Humanin Nanoparticles for Reducing Pathological Factors Characteristic of Age-Related Macular Degeneration

Author(s): Aum Solanki, Rudy Smalling, Abraham H. Parola, Ilana Nathan, Roni Kasher, Yashwant Pathak, Vijaykumar Sutariya*.

Journal Name: Current Drug Delivery

Volume 16 , Issue 3 , 2019

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Abstract:

Background: Humanin is a novel neuronal peptide that has displayed potential in the treatment of Alzheimer’s Disease through the suppression of inflammatory IL-6 cytokine receptors. Such receptors are found throughout the body, including the eye, suggesting its other potential applications. Age-related Macular Degeneration (AMD) is the leading cause of blindness in the developing world. There is no cure for this disease, and current treatments have several negative side effects associated with them, making finding other treatment options desirable.

Objective: In this study, the potential applications in treating AMD for a more potent humanin derivative, AGA-HNG, were studied.

Methods: AGA-HNG was synthesized and encapsulated in chitosan Nanoparticles (NPs), which were then characterized for their size, Encapsulation Efficiency (EE), and drug release. Their ability to suppress VEGF secretion and protect against oxidative apoptosis was studied in vitro using ARPE-19 cells. The chitosan NPs exhibited similar anti-VEGF properties and oxidative protection as the free protein while exhibiting superior pharmaceutical characteristics including biocompatibility and drug release.

Results: Drug-loaded NPs exhibited a radius of 346nm with desirable pharmacokinetic properties including a stable surface charge (19.5 ± 3.7 mV) and steady drug release capacity. AGA-HNG showed great promise in mediating apoptosis in hypoxic cells. They were also able to significantly reduce VEGF expression in vitro with reduced cellular toxicity compared to the free drug.

Conclusion: The ability of this drug delivery system to reduce retinal apoptosis with desirable pharmacokinetic and biocompatible properties makes this a promising therapeutic option for AMD.

Keywords: Nanoparticles, humanin peptide, age-related macular degeneration, vascular endothelial growth factor, ARPE-19 cells, chitosan.

[1]
Friedman, D.S.; O’Colmain, B.J.; Muñoz, B.; Tomany, S.C.; McCarty, C.; de Jong, P.T.; Nemesure, B.; Mitchell, P.; Kempen, J. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol., 2004, 122(4), 564-572.
[2]
Vingerling, J.R.; Dielemans, I.; Hofman, A.; Grobbee, D.E.; Hijmering, M.; Kramer, C.F.; de Jong, P.T. The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology, 1995, 102(2), 205-210.
[3]
Jager, R.D.; Mieler, W.F.; Miller, J.W. Age-related macular degeneration. N. Engl. J. Med., 2008, 358(24), 2606-2617.
[4]
Al Gwairi, O.; Thach, L.; Zheng, W.; Osman, N.; Little, P.J. Cellular and molecular pathology of age-related macular degeneration: Potential role for proteoglycans. J. Ophthalmol., 2016, 2016, 2913612.
[5]
Nickla, D.L.; Wallman, J. The multifunctional choroid. Prog. Retin. Eye Res., 2010, 29(2), 144-168.
[6]
Bird, A.C.; Phillips, R.L.; Hageman, G.S. Geographic atrophy: A histopathological assessment. JAMA Ophthalmol., 2014, 132(3), 338-345.
[7]
Mettu, P.S. Retinal pigment epithelium response to oxidant injury in the pathogenesis of early age-related macular degeneration. Mol. Aspects Med., 2012, 33(4), 376-398.
[8]
Fernandez-Robredo, P.; Sancho, A.; Johnen, S.; Recalde, S.; Gama, N.; Thumann, G.; Groll, J.; García-Layana, A. Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering. J. Ophthalmol., 2014, 2014, 510285.
[9]
Pożarowska, D.; Pożarowski, P. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy. Cent. Eur. J. Immunol., 2016, 41(3), 311.
[10]
Vakalis, N.; Echiadis, G.; Pervena, A.; Deligiannis, I.; Kavalarakis, E.; Giannikakis, S.; Papaefthymiou, I. Intravitreal combination of dexamethasone sodium phosphate and bevacizumab in the treatment of exudative AMD. Sci. Rep., 2015, 5, 8627.
[11]
Cunningham, M.A.; Edelman, J.L.; Kaushal, S. Intravitreal steroids for macular edema: the past, the present, and the future. Surv. Ophthalmol., 2008, 53(2), 139-149.
[12]
Young, S.; Larkin, G.; Branley, M.; Lightman, S. Safety and efficacy of intravitreal triamcinolone for cystoid macular oedema in uveitis. Clin. Exp. Ophthalmol., 2001, 29(1), 2-6.
[13]
Graham, R.O.; Peyman, G.A. Intravitreal injection of dexamethasone: Treatment of experimentally induced endophthalmitis. Arch. Ophthalmol., 1974, 92(2), 149-154.
[14]
Reichle, M.L. Complications of intravitreal steroid injections. Optometry, 2005, 76(8), 450-460.
[15]
Offord, E.A.; Sharif, N.A.; Macé, K.; Tromvoukis, Y.; Spillare, E.A.; Avanti, O.; Howe, W.E.; Pfeifer, A.M. Immortalized human corneal epithelial cells for ocular toxicity and inflammation studies. Invest. Ophthalmol. Vis. Sci., 1999, 40(6), 1091-1101.
[16]
Urtti, A.; Salminen, L. Minimizing systemic absorption of topically administered ophthalmic drugs. Surv. Ophthalmol., 1993, 37(6), 435-456.
[17]
Duvvuri, S.; Majumdar, S.; Mitra, A.K. Drug delivery to the retina: Challenges and opportunities. Expert Opin. Biol. Ther., 2003, 3(1), 45-56.
[18]
Nayak, K.; Misra, M. A review on recent drug delivery systems for posterior segment of eye. Biomed. Pharmacother., 2018, 107, 1564-1582.
[19]
Kaji, H.; Nagai, N.; Nishizawa, M.; Abe, T. Drug delivery devices for retinal diseases. Adv. Drug Deliv. Rev., 2018, 128, 148-157.
[20]
Bisht, R.; Mandal, A.; Jaiswal, J.K.; Rupenthal, I.D. Nanocarrier mediated retinal drug delivery: Overcoming ocular barriers to treat posterior eye diseases. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2018, 10(2), e1473.
[21]
Bhattacharyya, K.; Mukherjee, S. Fluorescent metal nano-clusters as next generation fluorescent probes for cell imaging and drug delivery. Bull. Chem. Soc. Jpn., 2017, 91(3), 447-454.
[22]
Komiyama, M.; Yoshimoto, K.; Sisido, M.; Ariga, K. Chemistry can make strict and fuzzy controls for bio-systems: DNA nanoarchitectonics and cell-macromolecular nanoarchitectonics. Bull. Chem. Soc. Jpn., 2017, 90(9), 967-1004.
[23]
Hirani, A.; Grover, A.; Lee, Y.W.; Pathak, Y.; Sutariya, V. Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration. Pharm. Dev. Technol., 2016, 21(1), 61-67.
[24]
Grover, A.; Hirani, A.; Pathak, Y.; Sutariya, V. Brain-targeted delivery of docetaxel by glutathione-coated nanoparticles for brain cancer. AAPS PharmSciTech, 2014, 15(6), 1562-1568.
[25]
Hanus, J.; Anderson, C.; Wang, S. RPE necroptosis in response to oxidative stress and in AMD. Ageing Res. Rev., 2015, 24, 286-298.
[26]
Jang, K-H.; Do, Y.J.; Son, D.; Son, E.; Choi, J.S.; Kim, E. AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration. Cell Death Dis., 2017, 8(1), e2526.
[27]
Matsumoto, H.; Kataoka, K.; Tsoka, P.; Connor, K.M.; Miller, J.W.; Vavvas, D.G. Strain difference in photoreceptor cell death after retinal detachment in mice. Invest. Ophthalmol. Vis. Sci., 2014, 55(7), 4165-4174.
[28]
Telegina, D.; Kozhevnikova, O.; Kolosova, N. Molecular mechanisms of cell death in retina during development of age-related macular degeneration. Adv. Gerontol., 2017, 7(1), 17-24.
[29]
Charununtakorn, S.T.; Shinlapawittayatorn, K.; Chattipakorn, S.C.; Chattipakorn, N. Potential roles of humanin on apoptosis in the heart. Cardiovasc. Ther., 2016, 34(2), 107-114.
[30]
Cohen, A.; Lerner-Yardeni, J.; Meridor, D.; Kasher, R.; Nathan, I.; Parola, A.H. Humanin derivatives inhibit necrotic cell death in neurons. Mol. Med., 2015, 21(1), 505.
[31]
Kalam, M.A. Development of chitosan nanoparticles coated with hyaluronic acid for topical ocular delivery of dexamethasone. Int. J. Biol. Macromol., 2016, 89, 127-136.
[32]
Yu, K.; Wang, Y.; Wan, T.; Zhai, Y.; Cao, S.; Ruan, W.; Wu, C.; Xu, Y. Tacrolimus nanoparticles based on chitosan combined with nicotinamide: Enhancing percutaneous delivery and treatment efficacy for atopic dermatitis and reducing dose. Int. J. Nanomedicine, 2018, 13, 129.
[33]
D’Souza, S.S.; DeLuca, P.P. Development of a dialysis in vitro release method for biodegradable microspheres. AAPS PharmSciTech, 2005, 6(2), E323-E328.
[34]
Duan, S. Silencing the autophagy-specific gene Beclin-1 contributes to attenuated hypoxia-induced vasculogenic mimicry formation in glioma. Cancer Biomark., 2018, 21(3), 565-574.
[35]
Raveendran, S.; Rochani, A.K.; Maekawa, T.; Kumar, D.S. Smart carriers and nanohealers: A nanomedical insight on natural polymers. Materials, 2017, 10(8), 929.
[36]
Ahmadi, F.; Ghasemi-Kasman, M.; Ghasemi, S.; Tabari, M.G.; Pourbagher, R.; Kazemi, S.; Alinejad-Mir, A. Induction of apoptosis in HeLa cancer cells by an ultrasonic-mediated synthesis of curcumin-loaded chitosan–alginate–STPP nanoparticles. Int. J. Nanomedicine, 2017, 12, 8545.
[37]
Cheng, L.; Yu, H.; Yan, N.; Lai, K.; Xiang, M. Hypoxia-inducible factor-1α target genes contribute to retinal neuroprotection. Front. Cell. Neurosci., 2017, 11, 20.
[38]
Minasyan, L.; Sreekumar, P.G.; Hinton, D.R.; Kannan, R. Protective mechanisms of the mitochondrial-derived peptide humanin in oxidative and endoplasmic reticulum stress in RPE cells. Oxid. Med. Cell. Longev., 2017, 2017, 1675230.
[39]
Sreekumar, P.G.; Ishikawa, K.; Spee, C.; Mehta, H.H.; Wan, J.; Yen, K.; Cohen, P.; Kannan, R.; Hinton, D.R. The mitochondrial-derived peptide humanin protects RPE cells from oxidative stress, senescence, and mitochondrial dysfunctionhumanin protects RPE cells from oxidative stress. Invest. Ophthalmol. Vis. Sci., 2016, 57(3), 1238-1253.


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Article Details

VOLUME: 16
ISSUE: 3
Year: 2019
Page: [226 - 232]
Pages: 7
DOI: 10.2174/1567201815666181031163111

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