Sevinç ŞAHBAZ, Timuçin UĞURLU, Aysun ÇELİK SOYSAL, Ali Demir SEZER

Preparation and characterization of poly(lactic-co-glycolic acid) nanoparticles containing TGF-β1 and evaluation of in vitro wound healing effect

Wound healing involves many complex mechanisms, and many growth factors are effective in thisprocess. Growth factors are biologically active polypeptides. They perform activities such as cell growth, differentiation,proliferation and migration with molecular cascades by binding to specific receptors. Transforming growth factorstimulates (TGF-β) different cell types in the wound healing process. Poly(lactic-co-glycolic acid) (PLGA) degradationproduces lactate that expedites angiogenesis, activates pro-collagen factors. Therewith, we hypothesized to combine thetherapeutic effect of the TGF-β1with the positive effect of the drug delivery system including PLGA nanoparticles (TGFβ- PLGA NP). The burst effect decreases as the polymer concentration increases in PLGA nanoparticles. The inhibitoryeffect of TGF-β1 on keratinocytes was reduced by the improved nanoparticle formulations. It showed a proliferativeeffect of up to 92.5 per cent on fibroblast cells involved in wound healing. Although TGF-β1 has an inhibitory effect onkeratinocytes, it induces migration both NIH-3T3 and HaCaT cell lines in the scratch assay.

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[1] Hardwicke J, Schmaljohann D, Boyce D, Thomas D. Epidermal growth factor therapy and wound healing—past, present and future perspectives. The Surgeon. 2008; 6(3): 172-177. [CrossRef]
[2] Martin P. Wound healing--aiming for perfect skin regeneration. Science. 1997; 276 (5309): 75-81. [CrossRef]
[3] Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012; 25(7): 304-314. [CrossRef]
[4] Chereddy KK, Lopes A, Koussoroplis S, Payen V, Moia C, Zhu H, et al. Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomedicine. 2015; 11(8): 1975- 1984. [CrossRef]
[5] Chereddy KK, Vandermeulen G, Preat V. PLGA based drug delivery systems: Promising carriers for wound healing activity. Wound Repair Regen. 2016; 24(2): 223-236. [CrossRef]
[6] Puolakkainen PA, Twardzik DR, Ranchalis JE, Pankey SC, Reed MJ, Gombotz WR. The enhancement in wound healing by transforming growth factor-β1 (TGF-β1) depends on the topical delivery system. J Surg Res.1995; 58(3): 321-329. [CrossRef]
[7] Le M, Naridze R, Morrison J, Biggs LC, Rhea L, Schutte BC, et al. Transforming growth factor Beta 3 is required for excisional wound repair in vivo. PloS one. 2012; 7(10): e48040. [CrossRef]
[8] O'Kane S, Ferguson MW. Transforming growth factor βs and wound healing. Int J Biochem Cell Biol. 1997; 29(1): 63- 78. [CrossRef]
[9] Beanes SR, Dang C, Soo C, Ting K. Skin repair and scar formation: the central role of TGF-beta. Expert Rev Mol Med. 2003; 5(8): 1-22. [CrossRef]
[10] Gainza G, Villullas S, Pedraz JL, Hernandez RM, Igartua M. Advances in drug delivery systems (DDSs) to release growth factors for wound healing and skin regeneration. Nanomedicine. 2015; 11(6): 1551-1573. [CrossRef]
[11] Derman S, Kızılbey K, Akdeste Z. Polimeric Nanoparticles. Sigma Journal of Engineering and Natural Sciences. 2013; 31: 109-122.
[12] Dai C, Wang B, Zhao H. Microencapsulation peptide and protein drugs delivery system. Colloids Surf B Biointerfaces. 2005; 41(2-3): 117-120. [CrossRef]
[13] Jaklenec A, Hinckfuss A, Bilgen B, Ciombor DM, Aaron R, Mathiowitz E. Sequential release of bioactive IGF-I and TGF-beta 1 from PLGA microsphere-based scaffolds. Biomaterials. 2008; 29(10): 1518-1525. [CrossRef]
[14] Nie L, Zhang G, Hou R, Xu H, Li Y, Fu J. Controllable promotion of chondrocyte adhesion and growth on PVA hydrogels by controlled release of TGF-β1 from porous PLGA microspheres. Colloids Surf B Biointerfaces. 2015; 125: 51-57. [CrossRef]
[15] Sun SB, Liu P, Shao FM, Miao QL. Formulation and evaluation of PLGA nanoparticles loaded capecitabine for prostate cancer. Int J Clin Exp Med. 2015; 8(10): 19670-19681.
[16] Sezer AD, Cevher E, Hatipoğlu F, Oğurtan Z, Baş AL, Akbuğa J. The use of fucosphere in the treatment of dermal burns in rabbits. Eur J Pharm Biopharm. 2008; 69(1): 189-198. [CrossRef]
[17] Kockisch S, Rees GD, Young SA, Tsibouklis J, Smart JD. Polymeric Microspheres for Drug Delivery to the Oral Cavity: An In Vitro Evaluation of Mucoadhesive Potential. J Pharm Sci. 2003; 92(8): 1614-1623. [CrossRef]
[18] Erdem-Çakmak F, Özbaş-Turan S, Şalva E, Akbuğa J. Comparison of VEGF gene silencing efficiencies of chitosan and protamine complexes containing shRNA. Cell Biol Int. 2014; 38(11): 1260-1270. [CrossRef]
[19] Wolf NB, Küchler S, Radowski MR, Blaschke T, Kramer KD, Weindl G, et al. Influences of opioids and nanoparticles on in vitro wound healing models. Eur J Pharm Biopharm. 2009; 73(1): 34-42. [CrossRef]
[20] Silva AL, Soema PC, Slütter B, Ossendorp F, Jiskoot W. PLGA particulate delivery systems for subunit vaccines: Linking particle properties to immunogenicity. Hum Vaccin Immunother. 2016; 12(4): 1056-1069. [CrossRef]
[21] Mainardes RM, Evangelista RC. PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution. Int J Pharm. 2005; 290(1-2): 137-144. [CrossRef]
[22] Chaisri W, Hennink WE, Okonogi S. Preparation and characterization of cephalexin loaded PLGA microspheres. Curr Drug Deliv. 2009; 6(1): 69-75. [CrossRef]
[23] Kwon H-Y, Lee J-Y, Choi S-W, Jang Y, Kim J-H. Preparation of PLGA nanoparticles containing estrogen by emulsification–diffusion method. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2001; 182(1-3): 123-130. [CrossRef]
[24] Xu B, Mensah RA, Kirton SB, Cook MT, Styliari ID, Hutter V, et al. Optimising poly(lactic-co-glycolic acid) microparticle fabrication using a Taguchi orthogonal array design-of-experiment approach. Plos One. 2019; 14(9): e0222858. [CrossRef]
[25] Vaidya PK. Mater Thesis. Controlled Delivery of TGF-ß1 from PLGA Nanoparticles. Department of Biomedical Engineering, Cleveland State University, Ohio, USA, 2012.
[26] Jaklenec A, Wan E, Murray ME, Mathiowitz E. Novel scaffolds fabricated from protein-loaded microspheres for tissue engineering. Biomaterials. 2008; 29(2): 185-192. [CrossRef]
[27] Lu L, Stamatas GN, Mikos AG. Controlled release of transforming growth factor ?1 from biodegradable polymer microparticles. J Biomed Mater Res. 2000; 50(3): 440-451. [CrossRef]
[28] Jhunjhunwala S, Balmert SC, Raimondi G, Dons E, Nichols EE, Thomson AW, et al. Controlled release formulations of IL-2, TGF-β1 and rapamycin for the induction of regulatory T cells. J Control Release. 2012; 159(1): 78-84. [CrossRef]
[29] Javadzadeh Y, Ahadi F, Davaran S, Mohammadi G, Sabzevari A, Adibkia K. Preparation and physicochemical characterization of naproxen–PLGA nanoparticles. Colloids Surf B Biointerfaces. 2010; 81(2): 498-502. [CrossRef]
[30] Yang Z, Wang L, Tian L, Zhang X, Huang G. Tadalafil-loaded PLGA microspheres for pulmonary administration: preparation and evaluation. Braz J Pharm Sci. 2019; 55: e17536. [CrossRef]
[31] Son S, Lee WR, Joung YK, Kwon MH, Kim YS, Park KD. Optimized stability retention of a monoclonal antibody in the PLGA nanoparticles. Int J Pharm. 2009; 368(1-2): 178-185. [CrossRef]