Judging Enzyme-Responsive Micelles by Their Covers: Direct Comparison of Dendritic Amphiphiles with Different Hydrophilic Blocks

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.

Stimuli‐Responsive Nanoparticles for Controlled Drug Delivery in Synergistic Cancer Immunotherapy

“…The enzyme reactions observed in all pathological, physiological, and metabolic processes are efficient and selective, which have been employed as responsive modules for designing en‐srNPs. [ 113 ] Therefore, enzyme‐mediated en‐srNPs for controlled drug delivery are cataloged by the effector biomolecule, such as proteases, lipases, hydrolases, oxidoreductases, and glycosidase. [ 114 ] For example, the core‐shell ICG/DOX@Gel‐CuS en‐srNP was consisted of CuS en‐srNP and gelatin (Gel) en‐srNP with loading DOX/ICG.…”

Biological activity In vitro, absorption, BBB penetration and toxicity of nanoformulation of BT44, a RET agonist with disease-modifying potential for the treatment of neurodegeneration

“…It is commonly believed that the hydrophobic core is responsible for drug encapsulation and the hydrophilic shell interacts with solvent molecules (representing core-shell morphology) providing colloidal stability [22,23]. Depending on the nature of the hydrophilic domain, cargo and employed (cargo) load, it is becoming more evident that at certain threshold drug concentration, the hydrophilic domain also starts to interact [24][25][26][27][28][29] with the cargo, indicative of much complex morphologies [30][31][32]. To date, many polymeric micellar formulations underwent preclinical and clinical trials presenting improved pharmacological activity with lower systemic toxicity [20,[33][34][35], but successful translation into clinics have been few.…”

Dendron-Polymer Hybrids as Tailorable Coronae of Single-Walled Carbon Nanotube

“…40,41 Dendrons can be coupled to a variety of polymers to create a library of amphiphilic molecules with the ability to suspend SWCNTs in aqueous environment and providing designable wrapping agents to address the requirements of a particular application. 42 Previously, polystyrene coupled to pyrenefunctionalized dendrons were reported to suspend SWCNTs in THF, 43 while hydrophilic dendrons coupled to a hydrophobic alkyl-chain or pyrene have been reported to suspend SWCNTs in water, due to increasing hydrophilicity with increasing dendron generation. [44][45][46][47] Nevertheless, designing hydrophobic dendrons as the binding sites provides a high degree of control over their direct interaction with the SWCNT surface.…”