Calculating the Hydrodynamic Volume of Poly(ethylene oxylated) Single-Walled Carbon Nanotubes and Hydrophilic Carbon Clusters Alfredo D. Bobadilla, †,‡ Errol. L. G. Samuel, ¶ James M. Tour,* ,¶,∥,⊥ and Jorge M. Seminario* ,†,‡,§ † Department of Chemical Engineering, ‡ Department of Electrical and Computer Engineering, and § Materials Science and Engineering Graduate Program, Texas A&M University, College Station, Texas 77843, United States, and ¶ Department of Chemistry, ∥ Department of Mechanical Engineering and Materials Science, and ⊥ Smalley Institute for Nanoscale Science and Technology, Rice University, 6100 Main Street, Houston Texas 77005, United States ABSTRACT: Poly(ethylene glycol) (PEG) functionalization of carbon nanotubes (CNTs) is widely used to render CNTs suitable as vectors for targeted drug delivery. One recently described PEGylated version uses an oxidized single-walled carbon nanotube called a hydrophilic carbon cluster (HCC). The resulting geometric dimension of the hybrid PEG−CNT or PEG−HCC is an important factor determining its ability to permeate the cellular membrane and to maintain its blood circulation. Molecular dynamics (MD) simulations were performed to estimate the maximum length and width dimensions for a PEGylated single-walled carbon nanotube in water solution as a model for the PEG−HCC. We ensured maximum PEGylation by functionalizing each carbon atom in a CNT ring with an elongated PEG molecule, avoiding overlapping between PEGs attached to different CNT rings. We suggest that maximum PEGylation is important to achieve an optimal drug delivery platform. ■ INTRODUCTION Carbon nanotubes constitute an emerging class of drug delivery platforms. 1,2 The very small dimension of carbon nanotubes, especially in the radial direction, ensures efficient circulation through blood. 3 A very effective version of this consists of shortened (40−60 nm long) oxidized carbon nanotubes 4,5 to which solubilizing addends, 6 namely 5000 molecular weight poly(ethylene glycol) moieties, have been attached. 7 The entire constructs are termed poly(ethylene glycol)-functionalized hydro- philic carbon clusters (PEG−HCCs) and these have recently been shown to have enormous efficacy and ultralow toxicity. 8,9 These PEG−HCCs are very short compared to the CNTs used in earlier studiesthey are short enough that they show efficient clearance via the kidneys and nontoxicity in mammalsand are proving to be exceedingly effective for in vitro and in vivo drug delivery. 10−12 A considerable number of drugs with high therapeutic efficacy are of hydrophobic nature. 13,14 We would expect some affinity of these drugs to CNTs, as CNTs themselves are inherently hydrophobic. 15 In addition, in order to maintain the properties of these drugs, it is preferable that they be noncovalently loaded onto the CNT construct. 7,16 Studies of hydrophobicity in toxicity prediction were performed by Cronin 17 and Moyano et al.; 18 however, further research is needed to explore biological res- ponses to carbon nanomaterials. Fortunately, PEG has excellent solubility in water, and CNT functionalization with PEG imparts increased solubility in water solutions as well as reduced toxi- city. 19 We therefore expect PEG−CNT constructs to have strategically localized hydrophobic and hydrophilic sites, making them excellent therapeutic carriers. HCCs do in fact have hydro- phobic domains which ensure drug sequestration, but they also have oxidized sites for covalent PEG attachment. PEG−HCCs have demonstrated very high effectiveness for both untargeted and antibody-targeted delivery, but little is known regarding their actual hydrodynamic volume when water-association is man- ifested. This question is addressed here using a shortened single- walled carbon nanotube as the central core and PEG addends. Molecular simulations provide complementary information to experimental techniques by enabling the analysis of the structure and fast dynamics with atomistic detail. 20−22 Classical molecular dynamics simulations are playing an increasingly important role in drug discovery 23,24 to the point that they are becoming essen- tial and not just complementary. Simulation techniques are used for example in the identification of binding sites 25 and prediction of ligand binding energies 26,27 and to understand the atomistic energetics and mechanics of binding. 28 CHARMM is a widely used force field for molecular dynamics simulations and it has been parametrized for di fferent types of biological molecules, 29−31 for ethers (CHARMM35), 32 for hybrid nanomaterials 33−35 and recently also for drug-like molecules. 36 A revised version CHARMM-35r for ethers reported by Lee et al., 37 refitted the OCCO dihedral potential energy, yielding excellent agreement with experiment for persistence lengths and hydrodynamic radii at high and low molecular weights. In the present work, we perform molecular dynamics calcula- tions on a PEG 114-mer in water to obtain a PEG with globular shape. This 114-mer affords a 5040 molecular weight chain, the typical chain length found in PEG−CNTs for biological applica- tions. 7,16 We then analyze the maximum number of PEG mole- cules that can possibly be covalently linked to a CNT sidewall. Finally, after equilibration at room temperature, we analyze the geometry of the PEG−CNT construct. Received: May 31, 2012 Revised: December 2, 2012 Article pubs.acs.org/JPCB © XXXX American Chemical Society A dx.doi.org/10.1021/jp305302y | J. Phys. Chem. B XXXX, XXX, XXX−XXX