One‐Pot Synthesis of an Acid‐Labile Amphiphilic Triblock Copolymer and its pH‐Responsive Vesicular Assembly

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal trafficking disorder, in which the cholesterols are abnormally accumulated in lysosomes. Recently, the β-cyclodextrin (CD) derivatives are revealed to show therapeutic effect for NPC disease through the removal of accumulated cholesterols in lysosomes. Herein, to enhance the therapeutic effect and reduce the toxicity of β-CD derivatives, biocleavable Pluronic/β-CD-based polyrotaxanes (PRXs) bearing terminal disulfide linkages that can release threaded β-CDs in lysosomes were developed. The biocleavable PRXs show negligible interaction with the plasma membrane, leading to avoiding the toxicity of β-CDs derived from their hydrophobic cavity. Additionally, lysosomal release of threaded β-CDs from biocleavable PRXs by the intracellular cleavage of terminal disulfide linkages is found to achieve approximately 100-fold higher cholesterol removal ability from NPC disease-derived cells than β-CD derivatives. Consequently, the biocleavable PRXs is considered to be a noninvasive and effective therapeutics for NPC disease.

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“…S4)373839. These types of biocleavable PRXs exert degradation by the hydrolysis under acidic endosomes and lysosomes.…”

Section: Resultsmentioning

confidence: 99%

Lysosomal-specific Cholesterol Reduction by Biocleavable Polyrotaxanes for Ameliorating Niemann-Pick Type C Disease

Tamura

Yui

2014

Sci Rep

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“…This feature, along with the simplicity of the synthetic route, highlights the utility of peptide-based assemblies for protein-induced supramolecular disassembly. Although responsive molecular assemblies have been consistently targeted for applications such as delivery and diagnostics, 10 systems that respond to protein activity are very limited. These are interesting, because aberrant protein activity is the basis for all genetic diseases.…”

mentioning

confidence: 99%

Protein-Induced Supramolecular Disassembly of Amphiphilic Polypeptide Nanoassemblies

2015

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Mimicking non-covalent interaction based processes in nature has been an important goal of supramolecular chemistry. Here, we report on amphiphilic polypeptides that self-assemble to form nanoscale supramolecular assemblies and are programmed to disassemble in response to a specific protein. Benzenesulfonamide and carbonic anhydrase have been chosen as the ligand and protein respectively to demonstrate this possibility. Since the amphiphilic nanoassembly sequesters hydrophobic guest molecules, the protein-specific disassembly event provides a protein-sensitive molecular release as well. We envision that the binding induced disassembly and guest release might open up new opportunities for the next generation of supramolecular assemblies for protein-specific delivery and diagnostics.

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“…It is also important to note that the drug release profile of this kind of pH-responsive cleavable nanocarriers is dependent on the rate of hydrolysis of acid-labile bonds. For example, micellar aggregates and polymersomes with acid-labile b-thiopropionate linker have shown sustained release of the encapsulated molecules due to the slow acid-induced hydrolysis (Dan et al 2010;Dan and Ghosh 2013). Thus, drug release rate from the micelles can be tuned by selecting appropriate acid-labile linkers.…”

Section: Ph-responsive Nanoparticles Using Cleavable Linkersmentioning

confidence: 99%

Stimuli-Responsive Polymeric Nanocarriers as Promising Drug and Gene Delivery Systems

Saravanakumar

Kim

2014

Intracellular Delivery II

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Polymeric nanocarriers have emerged as promising drug delivery vehicles owing to their potential to selectively deliver the active agents to the disease sites through various targeting mechanisms, while minimizing the side effects. To realize more enhanced therapeutic effect, it is also highly essential to impart specific release mechanism into the nanocarriers in addition to the targeting capabilities. In this regard, stimuli-sensitive or smart polymeric nanocarriers that are responsive to inherent (e.g. pH, temperature, redox, hypoxia, enzymes, and reactive oxygen species) or external stimuli (e.g. light, ultrasound or magnetic) have received enormous attention because of their ability to control the drug release profile in a desirable fashion at the target site of action. The primary focus of this chapter is to highlight the recent advances of various stimuli-responsive nanocarriers that have been developed for a more efficient drug and gene delivery.

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One‐Pot Synthesis of an Acid‐Labile Amphiphilic Triblock Copolymer and its pH‐Responsive Vesicular Assembly

Cited by 113 publications

References 59 publications

Lysosomal-specific Cholesterol Reduction by Biocleavable Polyrotaxanes for Ameliorating Niemann-Pick Type C Disease

Lysosomal-specific Cholesterol Reduction by Biocleavable Polyrotaxanes for Ameliorating Niemann-Pick Type C Disease

Protein-Induced Supramolecular Disassembly of Amphiphilic Polypeptide Nanoassemblies

Stimuli-Responsive Polymeric Nanocarriers as Promising Drug and Gene Delivery Systems

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