Disassembly of polymeric nanoparticles with enzyme-triggered polymer unzipping: polyelectrolyte complexes <i>vs.</i> amphiphilic nanoassemblies

Kumar, Vikash; Munkhbat, Oyuntuya; Seçinti, Hatice; Thayumanavan, S.

doi:10.1039/d0cc03257c

Cited by 10 publications

(7 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is clear that DDS should be, on one hand, extremely stable to withstand the high dilution and interactions with blood components in order to allow their circulation in the body while maintaining their cargo of active drug molecules . On the other hand, the carriers should be able to release the drugs when the DDS has reached the target site. − To address this need, over the last three decades, there has been a great interest in utilizing stimuli-responsive polymeric micelles as DDS to allow selective release of their therapeutic cargo. , There are many reported examples of polymeric micelles that disassemble due to changes in pH, − temperature, − or redox potential, − while there are significantly fewer examples of polymeric nanocarriers that can disassemble due to the presence of a designated enzyme. − 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. − 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. It is clear that in the biological environment, most of the interactions between the micelle and its surroundings occur through the micelle’s corona. , It is interesting to note that although most reported DDS are based on poly(ethylene glycol) (PEG), , the use of additional types of promising hydrophilic polymers such as poly(2-oxazoline)s − and polyacrylates has also been reported, inspired by the increasing human population that carries anti-PEG antibodies leading to an immune-response upon treatment with PEG-based therapeutics. , To allow the rational design of DDS, it is critical to compare and study the behavior of different corona forming polymers in order to rationally select the most suited hydrophilic block .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

Section: Overcoming the Stability-responsiveness Limitationmentioning

confidence: 99%

“…A very different approach was very recently reported by Thayumanavan and co-workers that utilized an elegant molecular design that allows the translation of an enzymatic cleavage on the surface of polymeric assemblies into complete degradation of the assembled structures (Figure ). The design is based on the use of self-immolative polymer as the hydrophilic block. As in previous reports by Shabat, Moore, Gillies, and others, − the Thayumanavan group took advantage of the ability of the self-immolative polymers to undergo controlled self-degradation upon cleavage of its head group.…”

Section: Overcoming the Stability-responsiveness Limitationmentioning

confidence: 99%

Using High Molecular Precision to Study Enzymatically Induced Disassembly of Polymeric Nanocarriers: Direct Enzymatic Activation or Equilibrium-Based Degradation?

Slor

Amir

2021

Macromolecules

View full text Add to dashboard Cite

Enzyme-responsive polymers and their assemblies offer great potential to serve as key materials for the design of drug delivery systems and other biomedical applications. However, the utilization of enzymes to trigger the disassembly of polymeric amphiphiles, such as micelles, also suffers from the limited accessibility of the enzyme to moieties that are hidden inside the assembled structures. In this Perspective, we will discuss examples for the utilization of high molecular precision that dendritic structures offer to study the enzymatic degradation of polymeric amphiphiles with high resolution. Up to date, several different amphiphilic systems based on dendritic blocks have all shown that small changes in the hydrophobicity and amphiphilicity strongly affected the degree and rate of enzymatic degradation. The ability to observe the huge effects due to relatively small variations in the molecular structure of polymers can explain the limited enzymatic degradation that is often observed for many reported polymeric assemblies. The observed trends imply that the enzymes cannot reach the hydrophobic core of the micelles, and instead, they gain access to the amphiphiles by the unimer–micelle equilibrium, making the unimer exchange rate a key parameter in tuning the enzymatic degradation rate. Several approaches that are aimed at overcoming the stability–responsiveness challenge are discussed as they open the way to the design of stable and yet enzymatically responsive polymeric nanocarriers.

show abstract

“…Therefore, designing controllable responsive polymeric vesicles for overexpressed enzymes has applications in many fields, such as diagnostics, drug delivery, and sensing. Kumar et al designed an enzyme-responsive polymersome which cleaves with phosphatase (ALP) at the phosphate end of the polymer [11]. The study divided ALP into three types: ALP-responsive polysome P0, and hydrophilic modification into it forms P1 and hydrophobic modification into it forms P2.…”

Section: Enzyme-responsive Polymersomesmentioning

confidence: 99%

Synthesis and Application of Responsive Polymersomes

Cheng¹

2022

HSET

View full text Add to dashboard Cite

Polymersomes as drug carriers make up for the shortcomings of traditional chemotherapeutic drugs, such as easy to synthesize, short circulation time, early release, and continuous cytotoxicity. Responsive polymersomes can alter their properties such as composition, size, shape, and surface functional groups according to different stimuli, enabling the delivery of cargo at hydrophilic, hydrophobic or other specific sites, and the control of drug release. This article provides an overview of what is known about different types of responsive polymeric vesicles and describes the main design choices. In this review, the mechanism and advantages of four responsive polymersomes are discussed. Furthermore, the article focuses on the synthesis methods and applications of representative examples of each stimulus. In particular, the latest progress of four type of responsive polymersomes are emphasized. Finally, based on the great progress in the current research on responsive polymersomes, this paper discusses the potential for future development and selection of more biosafety responsive polymersomes directions.

show abstract

Disassembly of polymeric nanoparticles with enzyme-triggered polymer unzipping: polyelectrolyte complexes vs. amphiphilic nanoassemblies

Abstract: Enzyme-induced chain unzipping is shown to cause nanoparticle disassembly. The self-assembly and triggered disassembly are evaluated in two different formats.

Cited by 10 publications

References 24 publications

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

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

Using High Molecular Precision to Study Enzymatically Induced Disassembly of Polymeric Nanocarriers: Direct Enzymatic Activation or Equilibrium-Based Degradation?

Synthesis and Application of Responsive Polymersomes

Contact Info

Product

Resources

About