Generic placeholder image

Current Drug Delivery


ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Research Article

Simvastatin Nanoparticles Loaded Polymeric Film as a Potential Strategy for Diabetic Wound Healing: In Vitro and In Vivo Evaluation

Author(s): Saima Tufail, Muhammad Irfan Siddique*, Muhammad Sarfraz, Muhammad Farhan Sohail, Muhammad Nabeel Shahid, Muhammad Ovais Omer, Haliza Katas and Fatima Rasool

Volume 19, Issue 5, 2022

Published on: 10 January, 2022

Page: [534 - 546] Pages: 13

DOI: 10.2174/1567201818666210720150929

Price: $65


Introduction: The pleiotropic effects of statins are recently explored for wound healing through angiogenesis and lymph-angiogenesis that could be of great importance in diabetic wounds.

Aims: The aim of the present study is to fabricate nanofilm embedded with simvastatin-loaded chitosan nanoparticles (CS-SIM-NPs) and to explore the efficacy of SIM in diabetic wound healing.

Methods: The NPs, prepared via ionic gelation, were 173 nm ± 2.645 in size with a zeta potential of -0.299 ± 0.009 and PDI 0.051 ± 0.088 with excellent encapsulation efficiency (99.97%). The optimized formulation (CS: TPP, 1:1) that exhibited the highest drug release (91.64%) was incorporated into the polymeric nanofilm (HPMC, Sodium alginate, PVA), followed by in vitro characterization. The optimized nanofilm was applied to the wound created on the back of diabetes-induced (with alloxan injection 120 mg/kg) albino rats.

Results: The results showed a significant (p < 0.05) improvement in the wound healing process compared to the diabetes-induced non-treated group. The results highlighted the importance of nanofilms loaded with SIM-NPs in diabetic wound healing through angiogenesis promotion at the wound site.

Conclusion: Thus, CS-SIM-NPs loaded polymeric nanofilms could be an emerging diabetic wound healing agent in the industry of nanomedicines.

Keywords: Simvastatin, diabetic wound healing, chitosan nanoparticles, bio-degradable, polymeric nanofilm, in vitro release, alginate.

Graphical Abstract
Adelli, G.R.; Balguri, S.P.; Bhagav, P.; Raman, V.; Majumdar, S. Diclofenac sodium ion exchange resin complex loaded melt cast films for sustained release ocular delivery. Drug Deliv., 2017, 24(1), 370-379.
[] [PMID: 28165833]
Dimatteo, R.; Darling, N.J.; Segura, T. In situ forming injectable hydrogels for drug delivery and wound repair. Adv. Drug Deliv. Rev., 2018, 127, 167-184.
[] [PMID: 29567395]
Zhang, X.; Yang, D.; Nie, J. Chitosan/polyethylene glycol diacrylate films as potential wound dressing material. Int. J. Biol. Macromol., 2008, 43(5), 456-462.
[] [PMID: 18809431]
Wang, C.C.; Yang, P.W.; Yang, S.F.; Hsieh, K.P.; Tseng, S.P.; Lin, Y.C. Topical simvastatin promotes healing of Staphylococcus aureus-contaminated cutaneous wounds. Int. Wound J., 2016, 13(6), 1150-1157.
[] [PMID: 25752328]
Asai, J.; Takenaka, H.; Hirakawa, S.; Sakabe, J.; Hagura, A.; Kishimoto, S.; Maruyama, K.; Kajiya, K.; Kinoshita, S.; Tokura, Y.; Katoh, N. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am. J. Pathol., 2012, 181(6), 2217-2224.
[] [PMID: 23138019]
Wang, Y.; Han, G.; Guo, B.; Huang, J. Hyaluronan oligosaccharides promote diabetic wound healing by increasing angiogenesis. Pharmacol. Rep., 2016, 68(6), 1126-1132.
[] [PMID: 27588388]
Aly, U.F. Preparation and evaluation of novel topical gel preparations for wound healing in diabetics. Int. J. Pharm. Pharm. Sci., 2012, 4(4), 76-77.
Badr, G. Camel whey protein enhances diabetic wound healing in a streptozotocin-induced diabetic mouse model: the critical role of β-Defensin-1, -2 and -3. Lipids Health Dis., 2013, 12(1), 46.
[] [PMID: 23547923]
Veith, A.P. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv. Drug Deliv. Rev., 2018, 146(97), 125.
[PMID: 30267742]
Lee, C-C.; Lee, M.G.; Hsu, T.C.; Porta, L.; Chang, S.S.; Yo, C.H.; Tsai, K.C.; Lee, M. A population-based cohort study on the drug-specific effect of statins on sepsis outcome. Chest, 2018, 153(4), 805-815.
[] [PMID: 28962887]
Thangamani, S.; Mohammad, H.; Abushahba, M.F.; Hamed, M.I.; Sobreira, T.J.; Hedrick, V.E.; Paul, L.N.; Seleem, M.N. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent. Sci. Rep., 2015, 5, 16407.
[] [PMID: 26553420]
Rezvanian, M.; Amin, M.C.I.M.; Ng, S-F. Development and physicochemical characterization of alginate composite film loaded with simvastatin as a potential wound dressing. Carbohydr. Polym., 2016, 137, 295-304.
[] [PMID: 26686133]
Raposio, E.; Libondi, G.; Bertozzi, N.; Grignaffini, E.; Grieco, M.P. Effects of topic simvastatin for the treatment of chronic vascular cutaneous ulcers: a pilot study. J. Am. Coll. Clin. Wound Spec., 2016, 7(1-3), 13-18.
[] [PMID: 28053863]
Dey, S. Method devlopment and validation of simvastatin by uv spectrophotometric method. Journal of Pharmacy Research, 2012, 5(12)
Hassan, S.; Prakash, G.; Ozturk, A.; Saghazadeh, S.; Sohail, M.F.; Seo, J.; Dockmeci, M.; Zhang, Y.S.; Khademhosseini, A. Evolution and clinical translation of drug delivery nanomaterials. Nano Today, 2017, 15, 91-106.
[] [PMID: 29225665]
Yang, Y. Applications of nanotechnology for regenerative medicine; healing tissues at the nanoscale. In: Principles of regenerative medicine; Elsevier Natherlands, 2019; pp. 485-504.
Jawad, A.H.; Abdulhameed, A.S.; Mastuli, M.S. Mesoporous crosslinked chitosan-activated charcoal composite for the removal of thionine cationic dye: comprehensive adsorption and mechanism study. J. Polym. Environ., 2020, 28(3), 1095-1105.
Jawad, A.H.; Abdulhameed, A.S. Facile synthesis of crosslinked chitosan-tripolyphosphate/kaolin clay composite for decolourization and COD reduction of remazol brilliant blue R dye: Optimization by using response surface methodology. Colloids Surf. A Physicochem. Eng. Asp., 2020, 605, 125329.
Ghafar, H.; Khan, M.I.; Sarwar, H.S.; Yaqoob, S.; Hussain, S.Z.; Tariq, I.; Madni, A.U.; Shahnaz, G.; Sohail, M.F. Development and characterization of bioadhesive film embedded with lignocaine and calcium fluoride nanoparticles. AAPS PharmSciTech, 2020, 21(2), 60.
[] [PMID: 31912272]
Khatoon, M.; Sohail, M.F.; Shahnaz, G.; Ur Rehman, F.; Fakhar-Ud-Din, ; Ur Rehman, A.; Ullah, N.; Amin, U.; Khan, G.M.; Shah, K.U. Development and evaluation of optimized thiolated chitosan proniosomal gel containing duloxetine for intranasal delivery. AAPS PharmSciTech, 2019, 20(7), 288.
[] [PMID: 31410741]
Jawad, A.H. Synthesis of magnetic chitosan-fly ash/fe3o4 composite for adsorption of reactive orange 16 dye: optimization by box–behnken design. J. Polym. Environ., 2020, 28(3), 1068-1082.
Jawad, A.H.; Mubarak, N.S.A.; Abdulhameed, A.S. Hybrid crosslinked chitosan-epichlorohydrin/tio2 nanocomposite for reactive red 120 dye adsorption: kinetic, isotherm, thermodynamic, and mechanism study. J. Polym. Environ., 2020, 28(2), 624-637.
Negrea, P. The study of infrared spectrum of chitin and chitosan extract as potential sources of biomass. Dig. J. Nanomater. Biostruct., 2015, 10(4) [DJNB].
Jawad, A.H. Fabrication of schiff’s base chitosan-glutaraldehyde/activated charcoal composite for cationic dye removal: optimization using response surface methodology. J. Polym. Environ., 2021, 29, 2855-2868.
Ayumi, N.S.; Sahudin, S.; Hussain, Z.; Hussain, M.; Samah, N.H.A. Polymeric nanoparticles for topical delivery of alpha and beta arbutin: preparation and characterization. Drug Deliv. Transl. Res., 2019, 9(2), 482-496.
[] [PMID: 29569027]
Jaiswal, L.; Shankar, S.; Rhim, J-W. Carrageenan-based functional hydrogel film reinforced with sulfur nanoparticles and grapefruit seed extract for wound healing application. Carbohydr. Polym., 2019, 224, 115191.
[] [PMID: 31472875]
Obagi, Z.; Damiani, G.; Grada, A.; Falanga, V. Principles of wound dressings: a review. Surg. Technol. Int., 2019, 35, 50-57.
[PMID: 31480092]
Sajjad, M.; Khan, M.I.; Naveed, S.; Ijaz, S.; Qureshi, O.S.; Raza, S.A.; Shahnaz, G.; Sohail, M.F. Folate-functionalized thiomeric nanoparticles for enhanced docetaxel cytotoxicity and improved oral bioavailability. AAPS PharmSciTech, 2019, 20(2), 81.
[] [PMID: 30645705]
Siddique, M.I.; Katas, H.; Amin, M.C.I.M.; Ng, S.F.; Zulfakar, M.H.; Buang, F.; Jamil, A. Minimization of local and systemic adverse effects of topical glucocorticoids by nanoencapsulation: in vivo safety of hydrocortisone–hydroxytyrosol loaded chitosan nanoparticles. J. Pharm. Sci., 2015, 104(12), 4276-4286.
[] [PMID: 26447747]
Sarwar, H.S.; Ashraf, S.; Akhtar, S.; Sohail, M.F.; Hussain, S.Z.; Rafay, M.; Yasinzai, M.; Hussain, I.; Shahnaz, G. Mannosylated thiolated polyethylenimine nanoparticles for the enhanced efficacy of antimonial drug against Leishmaniasis. Nanomedicine (Lond.), 2018, 13(1), 25-41.
[] [PMID: 29173059]
Pereda, M. Chitosan-gelatin composites and bi-layer films with potential antimicrobial activity. Food Hydrocoll., 2011, 25(5), 1372-1381.
Sievens-Figueroa, L.; Bhakay, A.; Jerez-Rozo, J.I.; Pandya, N.; Romañach, R.J.; Michniak-Kohn, B.; Iqbal, Z.; Bilgili, E.; Davé, R.N. Preparation and characterization of hydroxypropyl methyl cellulose films containing stable BCS Class II drug nanoparticles for pharmaceutical applications. Int. J. Pharm., 2012, 423(2), 496-508.
[] [PMID: 22178619]
Thu, H-E.; Zulfakar, M.H.; Ng, S-F. Alginate based bilayer hydrocolloid films as potential slow-release modern wound dressing. Int. J. Pharm., 2012, 434(1-2), 375-383.
[] [PMID: 22643226]
Sukpat, S.; Israsena, N.; Patumraj, S. Pleiotropic effects of simvastatin on wound healing in diabetic mice. J. Med. Associ. Thailand, 2016, 99(2), 213-219.
Kant, V.; Gopal, A.; Kumar, D.; Pathak, N.N.; Ram, M.; Jangir, B.L.; Tandan, S.K.; Kumar, D. Curcumin-induced angiogenesis hastens wound healing in diabetic rats. J. Surg. Res., 2015, 193(2), 978-988.
[] [PMID: 25454972]
Zahiri, M.; Khanmohammadi, M.; Goodarzi, A.; Ababzadeh, S.; Sagharjoghi Farahani, M.; Mohandesnezhad, S.; Bahrami, N.; Nabipour, I.; Ai, J. Encapsulation of curcumin loaded chitosan nanoparticle within poly (ε-caprolactone) and gelatin fiber mat for wound healing and layered dermal reconstitution. Int. J. Biol. Macromol., 2020, 153, 1241-1250.
[] [PMID: 31759002]
Clogston, J.D.; Patri, A.K. Zeta potential measurement. In: Characterization of nanoparticles intended for drug delivery; McNeill, S.; Ed.; Springer: Germany, 2011; pp. 63-70.
Stie, M.B.; Thoke, H.S.; Issinger, O.G.; Hochscherf, J.; Guerra, B.; Olsen, L.F. Delivery of proteins encapsulated in chitosan-tripolyphosphate nanoparticles to human skin melanoma cells. Colloids Surf. B Biointerfaces, 2019, 174, 216-223.
[] [PMID: 30465996]
Ahmad, Z.; Khan, M.I.; Siddique, M.I.; Sarwar, H.S.; Shahnaz, G.; Hussain, S.Z.; Bukhari, N.I.; Hussain, I.; Sohail, M.F. Fabrication and characterization of thiolated chitosan microneedle patch for transdermal delivery of tacrolimus. AAPS PharmSciTech, 2020, 21(2), 68.
[] [PMID: 31950394]
Khan, Q.U.; Siddique, M.I.; Rasool, F.; Naeem, M.; Usman, M.; Zaman, M. Development and characterization of orodispersible film containing cefixime trihydrate. Drug Dev. Ind. Pharm., 2020, 46(12), 2070-2080.
[] [PMID: 33112681]
Alavi, T.; Rezvanian, M.; Ahmad, N.; Mohamad, N.; Ng, S.F. Pluronic-F127 composite film loaded with erythromycin for wound application: formulation, physicomechanical and in vitro evaluations. Drug Deliv. Transl. Res., 2019, 9(2), 508-519.
[] [PMID: 29181832]
Veeruraj, A.; Liu, L.; Zheng, J.; Wu, J.; Arumugam, M. Evaluation of astaxanthin incorporated collagen film developed from the outer skin waste of squid Doryteuthis singhalensis for wound healing and tissue regenerative applications. Mater. Sci. Eng. C, 2019, 95, 29-42.
[] [PMID: 30573252]
Aramwit, P.; Ratanavaraporn, J.; Siritientong, T. Improvement of physical and wound adhesion properties of silk sericin and polyvinyl alcohol dressing using glycerin. Adv. Skin Wound Care, 2015, 28(8), 358-367.
[] [PMID: 26181860]
Singh, B.; Kumar, A. Graft and crosslinked polymerization of polysaccharide gum to form hydrogel wound dressings for drug delivery applications. Carbohydr. Res., 2020, 489, 107949.
[] [PMID: 32050103]
Pereira, R.; Carvalho, A.; Vaz, D.C.; Gil, M.H.; Mendes, A.; Bártolo, P. Development of novel alginate based hydrogel films for wound healing applications. Int. J. Biol. Macromol., 2013, 52, 221-230.
[] [PMID: 23059189]
Kersani, D.; Mougin, J.; Lopez, M.; Degoutin, S.; Tabary, N.; Cazaux, F.; Janus, L.; Maton, M.; Chai, F.; Sobocinski, J.; Blanchemain, N.; Martel, B. Stent coating by electrospinning with chitosan/poly-cyclodextrin based nanofibers loaded with simvastatin for restenosis prevention. Eur. J. Pharm. Biopharm., 2020, 150, 156-167.
[] [PMID: 32179100]
Safdar, R. Preparation, characterization and stability evaluation of ionic liquid blended chitosan tripolyphosphate microparticles. J. Drug Deliv. Sci. Technol., 2019, 50, 217-225.
Abdulhameed, A.S.; Mohammad, A-T.; Jawad, A.H. Application of response surface methodology for enhanced synthesis of chitosan tripolyphosphate/TiO2 nanocomposite and adsorption of reactive orange 16 dye. J. Clean. Prod., 2019, 232, 43-56.
Siddique, M.I.; Katas, H.; Jamil, A.; Mohd Amin, M.C.I.; Ng, S.F.; Zulfakar, M.H.; Nadeem, S.M. Potential treatment of atopic dermatitis: tolerability and safety of cream containing nanoparticles loaded with hydrocortisone and hydroxytyrosol in human subjects. Drug Deliv. Transl. Res., 2019, 9(2), 469-481.
[] [PMID: 29159691]
Ko, H.H.T.; Lareu, R.R.; Dix, B.R.; Hughes, J.D. Statins: antimicrobial resistance breakers or makers? PeerJ, 2017, 5, e3952.
[] [PMID: 29085751]
Ko, H.H.T.; Lareu, R.R.; Dix, B.R.; Hughes, J.D. Effect of statins on sepsis outcome in a population-based cohort study. Chest, 2018, 154(3), 718-719.
[] [PMID: 30195354]
Bahrambeigi, S.; Rahimi, M.; Yousefi, B.; Shafiei-Irannejad, V. New potentials for 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase inhibitors: Possible applications in retarding diabetic complications. J. Cell. Physiol., 2019, 234(11), 19393-19405.
[] [PMID: 31004363]
Mustoe, T.A. Topical treatment of wounds with statins and cholesterol for scar reduction.US Patent 20190030045, 2019.
Olivetti, C.E.; Alvarez Echazú, M.I.; Perna, O.; Perez, C.J.; Mitarotonda, R.; De Marzi, M.; Desimone, M.F.; Alvarez, G.S. Dodecenylsuccinic anhydride modified collagen hydrogels loaded with simvastatin as skin wound dressings. J. Biomed. Mater. Res. A, 2019, 107(9), 1999-2012.
[] [PMID: 31071230]
Indumathi, M.P.; Saral Sarojini, K.; Rajarajeswari, G.R. Antimicrobial and biodegradable chitosan/cellulose acetate phthalate/ZnO nano composite films with optimal oxygen permeability and hydrophobicity for extending the shelf life of black grape fruits. Int. J. Biol. Macromol., 2019, 132, 1112-1120.
[] [PMID: 30926493]
Aslan, A.; Elanthikkal, S.; Bozkurt, A. Chitosan/hollow silica sphere nanocomposites for wound healing application. J. Mater. Res., 2019, 34(2), 231-239.
Qi, L.; Xu, Z.; Jiang, X.; Hu, C.; Zou, X. Preparation and antibacterial activity of chitosan nanoparticles. Carbohydr. Res., 2004, 339(16), 2693-2700.
[] [PMID: 15519328]
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.
[] [PMID: 27126165]
Noishiki, C.; Yuge, S.; Ando, K.; Wakayama, Y.; Mochizuki, N.; Ogawa, R.; Fukuhara, S. Live imaging of angiogenesis during cutaneous wound healing in adult zebrafish. Angiogenesis, 2019, 22(2), 341-354.
[] [PMID: 30607697]
Patrulea, V.; Ostafe, V.; Borchard, G.; Jordan, O. Chitosan as a starting material for wound healing applications. Eur. J. Pharm. Biopharm., 2015, 97(Pt B), 417-426.
[] [PMID: 26614560]
Pansara, C.; Mishra, R.; Mehta, T.; Parikh, A.; Garg, S. Formulation of chitosan stabilized silver nanoparticle-containing wound healing film: in vitro and in vivo characterization. J. Pharm. Sci., 2020, 109(7), 2196-2205.
[] [PMID: 32240689]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy