Document Detail


A novel system for trigger-controlled drug release from polymer capsules.
MedLine Citation:
PMID:  18755229     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Technologies currently available for the controlled release of protein therapeutics involve either continuous or tissue-specific discharge from implants or engineered extracellular matrix mimetics. For some therapeutic applications the trigger-controlled release of protein cargo from a synthetic implant could be highly desirable. We have designed the CellEase technology, a two-component system consisting of cellulose sulfate (CS) poly-diallyldimethyl ammonium chloride (pDADMAC) capsules harboring mammalian sensor cells transgenic for trigger-inducible expression of an engineered secreted mammalian cellulase (SecCell). SecCell is a Bacillus subtilis-derived (1-4)-beta-glucanase, which was modified by replacing the N-terminal part of the bacterial enzyme with a murine Igkappa-chain V-12-C region-derived secretion signal. SecCell was engineered for doxycycline- or erythromycin-inducible expression to enable trigger-controlled secretion by mammalian cells. Detailed characterization of SecCell showed that it was glycosylated and efficiently secreted by a variety of mammalian sensor cells such that it could internally rupture CS-pDADMAC capsules within which the cells had been encapsulated. When SecCell was inducibly expressed in sender cells, that were co-encapsulated with producer cell lines expressing therapeutic proteins, the removal of relevant inducer molecules enabled the time-dependent discharge of these therapeutic proteins, the kinetics of which could be modified by varying the concentration of inducer molecules or the amount of encapsulated sender cells. SecCell's capacity to rupture CS-pDADMAC capsules exclusively internally also enabled the independent trigger-induced release of different proteins from two capsule populations harboring different inducible SecCell sensor cells. CellEase-based protein release was demonstrated in vivo using capsules implanted intraperitoneally into mice that enabled the doxycycline-controlled release of a model glycoprotein and accumulation in the bloodstream of treated animals. Trigger-induced breakdown of tissue-compatible implants which provide a timely controlled release of biologics may foster novel opportunities in human therapy.
Authors:
David A Fluri; Christian Kemmer; Marie Daoud-El Baba; Martin Fussenegger
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-08-05
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  131     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-10-28     Completed Date:  2009-01-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  211-9     Citation Subset:  IM    
Affiliation:
Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Allyl Compounds / chemistry*
Animals
Antigens, Polyomavirus Transforming / genetics
Bacillus subtilis / enzymology
Biocompatible Materials / chemistry*
CHO Cells
Capsules
Cell Line
Cell Line, Tumor
Cellulase / analysis,  metabolism,  pharmacokinetics*
Cellulose / analogs & derivatives*,  chemistry
Cricetinae
Cricetulus
Delayed-Action Preparations / chemistry,  pharmacokinetics
Glycosylation
Hela Cells
Humans
Kidney / cytology
Polymers / chemistry*
Quaternary Ammonium Compounds / chemistry*
Chemical
Reg. No./Substance:
0/Allyl Compounds; 0/Antigens, Polyomavirus Transforming; 0/Biocompatible Materials; 0/Capsules; 0/Delayed-Action Preparations; 0/Polymers; 0/Quaternary Ammonium Compounds; 0/diallyldimethylammonium chloride; 9004-34-6/Cellulose; 9032-43-3/cellulose sulfate; EC 3.2.1.4/Cellulase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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