Fabrication of micellar nanoparticles for drug delivery through the self-assembly of block copolymers
Introduction
Block copolymers can be effective drug delivery vehicles because they spontaneously self-assemble in solution to form micelles with sizes ranging from tens of nanometers to several hundred nanometers [1], [2]. Micelles have been demonstrated to improve the apparent water solubility of hydrophobic drugs, including anti-cancer drugs [3], [4], [5], [6]. Increasing the apparent solubility of a hydrophobic drug is a key challenge in terms of drug delivery, as it increases the availability of the drug for action within the tumor. In other words, it permits drugs to be more effectively administered, transported, and ultimately delivered to the desired location through the bloodstream, which consists mostly of water.
In addition to improving the apparent water solubility, polymeric micelles can potentially provide both passive and active targeting capabilities, increasing the specificity of drug activity and thereby decreasing side effects [7]. Polymeric micelles have been shown to target tumor tissues preferentially, both as a result of passive accumulation through tumors’ enhanced permeability and retention (EPR) effect [8], [9], and through deliberate active targeting using ligands, such as folic acid, and antibodies [10]. The EPR effect exploits an increased porosity of the vasculature immediately surrounding a tumor and a poorly developed lymphatic system, which inhibits the ability of macromolecules to exit the tumor. The increased porosity permits the passage of large particles, with diameters around 100 nm, which are excluded by the endothelial cells lining healthy capillary walls, while the poorly developed lymphatic system enhances their retention [11].
Stealth micelles in the size range 10–100 nm are large enough to avoid excretion through the kidneys, but small enough to bypass filtration in the spleen, which leads to a prolonged circulation time of these particles [1]. A prolonged circulation time results in several therapeutic benefits: it permits increased passive accumulation through the EPR effect, and it increases the probability of contact between actively targeting drugs and their targets. Thus, polymeric micelles enable the administration of higher drug doses while reducing toxic side effects in healthy tissue [10].
A key technological challenge in the preparation and use of polymeric micelles as drug carriers lies in the loading and release of the intended drug. Low drug loading causes high drug cost and low therapeutic efficacy. Poor release profiles, for example, ‘burst release’, when the majority of the drug is released immediately upon introduction into the blood stream, limit the effectiveness of any drug delivery system. In response to these challenges, a wide array of materials and preparation methods have been proposed, creating a significant science base for these types of systems.
Drawing from this knowledge base, this review aims to present a substantive overview of the science and technology of preparing block copolymer nanoparticles for drug delivery applications, including examples of common materials and methods and the underlying principles that influence the outcomes and ultimately point the way toward optimizing polymeric drug delivery systems. Drug-loaded nanoparticles, if promising at the stage of physical characterization, typically undergo in vitro and in vivo tests. While the test results and their interpretation are a large subject, such test procedures are well-established and therefore not included in this review.
Section snippets
Self-assembly of block copolymers in solution
Self-assembly of block copolymers in solution is driven by the different affinity, also referred to as block selectivity, of the solvent to each block of the copolymer. For an amphiphilic diblock copolymer in water, for example, a micelle consists of a corona formed by the hydrophilic block extending into the solvent, and a core formed by the hydrophobic blocks clustered in the micelle center, away from the solvent. The specific size and morphology of such self-assembled structures is driven
Drug encapsulation physics
Micelles formed from amphiphilic block copolymers can encapsulate, and hence increase the apparent solubility of hydrophobic molecules in water, but the mechanisms of encapsulation are poorly understood. Factors that affect drug encapsulation include drug–core compatibility [94], [95], core-forming block length [96], [97] and crystallinity [98], solution concentrations of the polymer and drug [96], and micelle preparation method [99]. These factors are analyzed using the following terms. Drug
Direct dissolution
In a direct dissolution method, the polymer and drug are dissolved in an aqueous solvent, which leads to micellization, as illustrated in Fig. 6. This technique, used mainly for moderately hydrophobic polymers, such as PEG–PPO, and drugs, relies on heating the solution to promote micellization. The mechanism by which micellization occurs as a result of heating is hypothesized to be a result of dehydration of the hydrophobic core [110]. Highly hydrophobic drugs generally cannot be incorporated
Conclusions and challenges
In summary, block copolymers offer the ability to self-assemble into uniform, nanosized micelles and hence accumulate in tumors via the enhanced permeability and retention effect. The key strength of block copolymers as drug delivery vehicles is their customizability. Polymer composition can be chosen to control the micelle size and compatibility with the drug of choice, and the manner in which the micelles themselves are prepared can be used to optimize drug loading and, to an extent, drug
Acknowledgements
We gratefully acknowledge the financial support from the National Science Foundation (Grants CTS 0828472, DMR 0705298, CBET 0753109) and the Department of Defense (Grant BC083821) for our research in block copolymer micelles.
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