Abstract
Enzymatically degradable polymeric micelles have great potential as drug delivery systems, allowing the selective release of their active cargo at the site of disease. Furthermore, enzymatic degradation of the polymeric nanocarriers facilitates clearance of the delivery system after it has completed its task. While extensive research is dedicated toward the design and study of the enzymatically degradable hydrophobic block, there is limited understanding on how the hydrophilic shell of the micelle can affect the properties of such enzymatically degradable micelles. In this work, we report a systematic head-to-head comparison of well-defined polymeric micelles with different polymeric shells and two types of enzymatically degradable hydrophobic cores. To carry out this direct comparison, we developed a highly modular approach for preparing clickable, spectrally active enzyme-responsive dendrons with adjustable degree of hydrophobicity. The dendrons were linked with three different widely used hydrophilic polymers—poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid) using the CuAAC click reaction. The high modularity and molecular precision of the synthetic methodology enabled us to easily prepare well-defined amphiphiles that differ either in their hydrophilic block composition or in their hydrophobic dendron. The micelles of the different amphiphiles were thoroughly characterized and their sizes, critical micelle concentrations, drug loading, stability, and cell internalization were compared. We found that the micelle diameter was almost solely dependent on the hydrophobicity of the dendritic hydrophobic block, whereas the enzymatic degradation rate was strongly dependent on the composition of both blocks. Drug encapsulation capacity was very sensitive to the type of the hydrophilic block, indicating that, in addition to the hydrophobic core, the micellar shell also has a significant role in drug encapsulation. Incubation of the spectrally active micelles in the presence of cells showed that the hydrophilic shell significantly affects the micellar stability, localization, cell internalization kinetics, and the cargo release mechanism. Overall, the high molecular precision and the ability of these amphiphiles to report their disassembly, even in complex biological media, allowed us to directly compare the different types of micelles, providing striking insights into how the composition of the micelle shells and cores can affect their properties and potential to serve as nanocarriers.
Highlights
Polymeric nano-assemblies, amongst them polymeric micelles, have shown great potential as drug delivery systems (DDS) as well as in many other biomedical applications.[1−3] This is due to the ability to dramatically increase the very low water solubility of lipophilic drug molecules by encapsulating them inside the hydrophobic cavities of the assemblies, simultaneously shielding them from the hostile biological environment
There are many reported examples of polymeric micelles that disassemble due to changes in pH,[14−17] temperature,[18−22] or redox potential,[23−26] while there are significantly fewer examples of polymeric nanocarriers that can disassemble due to the presence of a designated enzyme.[27−30] Enzymes are very appealing for triggering the disassembly of drug containing micelles since they are already present in the body, known for their high substrate specificity and in many cases specific enzymes are overexpressed in diseased tissues.[31−33] Polymeric micelles are typically formed by the self-assembly of amphiphilic diblock copolymers so that the hydrophobic block forms the core and the hydrophilic block forms the micellar corona
Our synthetic methodology allows simple preparation of libraries of amphiphilic diblock copolymers that can be examined and compared in many aspects ranging from micellar stability and enzymatic degradability to more complex biological studies that are enabled due to the dendron’s unique fluorescent response
Summary
Polymeric nano-assemblies, amongst them polymeric micelles, have shown great potential as drug delivery systems (DDS) as well as in many other biomedical applications.[1−3] This is due to the ability to dramatically increase the very low water solubility of lipophilic drug molecules by encapsulating them inside the hydrophobic cavities of the assemblies, simultaneously shielding them from the hostile biological environment. The ratiometric images indicated the presence of unimers inside the cells, it is most likely that the increased internalization cannot be attributed to the disassembly of the micelles outside of the cells over time Upon addition of BSA, both PEtOx and PEG micelles showed a decrease of ∼30% in FRET-related emission, while a slight increase in both the micelle and unimer emission was observed (Figure 6B,C) These results indicate that the majority of encapsulated Cy5 molecules remained entrapped inside the micelles as complete Cy5 release would lead to a complete disappearance of the FRET signal and a substantial increase in micelle fluorescence would be expected.
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