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Receptor-Targeted Prodrug Approach for Retina and Posterior Segment Disease

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Drug Delivery for the Retina and Posterior Segment Disease

Abstract

Extensive research has been done in the field of ocular study, to develop and to enhance ocular bioavailability of drugs. Regardless it still faces challenges, as less than 5% of the dose administered reaches to the target site, which is insufficient to produce a pharmacological effect. The chemical methods including the development of prodrugs have proven to be a promising approach to improve ocular drug residence time and bioavailability.

Utilization of prodrugs for the treatment of posterior segment diseases was observed to be an innovative way to overcome barriers pertaining to drug delivery to the specific site. Prodrug effectively permeates the external ocular barriers, cornea and scleral tissues and has a greater partition coefficient. Prodrug approach offers a few points of interest like enhancement of drug solubility, stability, site-specific delivery, decreased toxicity and efflux pump evasion. This section stresses on hypothesis and uses of receptor-focused prodrug approach for ocular drug delivery systems.

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Abbreviations

ACV:

Acyclovir

ARMD/AMD:

Age-related macular degeneration

AV:

Arterial vein

BOB:

Blood–ocular barrier

BRB:

Blood–retinal barrier

BRVO:

Branched retinal vein occlusion

CRVO:

Central retinal vein occlusion

EAAT:

Excitatory amino acid receptors

GABA:

Gamma amino butyric acid

GCV:

Ganciclovir

HR:

Hypertensive retinopathy

HSV:

Herpes simplex virus

IV:

Intravenous

MCTs:

Monocarboxylic acid transporters

PCFT:

Proton-coupled folate transporter

P-gp:

P-glycoprotein

PHVP:

Persistent hyperplastic primary vitreous

PVD:

Posterior vitreous detachments

RBCs:

Red blood cells

RFC:

Reduced folate carrier

RVO:

Retinal vein occlusion

References

  1. Järvinen T, Niemi R. Prodrug approaches to ophthalmic drug delivery. Prodrugs: Springer; 2007. p. 125–55.

    Google Scholar 

  2. Hughes PM, Olejnik O, Chang-Lin J-E, Wilson CG. Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev. 2005;57(14):2010–32.

    Article  CAS  PubMed  Google Scholar 

  3. Thrimawithana TR, Young S, Bunt CR, Green C, Alany RG. Drug delivery to the posterior segment of the eye. Drug Discov Today. 2011;16(5):270–7.

    Article  CAS  PubMed  Google Scholar 

  4. Surajit D, Ashim K M., Transporters and receptors in ocular drug delivery: opportunities and challenges. Expert Opin on Drug Deliv. 2005;2(2):201–204.

    Google Scholar 

  5. Janoria KG, Gunda S, Boddu SH, Mitra AK. Novel approaches to retinal drug delivery. Expert Opin Drug Deliv. 2007;4(4):371–88.

    Article  CAS  PubMed  Google Scholar 

  6. Anand BS, Hill JM, Dey S, Maruyama K, Bhattacharjee PS, Myles ME, et al. In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. Invest Ophthalmol Vis Sci. 2003;44(6):2529–34.

    Article  PubMed  Google Scholar 

  7. Anand BS, Nashed YE, Mitra AK. Novel dipeptide prodrugs of acyclovir for ocular herpes infections: bioreversion, antiviral activity and transport across rabbit cornea. Curr Eye Res. 2003;26(3–4):151–63.

    Article  PubMed  Google Scholar 

  8. Majumdar S, Kansara V, Mitra AK. Vitreal pharmacokinetics of dipeptide monoester prodrugs of ganciclovir. J Ocul Pharmacol Ther. 2006;22(4):231–41.

    Article  CAS  PubMed  Google Scholar 

  9. Kanai Y, Segawa H, Chairoungdua A, Kim JY, Kim DK, Matsuo H, et al. Amino acid transporters: molecular structure and physiological roles. Nephrol Dial Transplant. 2000;15(suppl_6):9–10.

    Article  CAS  PubMed  Google Scholar 

  10. Hargreaves K, Pardridge W. Neutral amino acid transport at the human blood-brain barrier. J Biol Chem. 1988;263(36):19392–7.

    CAS  PubMed  Google Scholar 

  11. Jain-Vakkalagadda B, Pal D, Gunda S, Nashed Y, Ganapathy V, Mitra AK. Identification of a Na+−dependent cationic and neutral amino acid transporter, B0,+, in human and rabbit cornea. Mol Pharm. 2004;1(5):338–46.

    Article  CAS  PubMed  Google Scholar 

  12. Katragadda S, Gunda S, Hariharan S, Mitra AK. Ocular pharmacokinetics of acyclovir amino acid ester prodrugs in the anterior chamber: evaluation of their utility in treating ocular HSV infections. Int J Pharm. 2008;359(1):15–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Neal MJ. Amino acid transmitter substances in the vertebrate retina. Gen Pharmacol Vasc S. 1976;7(5):321–32.

    Article  CAS  Google Scholar 

  14. Thoreson WB, Witkovsky P. Glutamate receptors and circuits in the vertebrate retina. Prog Retin Eye Res. 1999;18(6):765–810.

    Article  CAS  PubMed  Google Scholar 

  15. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65(1):1–105.

    Article  CAS  PubMed  Google Scholar 

  16. Kanai Y, Hediger MA. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature. 1992;360(6403):467–71.

    Article  CAS  PubMed  Google Scholar 

  17. Pow DV. Amino acids and their transporters in the retina. Neurochem Int. 2001;38(6):463–84.

    Article  CAS  PubMed  Google Scholar 

  18. Vooturi SK, Kadam RS, Kompella UB. Transporter targeted gatifloxacin prodrugs: synthesis, permeability, and topical ocular delivery. Mol Pharm. 2012;9(11):3136–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Umapathy NS, Ganapathy V, Ganapathy ME. Transport of amino acid esters and the amino-acid-based prodrug valganciclovir by the amino acid transporter ATB0,+. Pharm Res. 2004;21(7):1303–10.

    Article  CAS  PubMed  Google Scholar 

  20. Hatanaka T, Haramura M, Fei Y-J, Miyauchi S, Bridges CC, Ganapathy PS, et al. Transport of amino acid-based prodrugs by the Na+−and cl--coupled amino acid transporter ATB0,+ and expression of the transporter in tissues amenable for drug delivery. J Pharmacol Exp Ther. 2004;308(3):1138–47.

    Article  CAS  PubMed  Google Scholar 

  21. Yamamoto A, Si A, Tachikawa M, Ki H. Involvement of LAT1 and LAT2 in the high-and low-affinity transport of L-leucine in human retinal pigment epithelial cells (ARPE-19 cells). J Pharm Sci. 2010;99(5):2475–82.

    Article  CAS  PubMed  Google Scholar 

  22. Yoon H, Fanelli A, Grollman EF, Philp NJ. Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem Biophys Res Commun. 1997;234(1):90–4.

    Article  CAS  PubMed  Google Scholar 

  23. Gerhart D, Leino R, Drewes L. Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina. Neuroscience. 1999;92(1):367–75.

    Article  CAS  PubMed  Google Scholar 

  24. Hosoya K-i, Kondo T, Tomi M, Takanaga H, Ohtsuki S, Terasaki T. MCT1-mediated transport of L-lactic acid at the inner blood–retinal barrier: a possible route for delivery of monocarboxylic acid drugs to the retina. Pharm Res. 2001;18(12):1669–76.

    Article  CAS  PubMed  Google Scholar 

  25. Poll-The B, de Buy Wenniger-Prick CM. The eye in metabolic diseases: Clues to diagnosis. Eur J Paediatr Neurol. 2011;15(3):197–204.

    Article  CAS  PubMed  Google Scholar 

  26. Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Investig. 1998;102(4):783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lieth E, Gardner TW, Barber AJ, Antonetti DA. Retinal neurodegeneration: early pathology in diabetes. Clin Exp Ophthalmol. 2000;28(1):3–8.

    Article  CAS  PubMed  Google Scholar 

  28. Gaudana R, Jwala J, Boddu SH, Mitra AK. Recent perspectives in ocular drug delivery. Pharm Res. 2009;26(5):1197.

    Article  CAS  PubMed  Google Scholar 

  29. Hsu S-C, Molday R. Glycolytic enzymes and a GLUT-1 glucose transporter in the outer segments of rod and cone photoreceptor cells. J Biol Chem. 1991;266(32):21745–52.

    CAS  PubMed  Google Scholar 

  30. Mantych GJ, Hageman GS, Devaskar SU. Characterization of glucose transporter isoforms in the adult and developing human eye. Endocrinology. 1993;133(2):600–7.

    Article  CAS  PubMed  Google Scholar 

  31. Koepsell H. The Na+-D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. Pharmacol Ther. 2017;170:148–65.

    Article  CAS  PubMed  Google Scholar 

  32. Wakisaka M, Nagao T. Sodium glucose cotransporter 2 in mesangial cells and retinal pericytes and its implications for diabetic nephropathy and retinopathy. Glycobiology. 2017;27:691.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wakisaka M, Kitazono T, Kato M, Nakamura U, Yoshioka M, Uchizono Y, et al. Sodium-coupled glucose transporter as a functional glucose sensor of retinal microvascular circulation. Circ Res. 2001;88(11):1183–8.

    Article  CAS  PubMed  Google Scholar 

  34. Jwala J, Boddu S, Paturi D, Shah S, Smith SB, Pal D, et al. Functional characterization of folate transport proteins in Staten’s Seruminstitut rabbit corneal epithelial cell line. Curr Eye Res. 2011;36(5):404–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Golnik KC, Schaible ER. Folate-responsive optic neuropathy. J Neuroophthalmol. 1994;14(3):163–9.

    Article  CAS  PubMed  Google Scholar 

  36. Bozard BR, Ganapathy PS, Duplantier J, Mysona B, Ha Y, Roon P, et al. Molecular and biochemical characterization of folate transport proteins in retinal Müller cells. Invest Ophthalmol Vis Sci. 2010;51(6):3226–35.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Spiegelstein O, Eudy JD, Finnell RH. Identification of two putative novel folate receptor genes in humans and mouse. Gene. 2000;258(1):117–25.

    Article  CAS  PubMed  Google Scholar 

  38. Boddu SH, Jwala J, Chowdhury MR, Mitra AK. In vitro evaluation of a targeted and sustained release system for retinoblastoma cells using Doxorubicin as a model drug. J Ocul Pharmacol Ther. 2010;26(5):459–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yoo HS, Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release. 2004;96(2):273–83.

    Article  CAS  PubMed  Google Scholar 

  40. Querques G, Bux AV, Martinelli D, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen®) for diabetic macular oedema. Acta Ophthalmol. 2009;87(6):623–30.

    Article  CAS  PubMed  Google Scholar 

  41. Perry CM, Balfour JAB. Fomivirsen. Drugs. 1999;57(3):375–80.

    Article  CAS  PubMed  Google Scholar 

  42. Russell R. Bioerodable eye implant may help treat macular edema. Pharma Technol. 2004;28(18):223.

    Google Scholar 

  43. Emerich DF, Thanos CG. NT-501: an ophthalmic implant of polymer-encapsulated ciliary neurotrophic factor-producing cells. Curr Opin Mol Ther. 2008;10(5):506–15.

    CAS  PubMed  Google Scholar 

  44. Kane FE, Burdan J, Cutino A, Green KE. Iluvien™: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Deliv. 2008;5(9):1039–46.

    Article  CAS  PubMed  Google Scholar 

  45. Montero JA, Ruiz-Moreno JM. Intravitreal inserts of steroids to treat diabetic macular edema. Curr Diabetes Rev. 2009;5(1):26–32.

    Article  CAS  PubMed  Google Scholar 

  46. Lee SS, Robinson MR. Novel drug delivery systems for retinal diseases. Ophthalmic Res. 2009;41(3):124–35.

    Article  CAS  PubMed  Google Scholar 

  47. Bourges J, Bloquel C, Thomas A, Froussart F, Bochot A, Azan F, et al. Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev. 2006;58(11):1182–202.

    Article  CAS  PubMed  Google Scholar 

  48. Bejjani RA, BenEzra D, Cohen H, Rieger J, Andrieu C, Jeanny J-C, et al. Nanoparticles for gene delivery to retinal pigment epithelial cells. Mol Vis. 2005;11(2):124–32.

    CAS  PubMed  Google Scholar 

  49. Bourges J-L, Gautier SE, Delie F, Bejjani RA, Jeanny J-C, Gurny R, et al. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci. 2003;44(8):3562–9.

    Article  PubMed  Google Scholar 

  50. Normand N, Valamanesh F, Savoldelli M, Mascarelli F, BenEzra D, Courtois Y, et al. VP22 light controlled delivery of oligonucleotides to ocular cells in vitro and in vivo. Mol Vis. 2005;11(21):184–91.

    CAS  PubMed  Google Scholar 

  51. Kaiser PK, Goldberg MF, Davis AA, Group AACS. Posterior juxtascleral depot administration of anecortave acetate. Surv Ophthalmol. 2007;52(1):S62–S9.

    Article  PubMed  Google Scholar 

  52. Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with poly (lactic-co-glycolic) acid microspheres. Invest Ophthalmol Vis Sci. 2003;44(1):290–9.

    Article  PubMed  Google Scholar 

  53. Jiang J, Moore JS, Edelhauser HF, Prausnitz MR. Intrascleral drug delivery to the eye using hollow microneedles. Pharm Res. 2009;26(2):395–403.

    Article  CAS  PubMed  Google Scholar 

  54. Kato A, Kimura H, Okabe K, Okabe J, Kunou N, Ogura Y. Feasibility of drug delivery to the posterior pole of the rabbit eye with an episcleral implant. Invest Ophthalmol Vis Sci. 2004;45(1):238–44.

    Article  PubMed  Google Scholar 

  55. Ambati J, Gragoudas ES, Miller JW, You TT, Miyamoto K, Delori FC, et al. Transscleral delivery of bioactive protein to the choroid and retina. Invest Ophthalmol Vis Sci. 2000;41(5):1186–91.

    CAS  PubMed  Google Scholar 

  56. Eljarrat-Binstock E, Domb AJ. Iontophoresis: a non-invasive ocular drug delivery. J Control Release. 2006;110(3):479–89.

    Article  CAS  PubMed  Google Scholar 

  57. Ayalasomayajula SP, Kompella UB. Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model. Eur J Pharmacol. 2005;511(2):191–8.

    Article  CAS  PubMed  Google Scholar 

  58. dos Santos ALG, Bochot A, Doyle A, Tsapis N, Siepmann J, Siepmann F, et al. Sustained release of nanosized complexes of polyethylenimine and anti-TGF-β2 oligonucleotide improves the outcome of glaucoma surgery. J Control Release. 2006;112(3):369–81.

    Article  Google Scholar 

  59. Zignani M, Einmahl S, Baeyens V, Varesio E, Veuthey J-L, Anderson J, et al. A poly (ortho ester) designed for combined ocular delivery of dexamethasone sodium phosphate and 5-fluorouracil: subconjunctival tolerance and in vitro release. Eur J Pharm Biopharm. 2000;50(2):251–5.

    Article  CAS  PubMed  Google Scholar 

  60. Gilbert JA, Simpson AE, Rudnick DE, Geroski DH, Aaberg TM, Edelhauser HF. Transscleral permeability and intraocular concentrations of cisplatin from a collagen matrix. J Control Release. 2003;89(3):409–17.

    Article  CAS  PubMed  Google Scholar 

  61. Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci. 2003;44(3):1192–201.

    Article  PubMed  Google Scholar 

  62. Saishin Y, Silva RL, Saishin Y, Callahan K, Schoch C, Ahlheim M, et al. Periocular injection of microspheres containing PKC412 inhibits choroidal neovascularization in a porcine model. Invest Ophthalmol Vis Sci. 2003;44(11):4989–93.

    Article  PubMed  Google Scholar 

  63. Olsen TW, Feng X, Wabner K, Conston SR, Sierra DH, Folden DV, et al. Cannulation of the suprachoroidal space: a novel drug delivery methodology to the posterior segment. Am J Ophthalmol. 2006;142(5):777–87. e2

    Article  CAS  PubMed  Google Scholar 

  64. Okabe J, Kimura H, Kunou N, Okabe K, Kato A, Ogura Y. Biodegradable intrascleral implant for sustained intraocular delivery of betamethasone phosphate. Invest Ophthalmol Vis Sci. 2003;44(2):740–4.

    Article  PubMed  Google Scholar 

  65. Wang Y, Challa P, Epstein DL, Yuan F. Controlled release of ethacrynic acid from poly (lactide-co-glycolide) films for glaucoma treatment. Biomaterials. 2004;25(18):4279–85.

    Article  CAS  PubMed  Google Scholar 

  66. Ideta R, Tasaka F, Jang W-D, Nishiyama N, Zhang G-D, Harada A, et al. Nanotechnology-based photodynamic therapy for neovascular disease using a supramolecular nanocarrier loaded with a dendritic photosensitizer. Nano Lett. 2005;5(12):2426–31.

    Article  CAS  PubMed  Google Scholar 

  67. Ebrahim S, Peyman GA, Lee PJ. Applications of liposomes in ophthalmology. Surv Ophthalmol. 2005;50(2):167–82.

    Article  PubMed  Google Scholar 

  68. Mishra GP, Bagui M, Tamboli V, Mitra AK. Recent applications of liposomes in ophthalmic drug delivery. J Drug Deliv. 2011;2011:1.

    Article  Google Scholar 

  69. Yellepeddi VK, Palakurthi S. Recent advances in topical ocular drug delivery. J Ocul Pharmacol Ther. 2016;32(2):67–82.

    Article  CAS  PubMed  Google Scholar 

  70. Barar J, Aghanejad A, Fathi M, Omidi Y. Advanced drug delivery and targeting technologies for the ocular diseases. Bioimpacts. 2016;6(1):49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India

    Tejal Mehta & Viral Patel

  2. Pharmaceutical Technology Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, Gujarat, India

    Om Prakash Sharma

Authors
  1. Tejal Mehta
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  2. Viral Patel
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  3. Om Prakash Sharma
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Correspondence to Tejal Mehta .

Editor information

Editors and Affiliations

  1. Faculty of Pharmacy, Sankalchand Patel University, Gujarat, India

    Jayvadan K. Patel

  2. College of Pharmacy, University of South Florida, Tampa, FL, USA

    Vijaykumar Sutariya

  3. School of Medicine, Faculty of Health, Deakin University, Victoria, Australia

    Jagat Rakesh Kanwar

  4. College of Pharmacy, University of South Florida, Tampa, FL, USA

    Yashwant V. Pathak

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Mehta, T., Patel, V., Sharma, O.P. (2018). Receptor-Targeted Prodrug Approach for Retina and Posterior Segment Disease. In: Patel, J., Sutariya, V., Kanwar, J., Pathak, Y. (eds) Drug Delivery for the Retina and Posterior Segment Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-95807-1_21

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