Abstract
Drug uptake by polymer was modeled using a molecular dynamics (MD) simulation technique. Three drugs—doxorubicin (water soluble), silymarin (sparingly water soluble) and gliclazide (water insoluble)—and six polymers with varied functional groups—alginic acid, sodium alginate, chitosan, Gantrez AN119 (methyl-vinyl–ether-co-malic acid based), Eudragit L100 and Eudragit RSPO (both acrylic acid based)—were selected for the study. The structures were modeled and minimized using molecular mechanics force field (MM+). MD simulation (Gromacs-forcefield, 300 ps, 300 K) of the drug in the vicinity of the polymer molecule in the presence of water molecules was performed, and the interaction energy (IE) between them was calculated. This energy was evaluated with respect to electric-dipole, van der Waals and hydrogen bond forces. A good linear correlation was observed between IE and our own previous data on drug uptake* [R 2 = 0.65, \( {\hbox{R}}_{\rm{adj}}^2 = 0.65,{\hbox{R}}_{\rm{pre}}^2 = 0.56, \) and a F ratio of 30.25, P < 0.001; Devarajan et al. (2005) J Biomed Nanotechnol 1:1–9]. Maximum drug uptake by the polymeric nanoparticles (NP) was achieved in water as the solvent environment. Hydrophilic interaction between NP and water was inversely correlated with drug uptake. The MD simulation method provides a reasonable approximation of drug uptake that will be useful in developing polymer-based drug delivery systems.
Similar content being viewed by others
Notes
The modeling study reported here is novel and such techniques have not been exploited fully. The polymers built are also reasonably large (6–10 mers)
Abbreviations
- MD:
-
Molecular dynamics
- MM:
-
Molecular mechanics
- IE:
-
Interaction energy
- TE:
-
Total energy
- Doxo:
-
Doxorubicin
- Glic:
-
Gliclazide
- Sily:
-
Silymarin
- NaA:
-
Sodium alginate
- Alg:
-
Alginic acid
- Gant:
-
Gantrez
- Chit:
-
Chitosan
- EL100:
-
Eudragit L100
- ERSPO:
-
Eudragit RSPO
- DDS:
-
Drug delivery system
- NP:
-
Nanoparticles
- GIT:
-
Gastro intestinal tract
- EM:
-
Energy minimization
- RMSD:
-
Root mean square deviation
References
Duncan R (2003) The drawing era of polymer therapeutics. Nat Rev Drug Discov 2:347–360
Poupaerta JH, Couvreur P (2003) A computationally derived structural model of doxorubicin interacting with oligomeric polyalkylcyanoacrylate in nanoparticles. J Control Release 92:19–26
Kataoka K, Harada A, Nagasaki Y (2001) Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev 47:113–131
Kabanov AV, Chekhonin VP, Alakhov VY, Batrakova EV, Lebedev AS, Melik-Nubarov NS, Arzhakov SA, Levashov AV, Morozov GV, Severin ES, Kabanov VA (1989) Enhancement of the polycation-mediated DNA uptake and cell transfection with Pluronic P85 block copolymer. FEBS Lett 258:343
Koziara JM, Lockman PR, Allen DD, Mumper RJ (2003) In situ blood-brain barrier transport of nanoparticles. Pharm Res 20:1772–1778
Yang L, Alexandridis P (2000) Physicochemical aspects of drug delivery and release from polymer-based colloids. Curr Opin Colloid Interface Sci 5:132–143
Bu H, Kjøniksen AL, Knudsen KD, Nyströma B (2007) Characterization of interactions in aqueous mixtures of hydrophobically modified alginate and different types of surfactant. Colloids Surf A 293:105–113
Felt O, Furrer P, Mayer JM, Plazonnet B, Buri P, Gurny R (1999) Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention. Int J Pharm 180:185–193
Yasukawa TMD, Kimura H, Tabata Y, Ogura Y (2001) Biodegradable scleral plugs for vitreoretinal drug delivery. Adv Drug Deliv Rev 52:25–36
Gomez S, Carlos C, Luquin E, San Roman B, Espuelas S, Sanz ML, Ferrer M, Irachel JM (2001) New adjuvant for immunotherapy: Gantrez® AN nanoparticles. J Allergy Clin Immunol 115:2, Abstracts S223
Weiss G, Knoch A, Laicher A, Stanislaus F, Daniels R (1993) Microencapsulation of ibuprofen by a coacervation process using Eudragit L100-55 as an enteric polymer. Drug Dev Ind Pharm 19:2751–2764
Song Y, Guallar V, Baker NA (2005) Molecular dynamics simulations of salicylate effects on the micro- and mesoscopic properties of a dipalmitoyl-phosphatidylcholine bilayer. Biochemistry 44:13425–13438
Heurtault B, Saulnier P, Pech B, Proust J, Benoit J (2003) Physicochemical stability of colloidal lipid particles. Biomaterials 24:4283–4300
Bourrel M, Schechter RS (1988) Microemulsions and related systems; formulation, solvency and physical properties. J Dispersion Sci Technol 11:431–432
Heurtault B, Saulnier P, Pech B, Proust JE, Benoit JP (2002) A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm Res 19:875–880
Devarajan PV, Sonavane GS, Doble M (2005) Computer-aided molecular modeling: a predictive approach in the design of nanoparticulate drug delivery system. J Biomed Nanotechnol 1:1–9
Xinhuai Z (2006) Three leading molecular dynamics simulation packages. SVU/Academic Computing, Computer Centre, National University of Singapore
Haddish-Berhane N, Nyquist C, Haghighi K, Corvalan C, Keshavarzian A, Campanella O, Rickus J, Farhadi A (2006) A multi-scale stochastic drug release model for polymer-coated targeted drug delivery systems. J Control Release 110:314–322
Heun G, Lambov N, Groning R (1998) Experimental and molecular modeling studies on interactions between drugs and Eudragit® RL/RS resins in aqueous environment. Pharm Acta Helv 73:57–62
Haznedar S, Dortunç B (2004) Preparation and invitro evaluation of Eudragit microspheres containing acetazolamide. Int J Pharm 269:131–140
Berendsen HJC, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56
Van der Spoel D, Lindahl E, Hess B, van Buuren AR, Apol E, Meulenhoff PJ, Tieleman DP, Sijbers ALTM, Feenstra KA, van Drunen R, Berendsen HJC (2005) Gromacs User Manual version 4.0. www.gromacs.org
Kaushik Ramakrishanan S, Krishna V, Kumar SV, Lakshmi BS, Anishetty S, Gautham P (2008) Molecular dynamics simulation of lipases. Int J Integr Biol 2:204–213
Zhang J, Lou J, Ilias S, Krishnamachari P, Yan J (2008) Thermal properties of poly(lactic acid) fumed silica nanocomposites: experiments and molecular dynamics simulations. Polym J 49:2381–2386
Stone JE (2007) VMD User's Guide Version 1.8.6, Theoretical and Computational Biophysics Group1 University of Illinois and Beckman Institute 405N. Mathews Urbana, IL 61801, April 3. http://www.ks.uiuc.edu/Research/vmd
Elmer SP, Park S, Pande VS (2005) Foldamer dynamics expressed via Markov state models. I. Explicit solvent molecular-dynamics simulations in acetonitrile, chloroform, methanol, and water. J Chem Phys 123:114902
Zhou R (2003) Free energy landscape of protein folding in water: explicit vs implicit solvent. Proteins 53:148–161
Twaites B, de las Heras Alarcón C, Alexander C (2004) Synthetic polymers as drugs and therapeutics. J Mater Sci 15:441–455
Author information
Authors and Affiliations
Corresponding author
Additional information
* Data obtained from our previous work [16]
Rights and permissions
About this article
Cite this article
Subashini, M., Devarajan, P.V., Sonavane, G.S. et al. Molecular dynamics simulation of drug uptake by polymer. J Mol Model 17, 1141–1147 (2011). https://doi.org/10.1007/s00894-010-0811-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00894-010-0811-8