Skip to main content

Advertisement

SpringerLink
Log in

In Vitro, In Vivo, and In Silico Evaluation of the Bioresponsive Behavior of an Intelligent Intraocular Implant

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

An autofeedback complex polymeric platform was used in the design of an intelligent intraocular implant—the I3—using stimuli-responsive polymers, producing a smart release system capable of delivering therapeutic levels of an anti-inflammatory agent (indomethacin) and antibiotic (ciprofloxacin) for posterior segment disorders of the eye in response to inflammation.

Methods

Physicochemical and physicomechanical analysis of the I3 was undertaken to explicate the highly crosslinked make-up and ‘on-off’ inflammation-responsive performance of the I3. In addition, energetic profiles for important complexation reactions were generated using Molecular Mechanics Energy Relationships by exploring the spatial disposition of energy minimized molecular structures. Furthermore, preliminary in vivo determination of the inflammation-responsiveness of the I3 was ascertained following implantation in the normal and inflamed rabbit eye.

Results

In silico modeling simulating a pathological inflammatory intraocular state highlighted the interaction potential of hydroxyl radicals with the selected polysaccharides comprising the I3. The intricately crosslinked polymeric system forming the I3 thus responded at an innate level predicted by its molecular make-up to inflammatory conditions as indicated by the results of the drug release studies, rheological analysis, magnetic resonance imaging and scanning electron microscopic imaging. In vivo drug release analysis demonstrated indomethacin levels of 0.749 ± 0.126 μg/mL and 1.168 ± 0.186 μg/mL, and ciprofloxacin levels of 1.181 ± 0.150 μg/mL and 6.653 ± 0.605 μg/mL in the normal and inflamed eye, respectively.

Conclusions

Extensive in vitro, molecular, and in vivo characterization therefore highlighted successful inflammation-responsiveness of the I3. The I3 is a proposed step forward from other described ocular systems owing to its combined bioresponsive, nano-enabled architecture.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

ALG:

Alginate

BPMs:

Bioresponsive polymeric matrices

CMV:

Cytomegalovirus

DCC:

N,N′-dicyclohexylcarbodiimide

DSPC:

Distearoylphosphatidylcholine

DSPE:

Distearoylphosphatidylethanolamine

HA:

Hyaluronic acid

I3 :

Intelligent Intraocular Implant

Lipo-CHT-PCL NS:

Lipoidal-chitosan-poly(ε-caprolactone) nanosystem

LPS:

Lipopolysaccharide

MMER:

Molecular Mechanics Energy Relationships

NS:

Nanosystem/s

OH:

Hydroxyl radicals

PAA:

Poly(acrylic acid)

PCL:

Poly(ε-caprolactone)

SRHS:

Stimulus-responsive hydrogel system

SVH:

Simulated vitreous humor

REFERENCES

  1. Herrero-Vanrell R, Refojo MF. Biodegradable microspheres for vitreoretinal drug delivery. Adv Drug Deliv Rev. 2001;52(1):5–16.

    Article  CAS  PubMed  Google Scholar 

  2. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov Today. 2008;13(3–4):135–43.

    PubMed  Google Scholar 

  3. Alvarez-Lorenzo C, Concheiro A. Molecularly imprinted polymers for drug delivery. J Chromatogr B. 2004;804(1):231–45.

    Article  CAS  Google Scholar 

  4. Barbu E, Verestiuc L, Nevell TG, Tsibouklis J. Polymeric materials for ophthalmic drug delivery: trends and perspectives. J Mater Chem. 2006;16:3439–43.

    Article  CAS  Google Scholar 

  5. Panyam J. Inflammation-responsive drug delivery system. Pharmaceutical Sciences, WSU__.htm. Available from: http://research.wayne.edu/idre/db/?view=person&id=42. Relocated in part to: http://research.wayne.edu/idre/tools/faculty-interests.php?id=70.

  6. Ahn BJ, Moshfeghi AA. Implantable Posterior Segment Drug Delivery Devices. Ophthalmology Web; 2008. Available from: http://www.ophthalmologyweb.com/Spotlight.aspx?spid=23&aid=253&headerid=23.

  7. Thilek Kumar M, Pandit JK, Balasubramaniam J. Novel therapeutic approaches for uveitis and retinitis. J Pharm Pharm Sci. 2001;4(3):248–54.

    Google Scholar 

  8. Allergan Inc. EP1750688—Steroid intraocular implants having an extended sustained release for a period of greater than 2 months; 2007. Available from: https://register.epo.org/espacenet/application?number=EP05744945.

  9. Saliba JB, Gomes Faraco AA, Yoshida MI, de Vasconcelos WL, da Silva-Cunha A, Mansur HS. Development and characterization of an intraocular biodegradable polymer system containing cyclosporine A for the treatment of posterior uveitis. Mat Res. 2008;11(2):207–11.

    Article  CAS  Google Scholar 

  10. Barcia E, Herrero-Vanrell R, Díez A, Alvarez-Santiago C, López I, Calonge M. Downregulation of endotoxin-induced uveitis by intravitreal injection of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone. Exp Eye Res. 2009;89:238–45.

    Article  CAS  PubMed  Google Scholar 

  11. Haesslein A, Hacker MC, Ueda H, Ammonb DM, Borazjani RN, Kunzler JF, et al. Matrix modifications modulate ophthalmic drug delivery from photo-cross-linked poly(propylene fumarate)-based networks. J Biomat Sci. 2009;20:49–69.

    Article  CAS  Google Scholar 

  12. Ligório Fialho S, Behar-Cohen F, Silva-Cunha A. Dexamethasone-loaded poly(ε-caprolactone) intravitreal implants: a pilot study. Eur J Pharm Biopharm. 2008;68(3):637–46.

    Article  Google Scholar 

  13. Holekamp NM, Thomas MA, Pearson A. The safety profile of long-term, high-dose intraocular corticosteroid delivery. Am J Ophthalmol. 2005;139(3):421–8.

    Article  CAS  PubMed  Google Scholar 

  14. Zeimer R, Goldberg MF. Novel ophthalmic therapeutic modalities based on noninvasive light-targeted drug delivery to the posterior pole of the eye (Drug Delivery to the Posterior Segments of the Eye). Adv Drug Deliv Rev. 2001;52(1):49–61.

    Article  CAS  PubMed  Google Scholar 

  15. Hawkins CL, Davies MJ. Direct detection and identification of radicals generated during the hydroxyl radical-induced degradation of hyaluronic acid and related materials. Free Radical Biol Med. 1996;21:275–90.

    Article  CAS  Google Scholar 

  16. Zhao XB, Fraser JE, Alexander C, Lockett C, White BJ. Synthesis and characterisation of novel double crosslinked hyaluronan hydrogel. J Mater Sci Mater Med. 2002;13:11–6.

    Article  PubMed  Google Scholar 

  17. Saltzman WM. Drug delivery: engineering principles for drug therapy. Oxford: Oxford University Press; 2001.

    Google Scholar 

  18. Hermanson T. Bioconjugate Techniques. 2nd Ed. London: Elsevier; 2008. P. 220.

  19. Choonara YE, Pillay V, Ndesendo VMK, du Toit LC, Kumar P, Khan RA, et al. Design of polymeric nanoparticles by synthetic wet chemical processing strategies for the sustained delivery of anti-tuberculosis drugs. Coll Interf B Biointerface. 2011;87:243–54.

    Article  CAS  Google Scholar 

  20. Warhurst DC, Craig JC, Adagu IS, Meyer DJ, Lee SY. The relationship of physico-chemical properties and structure to the differential antiplasmodial activity of the cinchona alkaloids. Malar J. 2003;2:26.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Pearlman DA, Case DA, Caldwell JW, Ross WS, Cheatham TE, De-Bolt III S, et al. AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comp Phys Commun. 1995;91:1–41.

    Article  CAS  Google Scholar 

  22. Yu BY, Chung JW, Kwak S-Y. Reduced migration from flexible poly(vinyl chloride) of a plasticizer containing β-cyclodextrin derivative. Environ Sci Technol. 2008;42:7522–7.

    Article  CAS  PubMed  Google Scholar 

  23. Herh P, Tkachuk J, Wu S, Bernzen M, Rudolph B. The rheology of pharmaceutical and cosmetic semisolids. ATS RheoSystems. 1998:12–14.

  24. Takka S. Propranolol hydrochloride—anionic polymer binding interaction. Il Farmaco. 2003;58(10):1051–6.

    Article  CAS  PubMed  Google Scholar 

  25. Nielson LE. Mechanical properties of polymers and composites, vol. 1. New York: Marcel Dekker; 1974.

    Google Scholar 

  26. Yui N, Nihira J, Okano T, Sakurai Y. Inflammation responsive degradation of crosslinked hyaluronic acid gels. J Control Release. 1992;22:105–16.

    Article  CAS  Google Scholar 

  27. Tajiri T, Morita S, Sakamoto R, Suzuki M, Yamanashi S, Ozaki Y, et al. Release mechanisms of acetaminophen from polyethylene oxide/polyethylene glycol matrix tablets utilizing magnetic resonance imaging. Int J Pharm. 2010;395(1–2):147–53.

    Article  CAS  PubMed  Google Scholar 

  28. Shaikh RP, Kumar P, Choonara YE, du Toit LC, Pillay. Crosslinked electrospun PVA nanofibrous membranes: elucidation of their physicochemical, physicomechanical and molecular disposition. Biofabr. 2012;4(025002):doi 10.1088/1758-5082/4/2/025002.

  29. Koura Y, Fukushima A, Nishino K, Ishida W, Nakakuki T, Sento M, et al. Inflammatory reaction following cataract surgery and implantation of acrylic intraocular lens in rabbits with endotoxin-induced uveitis. Eye (Lond). 2006;20(5):606–10.

    Article  CAS  Google Scholar 

  30. Cheruvu NP, Ayalasomayajula SP, Kompella UB. Retinal delivery of sodium fluorescein, budesonide & celecoxib following subconjunctival injection. Drug Dev Deliv. 2003;3(6):posted on: 3/28/2008.

  31. Kobayashi A, Naito S, Enomoto H, Shiomoi T, Kimura T, Obata K, et al. Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Path Lab Med. 2007;131(4):563–70.

    CAS  PubMed  Google Scholar 

  32. Tian Y, Li Y, Xu X, Jin Z, Jiao A, Wang J, et al. A novel size-exclusion high performance liquid chromatography (SE-HPLC) method for measuring degree of amylose retrogradation in rice starch. Food Chem. 2010;118:445–8.

    Article  CAS  Google Scholar 

  33. Xie YH, Soh AK. Investigation of non-covalent association of single-walled carbon nanotube with amylose by molecular dynamics simulation. Mat Lett. 2005;59(8–9):971–5.

    Article  CAS  Google Scholar 

  34. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49:1993–2007.

    Article  CAS  Google Scholar 

  35. Tammi MI, Day AJ, Turley EA. Hyaluronan and homeostasis: a balancing act. J Biol Chem. 2002;277(7):4581–4.

    Article  CAS  PubMed  Google Scholar 

  36. Mlčochová P, Bystrický S, Steiner B, Machová E, Koóš M, Velebný V, et al. Synthesis and characterization of new biodegradable hyaluronan alkyl derivatives. Biopolymers. 2006;82(1):74–9.

    Article  PubMed  Google Scholar 

  37. Magnani A, Rappuoli R, Lamponi S, Barbucci R. Novel polysaccharide hydrogels: characterization and properties. Polym Adv Tech. 2000;11(8–12):488–95.

    Article  CAS  Google Scholar 

  38. Beppu MM, Vieira RS, Aimoli CG, Santana CC. Crosslinking of chitosan membranes using glutaraldehyde: effect on ion permeability and water absorption. J Membr Sci. 2007;301(1–2):126–30.

    Article  CAS  Google Scholar 

  39. Kildeeva NR, Perminov PA, Vladimirov LV, Novikov VV, Mikhailov SN. About mechanism of Chitosan cross-linking with glutaraldehyde. Russ J Bioorg Chem. 2009;35:360–9.

    Article  CAS  Google Scholar 

  40. Yui N, Nihira J, Okano T, Sakurai Y. Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid. J Control Release. 1993;25(1–2):133–43.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road Parktown, 2193, Johannesburg, South Africa

    Lisa C. du Toit, Pradeep Kumar, Yahya E. Choonara & Viness Pillay

  2. Ophthalmology Division, Department of Neurosciences Faculty of Health Sciences, University of the Witwatersrand, 7 York Road Parktown, 2193, Johannesburg, South Africa

    Trevor Carmichael

  3. Department of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu Natal, University Road Westville, 4000, Durban, South Africa

    Thirumala Govender

Authors
  1. Lisa C. du Toit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Trevor Carmichael
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thirumala Govender
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pradeep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yahya E. Choonara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Viness Pillay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Viness Pillay.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

(WMV 4278 kb)

Supplementary Table I

(DOCX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

du Toit, L.C., Carmichael, T., Govender, T. et al. In Vitro, In Vivo, and In Silico Evaluation of the Bioresponsive Behavior of an Intelligent Intraocular Implant. Pharm Res 31, 607–634 (2014). https://doi.org/10.1007/s11095-013-1184-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-1184-3

KEY WORDS

Search

Navigation