Morphology prediction of block copolymers for drug delivery by mesoscale simulations Paola Posocco, Maurizio Fermeglia and Sabrina Pricl * Received 3rd May 2010, Accepted 13th June 2010 DOI: 10.1039/c0jm01301c Polymeric drug carriers have traditionally been considered important for enhancing drug stability and solubility, and improving transport properties of pharmaceutical molecules. Two polymers extensively studied in this regard are poly(lactide) (PLA) and poly(ethylene oxide) (PEO). Nonetheless, a systematic investigation of the main structural and physical factors influencing the ultimate morphology and structure of these block polymer nanoscopic aggregates is still lacking. In this work we report the results of a complete study on the self-assembly of (D-L)-PLA/PEO di/triblock copolymers in aqueous environment and in the presence of a model drug based on a molecular simulation recipe. In detail, atomistic molecular dynamics simulations were used to obtain dissipative particle dynamics (DPD) input parameters, and this mesoscale technique was employed to derive the entire phase diagrams for these systems. Scaling laws for micellar dimensions were applied, and micellar characteristics (e.g., aggregation number) were derived accordingly. The effect of drug-loading on the nanocarrier aggregated morphology was also investigated. Introduction Despite remarkable progress in the past century, acute and chronic maladies such as bacterial and viral infections, cancer, cardiovascular disease, and strongly debilitating central nervous system afflictions continue to take a significant toll around the world. Various types of drugs and gene therapy strategies are currently employed for the treatment of diseases based on differences between the normal and pathological tissues. These differences can be subtle and in remote areas of the body at the organ, tissue, cell, or sub-cellular levels. As pathological knowledge is leading to the molecular distinction between normal and abnormal tissue, it is predicted that more therapeutic targets will emerge at all these levels. However, the use of a specific carrier system that can overcome biological barriers and provide optimum drug concentration at the disease target at each level is required. Nanoscale drug delivery systems – or nanovectors – are ideal candidates to provide essential solutions to the time-honored problem of optimizing the therapeutic index for a treatment (i.e., to maximize efficacy while reducing health-adverse side effects). 1 Three main aspects neatly summarize the essential breakthrough opportunities for nanovector delivery; (i) selective cells and tissue targeting; (ii) ability to reach disease sites where the target cells and tissues are located, and (iii) capacity to deliver even multiple active agents on site. The use of nano- particle-based pharmaceutical carriers has well established itself over the past decade both in the pharmaceutical research and clinical settings. Nonetheless, many issues are yet to be solved before one new such material can reach the stage of clinical routine. Soft materials, which have characteristic fluid-like disorder on short scale and high order at longer length scale, are increasingly drawing the attention of both scientists and engineers as possible nanocarriers systems. Much of the interest in soft matter, which includes colloids, surfactants, membranes, (bio)polymers and their composites, stems from the inherent capacity for many of these materials to self-assemble into nanostructures. Self- organization is a powerful mean to fabricate useful nano- structured materials and is currently heavily exploited by nature in many of its systems. 2 From the standpoint of pharmaceutical technology, whose main goal is the design of technologically optimal vehicles for the administration of drugs, self-assembly represents a low-cost, fast, and easily scalable process. Among the plethora of polymeric systems with promising potential as nanoscale drug delivery systems, 3 block copolymers (BCPs) have been widely studied as long-circulating carrier for hydrophobic drugs. BCPs are composed of two or more chemi- cally distinct, and most frequently immiscible, polymer blocks covalently bound together. In the myriad of ways in which blocks can be linked to one another, the simplest and most widely employed categories so far are the AB diblock copolymers – composed of a linear chain of type A monomers bound to one end to a linear chain of type B monomers – and the ABA triblock copolymers, in which a linear chain of type B monomers is bound to both ends to a linear chain of type A monomers (see Scheme 1 (left)). Thermodynamic incompatibility between the A and B blocks drives a collection of AB or ABA copolymers to self- organize via microphase separation in which the contacts between like and unlike entities tends to be maximized and minimized, respectively. Macrophase separation is prevented by entropic forces stemming from the covalent bonds between the A- and B-blocks, and the system ultimately reaches a compromise between mixing and separation. The tendency for microphase segregation and the free energy cost of bringing into contact unlike monomers are accounted for by the corresponding values MOSE-DMNR, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy. E-mail: sabrina.pricl@dicamp.units.it; Fax: +39 040 569823; Tel: +39 040 5583750 7742 | J. Mater. Chem., 2010, 20, 7742–7753 This journal is ª The Royal Society of Chemistry 2010 PAPER www.rsc.org/materials | Journal of Materials Chemistry Downloaded by Universita Studi di Trieste on 17 February 2012 Published on 11 August 2010 on http://pubs.rsc.org | doi:10.1039/C0JM01301C View Online / Journal Homepage / Table of Contents for this issue