Factors Affecting Drug Loading

The partitioning behavior of drugs into the micelle core, core-corona interface and/or corona controls the amount of drug that can be solubilized in the micelles. However, for a block copolymer micelle system to act as a true carrier, it must retain the drug within the micelles for prolonged periods of time following administration. Also, it is highly unlikely that a single block copolymer micelle system can effectively deliver all types of drugs. Therefore, selecting a core block for the drug of interest is an important consideration in the design of an effective micelle delivery system. Micelle drug loading is influenced by several factors, including the hydrophobicity and length of the core-forming block, the length of the corona-forming block, the specific interactions between the drug and core, and the method of micelle preparation.

The hydrophobicity and length of the core-forming block have a great influence on the size of the micelles and the loading into the core of the micelle. For example, Lin et al. reported that increasing the degree of hydrophobicity of the core-forming block improved the drug loading into the micelles.54 Also a larger amount of drug can be incorporated into micelles formed from copolymers having a larger core-forming block in comparison to a shorter hydrophobic block. For example, Shuai et al. demonstrated that for doxorubicin-loaded micelles formed from PEG-b-PCL copolymers with a constant PEG block length, increasing the PCL block length resulted in an increase in doxorubicin loading from 3.1% to 4.3% (wt./wt.). The hydrophilic block length can also influence drug loading. By increasing the corona-forming block, the CMC will also increase, and this may result in a decrease in the aggregation number (Nagg). For example, Gadelle et al.

showed that increasing the PEG block length caused an increase in the CMC, a decrease in the Nagg, and a decrease in the degree of solubilization of hydrophobic agent into the micelles.55

Specific interactions between the core-forming block and entrapped drug can also affect drug loading in the micelles. This is referred to as polymer-drug compatibility where the compatibility is defined as interaction between the two species that does not involve any chemical change to either the drug or the polymer. Typically, the interactions that are present between polymer and drug are hydrogen bonding, ionic, and pi-pi. Lee et al. showed that by increasing the number of functiona-lized carboxylic acid (COOH) groups from 0% to 19.5% (weight percent of repeat units), they were able to augment papaverine loading from 3.5% to 15% (wt./wt.) in PEG-b-PDLLA micelles. They attributed the increase in papaverine loading levels to hydrogen bonding interactions between the COOH groups of the copolymer and the unpaired electron groups of the oxygen and/or nitrogen atoms in the drug.56 Other approaches include improving drug loading by enhancing the local microenvironment of the micelle core through the means of conjugation of a small amount of drug16 or conjugation of side chains with similar structures to the drug.57,58

Finally, the method that is selected for preparation of the micelles has also been shown to have an effect on the overall degree of drug loading. Yokoyama et al. have shown that using different micelle preparation techniques led to distinctly different drug loading efficiencies for campthothecin (CPT) in a series of PEG-b-poly(aspartate ester) copolymers.38,59 The use of the dialysis method resulted in a CPT loading efficiency of 19% and a cloudy formulation with large aggregates and drug precipitates. In contrast, when CPT was loaded using the evaporation method, a loading efficiency of 73% was obtained and also a clear solution was observed.38 In addition to the selection of the preparation method, method-specific parameters (nature of organic solvent, solvent ratio) have also been proven to affect drug loading into the micelles. Yokoyama et al. showed that the use of dimethylformamide to prepare KRN 5500 loaded PEG-b-poly(16-b-cetyl-L-aspartate-co-b-benzyl-L-aspartate) micelles resulted in a higher drug loading level when compared to using dimethylsulfoxide.60 The ability to achieve a high drug loading level is important as this allows for maximization of the drug to polymer ratio that, in turn, means that less copolymer will need to be administered per dose of formulation.

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