Supramolecular polymer-based transformable material for reversible PEGylation of protein drugs

Utatsu, Kosei; Kogo, Tetsuya; Taharabaru, Toru; Onodera, Risako; Motoyama, Keiichi; Higashi, Taishi

doi:10.1016/j.mtbio.2021.100160

Cited by 8 publications

(15 citation statements)

References 28 publications

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“…24) We also reported that simply mixing cationic PEG and protein prevented protein aggregation. 34) Therefore, it is possible that FP-CDE alone and the TTR-CRISPR pDNA complex may also have inhibited TTR aggregation and reduced the β-sheet structure in TTR via the interaction of TTR with dendrimers and PEG. Although the factors that contributed to the higher TTR amyloid inhibitory and breaking effect of the FP-CDE/TTR-CRISPR pDNA complex compared to the FP-CDE alone are unknown, it is possible that the complexation of FP-CDE increased the steric hindrance to TTR and clustered FP-CDE molecules to enhance their electrostatic and hydrophobic interactions.…”

Section: Discussionmentioning

confidence: 99%

Feasibility Study of Dendrimer-Based TTR-CRISPR pDNA Polyplex for Ocular Amyloidosis <i>in Vitro</i>

Inoue

Muta

Mohammed

et al. 2022

Biological & Pharmaceutical Bulletin

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Hereditary amyloidgenic transthyretin (ATTR) amyloidosis is caused by a genetic point-mutated transthyretin such as TTR Val30Met (TTR V30M), since it forms protein aggregates called amyloid resulting in the tissue accumulation and functional disorders. In particular, ATTR produced by retinal pigment epithelial cells often causes ATTR ocular amyloidosis, which elicits deterioration of ocular function and ultimately blindness. Therefore, development of novel therapeutic agents is urgently needed. Genome-editing technology using Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated proteins (CRISPR-Cas9) system is expected to be a therapeutic approach to treat genetic diseases, such as ATTR amyloidosis caused by a point mutation in TTR gene. Previously, we reported that glucuronylglucosyl-βcyclodextrin conjugated with a polyamidoamine dendrimer (CDE) had excellent gene transfer ability and that underlying dendrimer inhibited TTR aggregation. Conversely, folate receptors are known to be highly expressed in retina; thus, folate has potential as a retinal target ligand. In this study, we prepared a novel folate-modified CDE (FP-CDE) and investigated its potential as a carrier for the retinal delivery of TTR-CRISPR plasmid DNA (pDNA). The results suggested that FP-CDE/TTR-CRISPR pDNA could be taken up by retinal pigment epithelial cells via folate receptors, exhibited TTR V30M amyloid inhibitory effect, and suppressed TTR production via the genome editing effect (knockout of TTR gene). Thus, FP-CDE may be useful as a novel therapeutic TTR-CRISPR pDNA carrier in the treatment of ATTR ocular amyloidosis.

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Section: Discussionmentioning

confidence: 99%

Feasibility Study of Dendrimer-Based TTR-CRISPR pDNA Polyplex for Ocular Amyloidosis <i>in Vitro</i>

Inoue

Muta

Mohammed

et al. 2022

Biological & Pharmaceutical Bulletin

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“…The multilineage differentiation of the cells was induced by replacing the culture medium with NeuroCult NS‐A Differentiation Kit (StemCell Technologies; Vancouver, BC, Canada), as previously described. [ 19 ] For immunostaining, cells were rinsed in PBS (pH 7.4) twice and fixed with 4% paraformaldehyde in PBS for 20 min at room temperature, and then rinsed in PBS for three times (10 min each). Then the cells were incubated with 10% goat serum in PBS in the presence (for intracellular antigens) or absence (for surface markers) of 0.3% Triton X‐100 for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…The detailed acquisition parameters and derivation of T2 relaxation times from T2‐mapping were described previously. [ 19 ] The experiment was performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…[14,17] Among them, polymeric nanoparticles, especially PEGylated nanoparticles (PEG, polyethylene glycol), have been maturely applied to deliver peptide drugs. [18,19] Moreover, polymeric nanoparticles loaded with superparamagnetic iron oxide nanoparticles (SPIO) have been shown as a theranostic nanoplatform for gene delivery to direct neuronal differentiation of NSCs and for simultaneous magnetic resonance imaging (MRI) tracking of transplanted NSCs in vivo in stroke therapy. [20,21] However, whether SPIO-loaded MRI-visible polymeric nanoparticles can be used to deliver peptide drugs targeting HIF-1𝛼 into NSCs to regulate their survival and migration in ischemia stroke remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Upregulating HIF‐1α to Boost the Survival of Neural Stem Cells via Functional Peptides‐Complexed MRI‐Visible Nanomedicine for Stroke Therapy

Wang

Cai

Zhang

et al. 2022

Adv Healthcare Materials

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Neural stem cells (NSCs) transplantation has been considered as a promising strategy for the treatment of ischemic stroke. However, the therapeutic prospect is limited by the poor control over the survival, migration, and maturation of transplanted NSCs. Upregulating hypoxia inducible factor (HIF)-1𝜶 expression in stem cells can improve the survival and migration of NSCs grafted for stroke therapy. Functional peptide drugs, which could inhibit endogenous HIF-1𝜶 ubiquitination, might be used to effectively upregulate the HIF-1𝜶 expression in NSCs, thereby to improve the therapeutic effect in ischemia stroke. Herein, a magnetic resonance imaging (MRI)-visible nanomedicine is developed to codeliver functional peptides and superparamagnetic iron oxide (SPIO) nanoparticles into NSCs. This nanomedicine not only promotes the survival and migration ability of NSCs but also allows an in vivo tracking of transplanted NSCs with MRI. The results demonstrate the great potential of the functional peptides-complexed multifunctional nanomedicine in boosting the therapeutic effect of stem cell-based therapy in stroke.

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“…Cyclodextrin (CD)-based polyrotaxanes (PRXs) are a class of supramolecular polymers in which CDs are interlocked on an axis polymer by capping its terminal ends with bulky stopper molecules. − Recently, the material applications of PRXs are receiving increasing attention because the molecular mobility of interlocked CDs contributes to emerging an unique material characteristics . For example, PRX-cross-linked hydrogels and elastomers exhibit high toughness and stretchability because the movable CDs reduce stress concentration. − This mobility also contributes to unique functions of biomaterials, such as the modulation of cellular functions and enhanced interactions with proteins. − Recently, the therapeutic applications of β-CD-containing PRXs as a carrier for β-CD are proposed, − as β-CDs exhibit therapeutic effects in Niemann–Pick type C (NPC) disease, atherosclerosis, and diabetic kidney disease. − It is believed that the therapeutic effects of β-CDs can be attributed to the removal of excess intracellular cholesterol by an inclusion complex formation. Clinical trials are being performed for 2-hydroxypropyl-β-CD (HP-β-CD) in NPC disease, which is characterized by free cholesterol overload in lysosomes .…”

Section: Introductionmentioning

confidence: 99%

Cothreading of Unmodified and Monoazidated β-Cyclodextrins in Polyrotaxanes for Orthogonal Modification of Cell-Penetrating Peptides via Click Chemistry

Zhang

Tamura

Yui

2022

ACS Appl. Polym. Mater.

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To establish a method for the orthogonal chemical functionalization of β-cyclodextrin (β-CD)-based polyrotaxane (PRX), unmodified and monoazidated β-CDs (N 3 -β-CDs) were utilized as cyclic host molecules for synthesizing PRXs. PRXs were successfully synthesized by using N 3 -β-CD, and the molar ratio of unmodified β-CD and N 3 -β-CD in the resulting PRXs could be regulated by the feed ratio of unmodified β-CD and N 3 -β-CD. It was revealed that all PRX molecules contained N 3 -β-CD, indicating that unmodified and monoazidated β-CDs were cothreaded onto a single polymer axis. Physicochemical characterization of β-CD/N 3β-CD cothreaded PRXs suggested that their crystalline structures were unaffected by the molar ratio of N 3 -β-CD, whereas their thermal stability was slightly improved with increasing molar ratio of N 3 -β-CD. To facilitate cellular internalization of PRXs, threaded N 3 -β-CD in PRXs was modified with cell-penetrating octaarginine (R8) peptides via a copper(I)-catalyzed azide−alkyne click reaction. The cellular internalization efficiency of the R8-modified PRXs increased with the number of R8 peptides modified on PRXs. However, PRXs modified with a large number of R8 peptides precipitated in serum solutions and exhibited high cytotoxicity. PRXs modified with the optimal number of R8 peptides did not exhibit precipitation and showed high cellular uptake compared to unmodified PRXs without cytotoxicity. Consequently, PRXs modified with the optimal number of R8 peptides showed superior cholesterol-reducing effects in fibroblasts derived from patients with Niemann−Pick type C disease. As demonstrated here, the number of modified functional molecules plays a crucial role in the treatment effects of PRXs, and β-CD/N 3 -β-CD cothreaded PRXs can offer potential for orthogonal postmodification. Thus, β-CD/N 3 -β-CD cothreaded PRXs could introduce benefits that enable the material applications of PRXs.

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Supramolecular polymer-based transformable material for reversible PEGylation of protein drugs

Cited by 8 publications

References 28 publications

Feasibility Study of Dendrimer-Based TTR-CRISPR pDNA Polyplex for Ocular Amyloidosis <i>in Vitro</i>

Feasibility Study of Dendrimer-Based TTR-CRISPR pDNA Polyplex for Ocular Amyloidosis <i>in Vitro</i>

Upregulating HIF‐1α to Boost the Survival of Neural Stem Cells via Functional Peptides‐Complexed MRI‐Visible Nanomedicine for Stroke Therapy

Cothreading of Unmodified and Monoazidated β-Cyclodextrins in Polyrotaxanes for Orthogonal Modification of Cell-Penetrating Peptides via Click Chemistry

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