Polypseudorotaxane and polydopamine linkage-based hyaluronic acid hydrogel network with a single syringe injection for sustained drug delivery.

Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection.

Synthesis, characterization and in vitro evaluation of a series of novel polyrotaxane-based delivery system for artesunate.

A series of novel artesunate-polyrotaxanes (ATS-PRs) with folic acid capped, in which artesunate (ATS) was covalently bound to a cyclodextrin (CD) of the polyrotaxane (PR), were synthesized and were characterized by NMR, XRD, TG and DSC. The cytotoxicities of ATS-PRs on human colon cancer cell lines HT-29, SW480, HTC116 and DLD-1 showed that their antitumor activities were better than that of artesunate (ATS) and dihydroartemisinin (DHA). These ATS-PRs may provide a useful approach to the development of a highly effective drug candidate for the chemotherapy of human colon cancer.

Cationic polyrotaxanes as gene carriers: physicochemical properties and real-time observation of DNA complexation, and gene transfection in cancer cells.

Cationic polymers have been studied as promising nonviral gene delivery vectors. In contrast to the conventional polycations with long sequences of covalently bonded repeating units, we have developed a series of novel cationic polyrotaxanes consisting of multiple oligoethyleneimine-grafted beta-cyclodextrin rings threaded on a poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) triblock copolymer chain. In this study, these cationic polyrotaxanes with different oligoethyleneimine chain lengths were investigated for DNA binding ability, cytotoxicity, and gene transfection efficiency in cancer cells. Fluorescent titration assay results indicated that all the polyrotaxanes could completely condense plasmid DNA and form stable complexes at N/P ratio of 2, where the N/P ratio is the molar ration of amine groups in the cationic molecule to phosphate groups in the DNA. Particularly, tapping mode AFM imaging in aqueous environment was conducted to observe the morphology of the polyrotaxane/DNA complexes and their formation processes in real time. In both SK-OV-3 and PC3 cancer cells, these polyrotaxanes showed low cytotoxicity and high transfection efficiency which is comparable to or significantly higher than that of high molecular weight branched polyethylenimine (25 kDa), one of the most effective gene-delivery polymers studied to date. In addition, the synthesized polyrotaxanes displayed sustained gene delivery capability in PC3 cells in the presence or absence of serum. Therefore, these cationic polyrotaxanes with strong DNA binding ability, low cytotoxicity, and high and sustained gene delivery capability have a high potential as novel nonviral gene carriers in clinical cancer gene therapy.

Synthesis and characterization of polyrotaxanes consisting of cationic alpha-cyclodextrins threaded on poly[(ethylene oxide)-ran-(propylene oxide)] as gene carriers.

Cationic polymers have been receiving growing attention as gene delivery carriers. Herein, a series of novel cationic supramolecular polyrotaxanes with multiple cationic alpha-cyclodextrin (alpha-CD) rings threaded and blocked on a poly[(ethylene oxide)-ran-(propylene oxide)] (P(EO-r-PO)) random copolymer chain were synthesized and investigated for gene delivery. In the cationic polyrotaxanes, approximately 12 cationic alpha-CD rings were threaded on the P(EO-r-PO) copolymer with a molecular weight of 2370 Da and an EO/PO molar ratio of 4:1, while the cationic alpha-CD rings were grafted with linear or branched oligoethylenimine (OEI) of various chain lengths and molecular weights up to 600 Da. The OEI-grafted alpha-CD rings were only located selectively on EO segments of the P(EO-r-PO) chain, while PO segments were free of complexation. This increased the mobility of the cationic alpha-CD rings and the flexibility of the polyrotaxanes, which enhanced the interaction of the cationic alpha-CD rings with DNA and/or the cellular membrane. All cationic polyrotaxanes synthesized in this work could efficiently condense plasmid DNA to form nanoparticles that were suitable for delivery of the gene. Cytotoxicity studies showed that the cationic polyrotaxanes with all linear OEI chains of molecular weights up to 423 Da exhibited much less cytotoxicity than high-molecular-weight branched polyethylenimine (PEI) (25 kDa) in both HEK293 and COS7 cell lines. The cationic polyrotaxanes displayed high gene transfection efficiencies in a variety of cell lines including HEK293, COS7, BHK-21, SKOV-3, and MES-SA. Particularly, the gene delivery capability of the cationic polyrotaxanes in HEK293 cells was much higher than that of high-molecular-weight branched PEI (25 k).