholar
  77. 77.
    Lovric J, et al. Unmodified cadmium telluride quantum dots induce reactive oxygen species formation leading to multiple organelle damage and cell death. Chem Biol. 2005;12(11):1227–34.CrossRefPubMedGoogle Scholar
  78. 78.
    Shrestha A, et al. Nanoparticulates for antibiofilm treatment and effect of aging on its antibacterial activity. J Endod. 2010;36(6):1030–5.CrossRefPubMedGoogle Scholar
  79. 79.
    Jones MN, Kaszuba M. Polyhydroxy-mediated interactions between liposomes and bacterial biofilms. Biochim Biophys Acta. 1994;1193(1):48–54.CrossRefPubMedGoogle Scholar
  80. 80.
    Jones MN, et al. The interaction of phospholipid liposomes with bacteria and their use in the delivery of bactericides. J Drug Target. 1997;5(1):25–34.CrossRefPubMedGoogle Scholar
  81. 81.
    Paster BJ, et al. The breadth of bacterial diversity in the human periodontal pocket and other oral sites. Periodontol. 2000;2006(42):80–7.Google Scholar
  82. 82.
    Narayanan LL, Vaishnavi C. Endodontic microbiology. J Conserv Dent. 2010;13(4):233–9.CrossRefPubMedCentralPubMedGoogle Scholar
  83. 83.
    Costerton JW, et al. Bacterial biofilms in nature and disease. Annu Rev Microbiol. 1987;41:435–64.CrossRefPubMedGoogle Scholar
  84. 84.
    George S, Kishen A, Song KP. The role of environmental changes on monospecies biofilm formation on root canal wall by Enterococcus faecalis. J Endod. 2005;31(12):867–72.CrossRefPubMedGoogle Scholar
  85. 85.
    Distel JW, Hatton JF, Gillespie MJ. Biofilm formation in medicated root canals. J Endod. 2002;28(10):​689–93.CrossRefPubMedGoogle Scholar
  86. 86.
    Robinson AM, Creeth JE, Jones MN. The specificity and affinity of immunoliposome targeting to oral bacteria. Biochim Biophys Acta. 1998;1369(2):​278–86.CrossRefPubMedGoogle Scholar
  87. 87.
    Neelakantan P, Subbarao CV. An analysis of the antimicrobial activity of ten root canal sealers–a duration based in vitro evaluation. J Clin Pediatr Dent. 2008;​33(2):117–22.PubMedGoogle Scholar
  88. 88.
    Peters OA, Schonenberger K, Laib A. Effects of four Ni-Ti preparation techniques on root canal geometry assessed by micro computed tomography. Int Endod J. 2001;34(3):221–30.CrossRefPubMedGoogle Scholar
  89. 89.
    Song CX, et al. Formulation and characterization of biodegradable nanoparticles for intravascular local drug delivery. J Control Release. 1997;43(2–3):​197–212.CrossRefGoogle Scholar
  90. 90.
    Labhasetwar V, et al. Arterial uptake of biodegradable nanoparticles: effect of surface modifications. J Pharm Sci. 1998;87(10):1229–34.CrossRefPubMedGoogle Scholar
  91. 91.
    Guzman LA, et al. Local intraluminal infusion of biodegradable polymeric nanoparticles. A novel approach for prolonged drug delivery after balloon angioplasty. Circulation. 1996;94(6):1441–8.CrossRefPubMedGoogle Scholar
  92. 92.
    Mundargi RC, et al. Development and evaluation of novel biodegradable microspheres based on poly(d, l-lactide-co-glycolide) and poly(epsilon-caprolactone) for controlled delivery of doxycycline in the treatment of human periodontal pocket: in vitro and in vivo studies. J Control Release. 2007;119(1):59–68.CrossRefPubMedGoogle Scholar
  93. 93.
    Uchino H, Matsumara Y, Negishi T, et al. Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplastin in rats. Br J Cancer. 2005;93(6):678–87.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Xu Wen Ng
    • 1
  • Raghavendra C. Mundargi
    • 1
  • Subbu S. Venkatraman
    • 1
    Email author
  1. 1.School of Materials Science & EngineeringNanyang Technological UniversitySingaporeSingapore

Personalised recommendations