Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst TAT-surface modified acyclovir-loaded albumin nanoparticles as a novel ocular drug delivery system Panita Suwannoi a , Mullika Chomnawang b , Amolnat Tunsirikongkon c , Angsuma Phongphisutthinan c , Christel C. Müller-Goymann d , Narong Sarisuta a,c,∗ a Department of Manufacturing Pharmacy, Mahidol University, Bangkok, Thailand b Department of Microbiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand c Division of Pharmaceutical Sciences, Faculty of Pharmacy, Thammasat University, Pathumthani, Thailand d Technische Universität Braunschweig, Institut für Pharmazeutische Technologie, Braunschweig 38106, Germany ARTICLEINFO Keywords: Nanoparticles Acyclovir Bovine serum albumin Transcorneal permeability Ocular drug delivery TAT peptide ABSTRACT Theaimofthisstudywastodevelopacyclovir(ACV)-loadedbovineserumalbumin(BSA)nanoparticles(NPs) whichweresurfacemodifiedwithtransactivatingtransduction(TAT)peptidetoimprovethetranscornealdrug deliveryintreatingviralrelatedkeratitis.TheTAT-surfacemodificationswerecarriedoutbybothconjugation (TAT-con)andcoating(TAT-coat)techniques.Characterizationofphysicochemicalpropertiesandassessmentof in vitro transcorneal permeation across human corneal epithelial (HCE-T) cell multilayers of prepared TAT- surface modified ACV-BSA NPs were subsequently investigated. The prepared TAT-surface modified ACV-BSA NPsappearedtobesphericalinshapeanduniforminsizeofabout200nmwithsurfacechargesrangingbetween −20 and −30 mV. Increasing TAT amount in TAT-coat ACV-BSA NPs resulted in an increased size of NPs as expected,butitwasnotthecaseforTAT-conACV-BSANPs.ThepreparedTAT-coatACV-BSANPswereshownto havelesscytotoxiceffectsonHCE-TcellsusedinpermeationstudiesthanthoseofTAT-conACV-BSANPsand ACV solution. The in vitro transcorneal permeation results indicated that TAT-coat ACV-BSA NPs could bring aboutthehighestACVpermeabilityascomparedtoACV-BSANPsandACVsolution.SuchTAT-surfacemodified ACV-BSA NPs could be developed as novel ocular drug delivery systems. 1. Introduction The eye is an organ protected from exogenous substances and ex- ternalstressbyvariousbarriers[1].Ocularviralinfections,forexample herpes simplex virus (HSV) and cytomegalovirus (CMV), are opportu- nisticpathogensassociatedwithsignificantmorbidityandmortalityin susceptible subjects such as immunocompromised patients [2–5]. Acyclovir(ACV),oneofnucleosideanalogs,hasshowntobeclinically effective against those viruses. The purine nucleoside analog acts se- lectively against viruses without causing substantial toxic effects on uninfected cells. However, due to its poor aqueous solubility and low lipophilicity, ACV exhibits low corneal permeability. As a result, ACV cannot be administered as a topical solution and is not very effective againstocularviralinfections[4–6].Severalstrategieshavebeenused toimproveocularACVbioavailabilityandtherapeuticefficacybothby chemical [4] and pharmaceutical modifications, i.e. ointments [7], microspheres[8],nanospheres[9],liposomes[6,10],andnanoparticles [11].Nanoparticlesaresolidcolloidalparticulatesystemscontainingan active pharmaceutical ingredient (API). They have been designed as drug delivery systems based on numerous advantages including the controllability of particles size, surface charge, and morphology; the versatilitytodeliveravarietyofAPI;theimprovementofsolubilityand stability of entrapped drugs; and ability to be fabricated to obtain prolonged circulation time or even enhanced cellular uptake and tar- geting abilities [12]. In general, protein nanoparticles are very promising due to bio- compatibilityandbiodegradability.Moreover,theycanbepreparedby using simple methods with mild conditions. According to their well- defined primary structure, protein-based nanoparticles could be sur- face-modified by various approaches including covalent attachment of API or ligand [12,13]. The presence of functional groups for example carboxylicandaminogroupsonalbumin-basednanoparticlesfacilitates surface modification via several techniques such as conjugation, coating, or electrostatic adsorption. In the albumin-ligand combina- tions,theproteinactsasacarrierfordrugdeliverywhiletheligandcan be used for many reasons such as modifying the pharmacokinetics https://doi.org/10.1016/j.jddst.2019.05.029 Received14December2018;Receivedinrevisedform21April2019;Accepted14May2019 ∗ Corresponding author. Department of Manufacturing Pharmacy, Mahidol University, Bangkok, Thailand. E-mail addresses: narong.sar@mahidol.ac.th, narong_s@tu.ac.th (N. Sarisuta). Journal of Drug Delivery Science and Technology 52 (2019) 624–631 Available online 17 May 2019 1773-2247/ © 2019 Published by Elsevier B.V. T