Advertisement

AAPS PharmSciTech

, 20:66 | Cite as

Multi-Layered Nanomicelles as Self-Assembled Nanocarrier Systems for Ocular Peptide Delivery

  • Abhirup Mandal
  • Pratikkumar Patel
  • Dhananjay Pal
  • Ashim K. Mitra
Research Article
  • 17 Downloads

Abstract

Despite the great potential of peptides as therapeutics, there is an unmet challenge in sustaining delivery of sufficient amounts in their native forms. This manuscript describes a novel nanocarrier capable of delivering functional small peptides in its native form. Self-assembling multi-layered nanomicelles composed of two polymers, polyoxyethylene hydrogenated castor oil 40 (HCO-40) and octoxynol 40 (OC-40), were designed to combine hydrophilic interaction and solvent-induced encapsulation of peptides and proteins. The polymers are employed to encapsulate peptide or protein in the core of the organo-nanomicelles which are further encapsulated with another layer of the same polymers to form an aqueous stable nanomicellar solution. The size of the multi-layered nanomicelles ranges from ~ 16 to 20 nm with zeta potential close to neutral (~ − 2.44 to 0.39 mV). In vitro release studies revealed that octreotide-loaded multi-layered nanomicelles released octreotide at much slower rate in simulated tear fluid (STF) (~ 27 days) compared to PBST (~ 11 days) in its native form. MTT assay demonstrated negligible toxicity of the multi-layered nanomicelles at lower concentrations in human retinal pigment epithelial (HRPE, D407), human conjunctival epithelial (CCL 20.2), and rhesus choroid-retinal endothelial (RF/6A) cells. This work demonstrates an efficient small peptide delivery platform with significant advantages over existing approaches, as it does not require modification of the peptide, is biodegradable, and has a small size and high loading capacity.

KEY WORDS

micelles sustained release self-assembly formulation acylation octreotide mass spectrometry 

Notes

Acknowledgments

This work was supported by R01EY09171-16 and R01EY010659-14 grants from the National Institute of Health.

Compliance with Ethical Standards

Conflict of Interest

This invention has been disclosed to the University of Missouri-Kansas City for potential patent filing.

Supplementary material

12249_2018_1267_MOESM1_ESM.docx (376 kb)
ESM 1 (DOCX 376 kb)

References

  1. 1.
    Lagasse HA, et al. Recent advances in (therapeutic protein) drug development. F1000Res. 2017;6:113.CrossRefGoogle Scholar
  2. 2.
    Kintzing JR, Filsinger Interrante MV, Cochran JR. Emerging strategies for developing next-generation protein therapeutics for cancer treatment. Trends Pharmacol Sci. 2016;37(12):993–1008.CrossRefGoogle Scholar
  3. 3.
    Jiang W, Boder ET. High-throughput engineering and analysis of peptide binding to class II MHC. Proc Natl Acad Sci U S A. 2010;107(30):13258–63.CrossRefGoogle Scholar
  4. 4.
    Shrivastava A, von Wronski MA, Sato AK, Dransfield DT, Sexton D, Bogdan N, et al. A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases. Protein Eng Des Sel. 2005;18(9):417–24.CrossRefGoogle Scholar
  5. 5.
    Shin M, Lee HA, Lee M, Shin Y, Song JJ, Kang SW, et al. Targeting protein and peptide therapeutics to the heart via tannic acid modification. Nat Biomed Eng. 2018;2(5):304–17.CrossRefGoogle Scholar
  6. 6.
    Mandal A, Pal D, Agrahari V, Trinh HM, Joseph M, Mitra AK. Ocular delivery of proteins and peptides: challenges and novel formulation approaches. Adv Drug Deliv Rev. 2018;126:67–95.CrossRefGoogle Scholar
  7. 7.
    Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20(1):122–8.CrossRefGoogle Scholar
  8. 8.
    Lau JL, Dunn MK. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26(10):2700–7.CrossRefGoogle Scholar
  9. 9.
    Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655–72.CrossRefGoogle Scholar
  10. 10.
    Dash TK, Konkimalla VB. Polymeric modification and its implication in drug delivery: poly-epsilon-caprolactone (PCL) as a model polymer. Mol Pharm. 2012;9(9):2365–79.CrossRefGoogle Scholar
  11. 11.
    Zhang Y, Schwendeman SP. Minimizing acylation of peptides in PLGA microspheres. J Control Release. 2012;162(1):119–26.CrossRefGoogle Scholar
  12. 12.
    Hamley IW. PEG-peptide conjugates. Biomacromolecules. 2014;15(5):1543–59.CrossRefGoogle Scholar
  13. 13.
    Shirangi M, Najafi M, Rijkers DTS, Kok RJ, Hennink WE, van Nostrum CF. Inhibition of octreotide acylation inside PLGA microspheres by derivatization of the amines of the peptide with a self-immolative protecting group. Bioconjug Chem. 2016;27(3):576–85.CrossRefGoogle Scholar
  14. 14.
    Werle M, Bernkop-Schnurch A. Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids. 2006;30(4):351–67.CrossRefGoogle Scholar
  15. 15.
    Houchin ML, Topp EM. Chemical degradation of peptides and proteins in PLGA: a review of reactions and mechanisms. J Pharm Sci. 2008;97(7):2395–404.CrossRefGoogle Scholar
  16. 16.
    Ibrahim MA, Ismail A, Fetouh MI, Göpferich A. Stability of insulin during the erosion of poly (lactic acid) and poly(lactic-co-glycolic acid) microspheres. J Control Release. 2005;106(3):241–52.CrossRefGoogle Scholar
  17. 17.
    Ghassemi AH, van Steenbergen MJ, Barendregt A, Talsma H, Kok RJ, van Nostrum CF, et al. Controlled release of octreotide and assessment of peptide acylation from poly(D,L-lactide-co-hydroxymethyl glycolide) compared to PLGA microspheres. Pharm Res. 2012;29(1):110–20.CrossRefGoogle Scholar
  18. 18.
    Vaishya RD, Mandal A, Gokulgandhi M, Patel S, Mitra AK. Reversible hydrophobic ion-paring complex strategy to minimize acylation of octreotide during long-term delivery from PLGA microparticles. Int J Pharm. 2015;489(1–2):237–45.CrossRefGoogle Scholar
  19. 19.
    Mandal A, Cholkar K, Khurana V, Shah A, Agrahari V, Bisht R, et al. Topical formulation of self-assembled antiviral prodrug nanomicelles for targeted retinal delivery. Mol Pharm. 2017;14(6):2056–69.CrossRefGoogle Scholar
  20. 20.
    Mandal A, Bisht R, Rupenthal ID, Mitra AK. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J Control Release. 2017;248:96–116.CrossRefGoogle Scholar
  21. 21.
    Grant MB, Mames RN, Fitzgerald C, Hazariwala KM, Cooper-DeHoff R, Caballero S, et al. The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care. 2000;23(4):504–9.CrossRefGoogle Scholar
  22. 22.
    Vrignaud S, Benoit JP, Saulnier P. Strategies for the nanoencapsulation of hydrophilic molecules in polymer-based nanoparticles. Biomaterials. 2011;32(33):8593–604.CrossRefGoogle Scholar
  23. 23.
    Patel SR, Berezovsky DE, McCarey BE, Zarnitsyn V, Edelhauser HF, Prausnitz MR. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci. 2012;53(8):4433–41.CrossRefGoogle Scholar
  24. 24.
    Haller JA, Kuppermann BD, Blumenkranz MS, Williams GA, Weinberg DV, Chou C, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128(3):289–96.CrossRefGoogle Scholar
  25. 25.
    Moller DE, et al. Octreotide suppresses both growth hormone (GH) and GH-releasing hormone (GHRH) in acromegaly due to ectopic GHRH secretion. J Clin Endocrinol Metab. 1989;68(2):499–504.CrossRefGoogle Scholar
  26. 26.
    Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery. Transl Vis Sci Technol. 2015;4(3):1.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Abhirup Mandal
    • 1
  • Pratikkumar Patel
    • 1
  • Dhananjay Pal
    • 1
  • Ashim K. Mitra
    • 1
    • 2
  1. 1.Division of Pharmacology and Pharmaceutical Sciences, School of PharmacyUniversity of Missouri-Kansas CityKansas CityUSA
  2. 2.Vision Research Center, Department of Ophthalmology, School of MedicineUniversity of Missouri-Kansas CityKansas CityUSA

Personalised recommendations