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Molecular logistics using cytocleavable polyrotaxanes for the reactivation of enzymes delivered in living cells.

ABSTRACT: The intracellular delivery of enzymes is an essential methodology to extend their therapeutic application. Herein, we have developed dissociable supermolecule-enzyme polyelectrolyte complexes based on reduction-cleavable cationic polyrotaxanes (PRXs) for the reactivation of delivered enzymes. These PRXs are characterized by their supramolecular frameworks of a polymeric chain threading into cyclic molecules, which can form polyelectrolyte complexes with anionic enzymes while retaining their three dimensional structure, although their enzymatic activity is reduced. Upon the addition of a reductant, the PRXs dissociate into their constituent molecules and release the enzymes, resulting in a complete recovery of enzymatic activity. Under the intracellular environment, the PRX-based enzyme complexes showed the highest intracellular enzymatic activity and efficient activation of anticancer prodrugs to induce cytotoxic effects in comparison with the non-dissociable complexes and the commercial cell-penetrating peptide-based reagents. Thus, the intracellularly dissociable supermolecules are an attractive system for delivering therapeutic enzymes into living cells.

SUBMITTER: Tamura A

PROVIDER: S-EPMC3718191 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Molecular logistics using cytocleavable polyrotaxanes for the reactivation of enzymes delivered in living cells.

Tamura Atsushi A Ikeda Go G Seo Ji-Hun JH Tsuchiya Koji K Yajima Hirofumi H Sasaki Yoshihiro Y Akiyoshi Kazunari K Yui Nobuhiko N

Scientific reports 20130101

The intracellular delivery of enzymes is an essential methodology to extend their therapeutic application. Herein, we have developed dissociable supermolecule-enzyme polyelectrolyte complexes based on reduction-cleavable cationic polyrotaxanes (PRXs) for the reactivation of delivered enzymes. These PRXs are characterized by their supramolecular frameworks of a polymeric chain threading into cyclic molecules, which can form polyelectrolyte complexes with anionic enzymes while retaining their thre ...[more]

PMID: 23872688

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Project description:BackgroundText message-delivered interventions have potential to prevent weight regain and maintain diet and physical activity behaviours through extending contact with participants following initial weight loss, lifestyle interventions. Using the RE-AIM Framework, this study evaluated the adoption, reach, implementation, effectiveness, and maintenance of an extended contact text-message intervention following the Healthy Living after Cancer (HLaC) program. HLaC was a 6-month, telephone-delivered intervention targeting healthy diet, physical activity and weight loss for adult cancer survivors, offered by Cancer Councils (CCs) in Australia.MethodsHLaC completers (n = 182) were offered extended contact via text messages for 6-months (HLaC+Txt). Text message content/frequency was individually tailored to participant's preferences, ascertained through two telephone-tailoring interviews with CC staff. Adoption (HLaC+Txt uptake among eligible CCs), reach (uptake by HLaC completers) and implementation (intervention cost/length; text dose) were assessed. The effectiveness of extended contact relative to historic controls was quantified by pre-to-post HLaC+Txt changes in self-reported: weight, moderate-vigorous physical activity (MVPA), fruit and vegetable intake, fat and fibre behaviour. Maintenance, following 6-months of noncontact for the intervention cohort, was assessed for these same variables. Semi-structured interviews with CC staff and participants contextualised outcomes.ResultsHLaC+Txt was adopted by all four CCs who had delivered HLaC. In total, 115 participants commenced HLaC+Txt, with reach ranging across CCs from 47 to 80% of eligible participants. The mean number of weeks participants received the text message intervention ranged across CCs from 18.5-22.2 weeks. Participants received (median, 25th,75th percentile) 83 (48, 119) texts, ranging across CCs from 40 to 112. The total cost of HLaC+Txt delivery was on average $AUD85.00/participant. No meaningful (p < 0.05) differences in self-reported outcomes were seen between HLaC+Txt and control cohorts. After 6-months no contact the intervention cohort had maintained weight, fruit intake, fat and fibre index scores relative to end of HLaC+Txt outcomes. Participants/CC staff perceived an important intervention component was maintaining accountability.ConclusionsWhile feasible to implement, HLaC+Txt was not effective in the short term. However, intervention effects during the non-contact period suggest the program supports longer term maintenance of weight and diet behaviour. Intervention delivery in this real-world context highlighted key considerations for future implementation.Trial registrationAustralian and New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12615000882527 (registered on 24/08/2015).

Dataset Information

Molecular logistics using cytocleavable polyrotaxanes for the reactivation of enzymes delivered in living cells.

Publications

Molecular logistics using cytocleavable polyrotaxanes for the reactivation of enzymes delivered in living cells.

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