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• W1998132616 abstract "Future Medicinal ChemistryVol. 5, No. 5 EditorialFree AccessSelf-assembling polyrotaxanes: drug carriers for anticancer drugs?Bin He & Zhongwei GuBin HeNational Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, ChinaSearch for more papers by this author & Zhongwei Gu* Author for correspondenceNational Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China. Search for more papers by this authorEmail the corresponding author at zwgu@scu.edu.cnPublished Online:10 Apr 2013https://doi.org/10.4155/fmc.13.21AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: anticancer drugspolyrotaxanesPolyrotaxanes (polypseudorotaxanes) are polymeric architectures with cyclic compounds threaded in polymeric chains [1]. The self-assembly of polyrotaxanes is due to the host–guest interaction between the host cyclic compounds and polymeric chains. Their apprearance is similar to a necklace and the cyclic compounds can slide along the polymeric chains. The polyrotaxanes with cyclodextrins (CDs) as hosts and PEG-based polymers as guest are the most important polyrotaxanes, which have attracted much interest for their unique properties in biomedical applications. As CDs and PEG have been approved by the US FDA in drug formulations, CD-based polyrotaxanes are favorable to be used as carriers for drug delivery. The advantages of the polyrotaxanes carriers include excellent biocompatibility, multiple functionality and specific self-assemblying capabilities. Polyrotaxanes have been fabricated as injectable hydrogels, drug–polyrotaxane conjugates and nanoparticles for drug/gene delivery.Most anticancer drugs are hydrophobic molecules with serious toxicity to normal tissues and cells. The focus of anticancer drug delivery is to enhance the solubility of anticancer drugs in aqueous medium and target to tumors. Hydrogels are widely used carriers for anticancer drug release. With the spontaneous self-assembly of polyrotaxanes in aqueous medium, the polyrotaxane crystals act as physical crosslinkers to form supramolecular hydrogels: this hydrogel is injectable. The first polyrotaxane injectable hydrogel was composed of high-molecular-weight PEG and α-CDs [2], it was suitable for the release of bioactive molecules such as drugs, proteins and plasmid DNAs as no chemical reagents were involved in the hydrogels. Other than PEG homopolymer, biodegradable PEG-based copolymers, such as PEO–PHB–PEO and PMA–g-PEG were developed to prepare polyrotaxane hydrogels [3,4]. The self-assembled hydrophobic domains in the copolymers also act as physical crosslinkers, thus low-molecular-weight PEG chains could be utilized to convenient for the kidney filtration. These hydrogels were called ‘biodegradable’. The drug release study of the injectable hydrogels using a high-molecular-weight model drug, as well as small anticancer drugs, exhibited long sustaining drug release. The polyrotaxane hydrogel exhibited a promising perspective for anticancer drug delivery, and it could be used for in situ cancers therapy.Drug-carriers conjugate is an important form to deliver anticancer drugs. There are plenty of hydroxyl functional groups on the CDs in the polyrotaxanes. Anticancer drugs were conjugated on the polyrotaxanes via stimuli-sensitive linkages with the combination of cleavable bonds in the end-caps of the polyrotaxanes [5,6]. The anticancer drugs were smartly released, triggered by the in vivo environments of tumors to fulfill targeting release. Because of the large amount of the hydroxyl groups on polyrotaxanes, high drug-loading content was easily achieved in the conjugates. Besides high drug-loading content, targeting efficiency is more important for anticancer drug delivery. Many researchers have found that the targeting design of anticancer delivery systems is efficient in vitro, however, the in vivo targeting efficiency is very poor. It is attributed to the complicated in vivo obstacles, which diminishes the targeting recognition. It is well known that the receptors on the cell membranes have the conformation recognition capability, in the traditional ligand–receptor targeting mode, the ligands are usually immobilized on the carriers, which limit their mobility to form multivalent interactions with the receptors on cell membranes [7,8], it is an important factor to decrease the targeting efficiency. In polyrotaxane–drug conjugates, both anticancer drugs and ligands were immobilized on CDs via the functional hydroxyl groups. As the modified CDs could slide along and rotate around the PEG chains, this flexible motion avoided the mismatch of ligand–receptor interaction and the multivalent interactions between the conjugates and cell membranes could be formed. This active recognition mode provides a promising strategy to enhance targeting efficiency.Polymeric micelles have attracted much interest as carriers for antitumor drug delivery due to their unique advantages of escaping the capture of reticuloendothelial system and passive targeting tumor tissues for the enhanced permeability and retention effect. Although several papers have reported the fabrication of polyrotaxane micelles via the crystallization of polyrotaxanes, however, the polyrotaxanes were located in the core of the micelles, which could not trap hydrophobic antitumor drugs because of the hydrophilicity and compact nanoarchitectures. Recently, the polyrotaxanes were modified with the terminal functionalization of PEG chains. Hydrophobic small molecules with π–π conjugated molecular structures, such as coumarin derivatives and cinnamic acid, were immobilized on PEG [9,10]. α-CDs were threaded in the modified PEG chains to form polypseudorotaxanes. The hydrophilic polypseudorotaxanes were folded as micellar shell and the π–π conjugated molecules formed the core. It provides a facile approach to prepare polyrotaxane micelles, which are favorable for anticancer drug delivery. The size of the end-cap molecules is smaller than that of the cavity of α-CD, it does not prevent the threading of PEG chains in the CDs. However, their relative large stereo hindrances diminish the CDs slide out from polyrotaxanes. As most hydrophobic anticancer drugs have partial π-conjugation structures, the π–π interactions formed between the drugs and end-caps would give contribution for drug loading and release. The micellar polyrotaxanes initiate a new design of carriers via the polyrotaxane crystallization as a driving force for micelle formation and the interactions between drugs and carriers for drug encapsulation.Gene therapy is the most promising treatment to cure cancers and polyrotaxanes could be fabricated as non-viral gene vectors. Cationic modification of CDs makes polyrotaxanes positively charged to condense negatively charged DNA plasmids [11,12]. With the multivalent electrostatic interactions resulted from the slide and rotation of the positively modified CDs along the PEG chains, the polyrotaxanes could condense pDNA in a ‘live’ form and the largest extent. Studies have verified that the N/P ratio of cationic modified polyrotaxane to pDNA was much lower than that of cationic polymers (for example PEI) to pDNA with the same DNA condensation effect. In the viewpoint of molecular biology, the dissociation of vectors and pDNAs in the right time in cytoplasm is the key factor to obtain high transfection efficiency. Stimuli-sensitive bonds in the end-caps of polyrotaxane vectors could control the dissociation and release time of pDNAs. Once the complexes are dissociated and the CDs are released from the polyrotaxanes in cytoplasm, the electrostatic interaction between pDNAs and cationic modified CDs are weakened greatly. In this condition, most CDs are diffused and rare CDs are condensed with pDNAs, thus, the pDNAs are likely free. These free pDNAs are favorable to penetrate into nuclei for efficient transfection. Other cationic polymers vectors condense pDNAs tightly via multiple electrostatic interaction sites like a ‘dead’ condensation form. When the complexes are escaped from the endosomes or lysosomes via ‘proton pump’ effect, the cationic polymers are hard to be dissociated from the complexes to free pDNAs. This is the essential reason for the low transfection efficiency of nonviral gene vectors. The unique multivalent interactions as well as the slide and rotation functions of polyrotaxanes could avoid the tightly condensation to overcome the obstacles of nonviral vectors for gene delivery.The polyrotaxanes for drug/gene delivery were only developed in the last two decades and there is a long way to go. Currently, most of the research highlights the fundamental aspects of the design of carrier architectures and in vitro studies. The preliminary success of the in vivo investigations of the polyrotaxanes for drug delivey has evoked more and more solicitudes to biomaterials scientists and pharmacists due to its great potential significance in cancer therapy. On the basis of current research, more in vivo research should be carried out in the coming 10 years, after all, efficient in vivo results are the driving force pushing the polyrotaxanes for clinical applications.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Li JJ, Zhao F, Li J. Polyrotaxanes for applications in life science and biotechnology. Appl. Microbiol. Biotechnol.90,427–443 (2011).Crossref, Medline, CAS, Google Scholar2 Li J, Ni XP, Leong KW. Injectable drug-delivery systems based on supramolecular hydrogels formed by poly(ethylene oxide) and alpha-cyclodextrin. J. Biomed. Mater. Res. A65A,196–202 (2003).Crossref, CAS, Google Scholar3 Li J, Loh XJ. Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. Adv. Drug Deliv. Rev.60,1000–1017 (2008).Crossref, Medline, CAS, Google Scholar4 He B, Zeng J, Nie Y et al.In situ gelation of supramolecular hydrogel for anti-tumor drug delivery. Macromol. Biosci.9,1169–1175 (2009).Crossref, Medline, CAS, Google Scholar5 Moon C, Kwon YM, Lee WK, Park YJ, Yang VC. In vitro assessment of a novel polyrotaxane-based drug delivery system integrated with a cell-penetrating peptide. J. Control. Release124,43–50 (2007).Crossref, Medline, CAS, Google Scholar6 Moon C, Kwon YM, Lee WK, Park YJ, Chang LC, Yang VC. A novel polyrotaxane-based intracellular delivery system for camptothecin: in vitro feasibility evaluation. J. Biomed. Mater. Res.84A,238–246 (2008).Crossref, CAS, Google Scholar7 Yui N, Ooya T. Molecular mobility of interlocked structures exploiting new functions of advanced biomaterials. Chem. Eur. J.12,6730–6737 (2006).Crossref, Medline, CAS, Google Scholar8 Yui N, Katoono R, Yamashita A. Functional cyclodextrin polyrotaxanes for drug delivery. Adv. Polym. Sci.222,55–77 (2009).Crossref, CAS, Google Scholar9 Chang J, Li Y, Wang G, He B, Gu ZW. Fabrication of novel coumarin derivative functionalized polypseudorotaxane micelles for drug delivery. Nanoscale5,813–820 (2013).Crossref, Medline, CAS, Google Scholar10 Liu R, Lai YS, He B et al. Supramolecular nanoparticles generated by the self-assembly of polyrotaxanes for anti-tumor drug delivery. Inter. J. Nanomed.7,5249–5258 (2012).Medline, CAS, Google Scholar11 Ooya T, Choi HS, Yamashita A et al. Biocleavable polyrotaxane-plasmid DNA polyplex for enhanced gene delivery. J. Am. Chem. Soc.128,3852–3853 (2006).Crossref, Medline, CAS, Google Scholar12 Li J, Yang C, Li HZ et al. Cationic supramolecules composed of multiple, oligoethylenimine-grafted beta-cyclodextrins threaded on a polymer, chain for efficient gene delivery. Adv. Mater.18,2969–2974 (2006).Crossref, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByCyclodextrin-Based Polymeric Drug Delivery Systems for Cancer Therapy11 March 2023 | Polymers, Vol. 15, No. 6Cyclodextrin-based polymeric nanosystemsBiomedical Applications of Supramolecular Systems Based on Host–Guest Interactions21 November 2014 | Chemical Reviews, Vol. 115, No. 15 Vol. 5, No. 5 STAY CONNECTED Metrics History Published online 10 April 2013 Published in print April 2013 Information© Future Science LtdKeywordsanticancer drugspolyrotaxanesFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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