Synthesis of Paclitaxel‐Conjugated β‐Cyclodextrin Polyrotaxane and Its Antitumor Activity

Yu, Shuling; Zhang, Yajun; Wang, Xin; Zhen, Xu; Zhang, Zhaoheng; Wu, Wei; Jiang, Xiqun

doi:10.1002/ange.201301397

Cited by 16 publications

(12 citation statements)

References 22 publications

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“…Beyond their characterization as MRI contrast agents, only two studies using tumor bearing mice and single PR architectures have been reported with biodistributions occurring predominantly in the liver. 31 , 32 Additional studies showing PR biocompatibility with blood components (e.g., platelets, fibrinogen, and albumin) in vitro, anticoagulant activity (e.g., inhibition of platelet cytoplasmic calcium increase and an increased clot formation time), and reduced fibrinogen binding to polyurethane surfaces with PR modification 33 − 35 have been reported; however, no data are available with regard to the PK, BD, and toxicity of PR materials as a function of their molecular and supramolecular structure. Understanding this relationship is crucially important because PRs can be synthesized with a vast diversity of polymer precursors and macrocycle types, and molar ratios can produce variations in PR average molecular weights, macrocycle copy numbers, and threading efficiencies that may dramatically affect their biological performance.…”

Section: Introductionmentioning

confidence: 99%

Influence of Molecular Structure on the In Vivo Performance of Flexible Rod Polyrotaxanes

et al. 2016

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Polyrotaxanes, a family of rod-shaped nanomaterials comprised of noncovalent polymer/macrocycle assemblies, are being used in a growing number of materials and biomedical applications. Their physiochemical properties can vary widely as a function of composition, potentially leading to different in vivo performance outcomes. We sought to characterize the pharmacokinetic profiles, toxicities, and protein corona compositions of 2-hydroxypropyl-β-cyclodextrin polyrotaxanes as a function of variations in macrocycle threading efficiency, molecular weight, and triblock copolymer core structure. We show that polyrotaxane fate in vivo is governed by the structure and dynamics of their rodlike morphologies, such that highly threaded polyrotaxanes are long circulating and deposit in the liver, whereas lung deposition and rapid clearance is observed for species bearing lower 2-hydroxypropyl-β-cyclodextrin threading percentages. Architecture differences also promote recruitment of different serum protein classes and proportions; however, physiochemical differences have little or no influence on their toxicity. These findings provide important structural insights for guiding the development of polyrotaxanes as scaffolds for biomedical applications.

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Section: Introductionmentioning

confidence: 99%

Influence of Molecular Structure on the In Vivo Performance of Flexible Rod Polyrotaxanes

et al. 2016

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“…These results are consistent with other reports which have demonstrated that PR behaves as random coils in good solvents, which explains their small sizes and spherical appearances. 20 …”

Section: Resultsmentioning

confidence: 99%

Enzymatically Biodegradable Polyrotaxane–Deferoxamine Conjugates for Iron Chelation

Liu

Lin

Purro

et al. 2016

ACS Appl. Mater. Interfaces

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Chelation therapy is frequently used to help reduce excess iron in the body, but current chelators such as Deferoxamine (DFO) are plagued by short blood circulation times, which necessitates infusions and can cause undesirable toxic side effects in patients. To address these issues, polyrotaxanes (PR) were synthesized by threading α-cyclodextrin (α-CD) onto poly(ethylene glycol) bis(amine) (PEG-BA, MW 3400 g/mol) capped with enzymatically cleavable bulky Z-L Phenylalanine (Z-L Phe) moieties. The resulting PR was conjugated to DFO and hydroxypropylated to generate the final polyrotaxane-DFO (hPR-DFO). The iron chelating capability of hPR-DFO was verified by UV-Vis absorption spectroscopy and the ability of materials to degrade into smaller CD-conjugated DFO fragments (hCD-DFO) in the presence of the protease was confirmed via Gel Permeation Chromatography (GPC). In vitro studies in iron-overloaded macrophages reveal that hPR-DFO can significantly reduce the cytotoxicity of the drug while maintaining its chelation efficacy, and that it is more rapidly endocytosed and trafficked to lysosomes of iron-overloaded cells in comparison to non-iron overloaded macrophages. In vivo studies indicate that iron-overloaded mice treated with hPR-DFO displayed lower serum ferritin levels (a measure of iron burden in the body) and could eliminate excess iron by both the renal and fecal routes. Moreover, there was no gross evidence of acute toxicological damage to the liver or spleen.

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“…For example, Yu et al used PEG oligomer as the side chain of polyrotaxanes (PR) and then linked PTX with a high drug loading content of ∼29 wt %. 16 The PR-PTX conjugate exhibited a unique in vivo fate, significant antitumor response, and deep intratumoral penetration.…”

Section: Introductionmentioning

confidence: 99%

Translatable High Drug Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers

et al. 2018

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Most nanocarriers possess low drug loading, resulting in frequently repeated administration and thereby high cost and increased side effects. Furthermore, the characteristics of nanocarrier materials, especially the drug loading capacity, plays a vital role in the drug delivery efficacy. In this review, we focus on the readily translatable polymeric drug delivery systems with high drug loading, which are comprised of biocompatible polymers such as poly(ethylene glycol), poly( N-vinylpyrrolidone), polyoxazoline, natural proteins like albumin and casein, non-natural proteins such as recombinant elastin-like polypeptides, as well as nucleic acids. At the end of this review, applications of these polymeric nanocarriers on the delivery of proteins and gene drugs are also briefly discussed.

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Synthesis of Paclitaxel‐Conjugated β‐Cyclodextrin Polyrotaxane and Its Antitumor Activity

Cited by 16 publications

References 22 publications

Influence of Molecular Structure on the In Vivo Performance of Flexible Rod Polyrotaxanes

Influence of Molecular Structure on the In Vivo Performance of Flexible Rod Polyrotaxanes

Enzymatically Biodegradable Polyrotaxane–Deferoxamine Conjugates for Iron Chelation

Translatable High Drug Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers

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