دورية أكاديمية
أعرض في EDS

Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.

التفاصيل البيبلوغرافية
العنوان: Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.
المؤلفون: Zhou C; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Lei F; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Sharma J; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Hui PC; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Wolkow N; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; David G. Cogan Laboratory of Eye Pathology and Ophthalmic Plastic Surgery Service, Massachusetts Eye and Ear, Boston, MA 02114, USA., Dohlman CH; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Vavvas DG; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Angiogenesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Chodosh J; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.; Disruptive Technology Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.; Department of Ophthalmology and Visual Sciences, University of New Mexico School of Medicine, Albuquerque, NM 87108, USA., Paschalis EI; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.; Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.; Disruptive Technology Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.
المصدر: Pharmaceutics [Pharmaceutics] 2023 Jul 31; Vol. 15 (8). Date of Electronic Publication: 2023 Jul 31.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101534003 Publication Model: Electronic Cited Medium: Print ISSN: 1999-4923 (Print) Linking ISSN: 19994923 NLM ISO Abbreviation: Pharmaceutics Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI
مستخلص: Purpose: This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye.
Methods: A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis.
Results: A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45 + immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45 + immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site.
Conclusions: Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.
References: Mol Vis. 2016 Feb 03;22:116-28. (PMID: 26900328)
Arthritis Rheum. 2004 May;50(5):1636-41. (PMID: 15146434)
Eye (Lond). 2013 Apr;27(4):569-71. (PMID: 23328798)
Arq Bras Oftalmol. 2013 May-Jun;76(3):180-4. (PMID: 23929080)
Acta Ophthalmol. 2010 Dec;88(8):862-7. (PMID: 19549103)
Cornea. 2014 Apr;33(4):382-9. (PMID: 24488127)
Ophthalmology. 2008 Jun;115(6):e33-8. (PMID: 18439681)
Scand J Rheumatol. 2009 Nov-Dec;38(6):439-44. (PMID: 19922018)
Am J Pathol. 2020 Oct;190(10):2056-2066. (PMID: 32693061)
Cornea. 2014 Apr;33(4):349-54. (PMID: 24531120)
Int J Pharm. 2015 Jul 25;490(1-2):375-83. (PMID: 26027491)
Prog Retin Eye Res. 2017 Mar;57:134-185. (PMID: 28028001)
Surv Ophthalmol. 2012 Sep;57(5):415-29. (PMID: 22898649)
Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6277-85. (PMID: 20435600)
Br J Ophthalmol. 2013 Apr;97(4):460-5. (PMID: 23390167)
Transl Vis Sci Technol. 2020 Jul 02;9(8):5. (PMID: 32855852)
Graefes Arch Clin Exp Ophthalmol. 2009 Oct;247(10):1375-82. (PMID: 19415316)
Ophthalmologe. 2007 Apr;104(4):336-44. (PMID: 17372736)
Am J Pathol. 2017 Jun;187(6):1327-1342. (PMID: 28412300)
Cornea. 2019 Dec;38(12):1589-1594. (PMID: 31453878)
Transl Vis Sci Technol. 2016 Mar 11;5(2):11. (PMID: 26981333)
Arthritis Res Ther. 2008;10(5):R125. (PMID: 18945353)
Cornea. 2018 Feb;37(2):248-251. (PMID: 29135604)
Arch Ophthalmol. 2008 Jan;126(1):71-7. (PMID: 18195221)
Mil Med. 2017 Mar;182(S1):114-119. (PMID: 28291461)
Br J Ophthalmol. 2007 Jun;91(6):804-7. (PMID: 17179168)
J Control Release. 2010 Nov 20;148(1):42-48. (PMID: 20831888)
Eye Contact Lens. 2015 Mar;41(2):72-6. (PMID: 25503908)
Pharmaceutics. 2023 Apr 13;15(4):. (PMID: 37111714)
Graefes Arch Clin Exp Ophthalmol. 2008 Feb;246(2):281-4. (PMID: 17934753)
Immunotherapy. 2013 Feb;5(2):113-5. (PMID: 23413901)
Invest Ophthalmol Vis Sci. 2009 Oct;50(10):4807-13. (PMID: 19324856)
Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):96-105. (PMID: 28114570)
Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11359-E11368. (PMID: 30442669)
Am J Pathol. 2018 Jul;188(7):1580-1596. (PMID: 29630857)
Ophthalmology. 1997 Jul;104(7):1166-73. (PMID: 9224471)
J Immunol. 2019 Jan 15;202(2):539-549. (PMID: 30541880)
Ocul Surf. 2012 Apr;10(2):67-83. (PMID: 22482468)
Cornea. 2011 Dec;30(12):1322-7. (PMID: 22001817)
Arch Ophthalmol. 2009 Apr;127(4):381-9. (PMID: 19365012)
معلومات مُعتمدة: R01 EY013124 United States EY NEI NIH HHS
فهرسة مساهمة: Keywords: TNF; VEFG; biologics; burn; cornea; degeneration; injury; neovascularization; retina
تواريخ الأحداث: Date Created: 20230826 Latest Revision: 20240511
رمز التحديث: 20240511
مُعرف محوري في PubMed: PMC10458495
DOI: 10.3390/pharmaceutics15082059
PMID: 37631272
قاعدة البيانات: MEDLINE
الوصف
تدمد:1999-4923
DOI:10.3390/pharmaceutics15082059