A cascade biodegradable polymer based on alternating cyclization and elimination reactions.

Polymers that depolymerize by a cascade of intramolecular reactions in response to the removal of a stabilizing end-cap can allow for an unprecedented degree of control over the polymer degradation process. Described here is the development of polymers comprising N,N'-dimethylethylenediamine and 4-hydroxybenzyl alcohol linked by carbamate linkages. The polycarbamate backbone is stable in aqueous solution, but removal of a protective end-cap from the amine terminus allows the diamine to cyclize, forming N,N'-dimethylimidazolidinone and releasing the phenol, which undergoes a 1,6-elimination followed by the release of CO(2) to reveal the next amine to continue the cascade. These polymers therefore degrade by alternating cyclization and elimination reactions. First, a tert-butylcarbamate (Boc) group was introduced as a cleavable end-cap, and the degradation kinetics and mechanism were studied by (1)H nuclear magnetic resonance (NMR) spectroscopy and size exclusion chromatography. Next, to demonstrate the degradability of these polymers under biologically relevant conditions, poly(ethylene oxide) was introduced as an end-cap via an ester linkage, to provide an amphiphilic block copolymer. This copolymer was found to assemble into cascade degradable nanoparticles that were capable of encapsulating and subsequently releasing a fluorescent dye in aqueous solution. This new class of polymers therefore provides highly promising materials that can be used for the development of medical devices, drug delivery vehicles, and tissue engineering scaffolds with unique biodegradation properties.

[1]  Cato T Laurencin,et al.  Polymers as biomaterials for tissue engineering and controlled drug delivery. , 2006, Advances in biochemical engineering/biotechnology.

[2]  Richard A Lerner,et al.  Prodrug activation gated by a molecular "OR" logic trigger. , 2005, Angewandte Chemie.

[3]  S. Smith,et al.  Cyclization-activated prodrugs. Basic carbamates of 4-hydroxyanisole. , 1990, Journal of medicinal chemistry.

[4]  Roland Faller,et al.  Molecular dynamics of a polymer in mixed solvent: atactic polystyrene in a mixture of cyclohexane and N,N-dimethylformamide. , 2005, The journal of physical chemistry. B.

[5]  B. Sumerlin,et al.  Sugar-responsive block copolymers by direct RAFT polymerization of unprotected boronic acid monomers. , 2008, Chemical communications.

[6]  M. Krishna Excited-State Kinetics of the Hydrophobic Probe Nile Red in Membranes and Micelles , 1999 .

[7]  P. Ferruti,et al.  New poly(amidoamine)s containing disulfide linkages in their main chain , 2005 .

[8]  A. Gast,et al.  Characterizing the Structure of pH Dependent Polyelectrolyte Block Copolymer Micelles , 1999 .

[9]  J Gillard,et al.  Preparation and characterization of protein-loaded poly(epsilon-caprolactone) microparticles for oral vaccine delivery. , 1999, International journal of pharmaceutics.

[10]  V. Bulmus,et al.  Acid-labile core cross-linked micelles for pH-triggered release of antitumor drugs. , 2008, Biomacromolecules.

[11]  Jeffrey A Hubbell,et al.  Glucose-oxidase based self-destructing polymeric vesicles. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[12]  Martin Müller,et al.  Oxidation-responsive polymeric vesicles , 2004, Nature materials.

[13]  Jean-François Lutz,et al.  Point by point comparison of two thermosensitive polymers exhibiting a similar LCST: is the age of poly(NIPAM) over? , 2006, Journal of the American Chemical Society.

[14]  J. Allard,et al.  A new two-photon-sensitive block copolymer nanocarrier. , 2009, Angewandte Chemie.

[15]  J. Fréchet,et al.  A new approach towards acid sensitive copolymer micelles for drug delivery. , 2003, Chemical communications.

[16]  Roey J. Amir,et al.  Self-immolative dendrimers. , 2003, Angewandte Chemie.

[17]  N. Pessah,et al.  A chemical adaptor system designed to link a tumor-targeting device with a prodrug and an enzymatic trigger. , 2003, Angewandte Chemie.

[18]  A. Chiralt,et al.  Recent Advances in Edible Coatings for Fresh and Minimally Processed Fruits , 2008, Critical reviews in food science and nutrition.

[19]  J. Feijen,et al.  Reducible poly(amido ethylenimine)s designed for triggered intracellular gene delivery. , 2006, Bioconjugate chemistry.

[20]  M. Zilberman,et al.  Drug-eluting bioresorbable stents for various applications. , 2006, Annual review of biomedical engineering.

[21]  I. Lee,et al.  Monocryl suture, a new ultra-pliable absorbable monofilament suture. , 1995, Biomaterials.

[22]  Jeffrey A Hubbell,et al.  PEG-SS-PPS: reduction-sensitive disulfide block copolymer vesicles for intracellular drug delivery. , 2007, Biomacromolecules.

[23]  Robert H Pierce,et al.  Polyketal copolymers: a new acid-sensitive delivery vehicle for treating acute inflammatory diseases. , 2008, Bioconjugate chemistry.

[24]  G. Kwon,et al.  Biodegradable polymers for drug delivery systems , 2007 .

[25]  R. Lerner,et al.  Single-triggered trimeric prodrugs. , 2005, Angewandte Chemie.

[26]  Kazunori Kataoka,et al.  Smart polymeric micelles for gene and drug delivery. , 2005, Drug discovery today. Technologies.

[27]  Michel Vert,et al.  Polymeric biomaterials: Strategies of the past vs. strategies of the future , 2007 .

[28]  C. Alexander,et al.  Stimuli responsive polymers for biomedical applications. , 2005, Chemical Society reviews.

[29]  C. Astete,et al.  Synthesis and characterization of PLGA nanoparticles , 2006, Journal of biomaterials science. Polymer edition.

[30]  S. Webber,et al.  pH-Dependent Micellization of Poly(2-vinylpyridine)-block-poly(ethylene oxide) , 1996 .

[31]  N. Murthy,et al.  Polyketal nanoparticles: a new pH-sensitive biodegradable drug delivery vehicle. , 2005, Bioconjugate chemistry.

[32]  M. Vert,et al.  Something new in the field of PLA/GA bioresorbable polymers? , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[33]  H. Lode,et al.  Bioactivation of self-immolative dendritic prodrugs by catalytic antibody 38C2. , 2004, Journal of the American Chemical Society.

[34]  Jean M. J. Fréchet,et al.  Development of acid-sensitive copolymer micelles for drug delivery , 2004 .

[35]  Jean-François Lutz,et al.  Preparation of Ideal PEG Analogues with a Tunable Thermosensitivity by Controlled Radical Copolymerization of 2-(2-Methoxyethoxy)ethyl Methacrylate and Oligo(ethylene glycol) Methacrylate , 2006 .

[36]  A S Hoffman,et al.  A pH-sensitive polymer that enhances cationic lipid-mediated gene transfer. , 2001, Bioconjugate chemistry.

[37]  J. Gardella,et al.  Surface chemistry of biodegradable polymers for drug delivery systems. , 2005, Chemical reviews.

[38]  Atsushi Harada,et al.  Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. , 2003, Angewandte Chemie.

[39]  Joel A. Cohen,et al.  Two-photon degradable supramolecular assemblies of linear-dendritic copolymers. , 2007, Chemical communications.

[40]  H. G. Schild Poly(N-isopropylacrylamide): experiment, theory and application , 1992 .

[41]  Jean M. J. Fréchet,et al.  Synthesis and Degradation of pH-Sensitive Linear Poly(amidoamine)s , 2007 .

[42]  J. Vacanti,et al.  Tissue engineering : Frontiers in biotechnology , 1993 .

[43]  J. Fréchet,et al.  pH-Responsive copolymer assemblies for controlled release of doxorubicin. , 2005, Bioconjugate chemistry.

[44]  Indu Bala,et al.  PLGA nanoparticles in drug delivery: the state of the art. , 2004, Critical reviews in therapeutic drug carrier systems.

[45]  Yuichi Yamasaki,et al.  PEG-detachable polyplex micelles based on disulfide-linked block catiomers as bioresponsive nonviral gene vectors. , 2008, Journal of the American Chemical Society.

[46]  Robert Gurny,et al.  Degradation and Healing Characteristics of Small-Diameter Poly(&egr;-Caprolactone) Vascular Grafts in the Rat Systemic Arterial Circulation , 2008, Circulation.

[47]  Dietmar W. Hutmacher,et al.  Biodegradable polymers applied in tissue engineering research: a review , 2007 .

[48]  J. Fréchet,et al.  Stimuli-responsive supramolecular assemblies of linear-dendritic copolymers. , 2004, Journal of the American Chemical Society.

[49]  R. Borchardt,et al.  Prodrug strategies based on intramolecular cyclization reactions. , 1997, Journal of pharmaceutical sciences.

[50]  N. Murthy,et al.  A novel strategy for encapsulation and release of proteins: hydrogels and microgels with acid-labile acetal cross-linkers. , 2002, Journal of the American Chemical Society.

[51]  Zhiyuan Zhong,et al.  Stimuli-responsive polymersomes for programmed drug delivery. , 2009, Biomacromolecules.

[52]  Michel Vert,et al.  Aliphatic polyesters: great degradable polymers that cannot do everything. , 2005, Biomacromolecules.

[53]  S. Fowler,et al.  Nile red: a selective fluorescent stain for intracellular lipid droplets , 1985, The Journal of cell biology.

[54]  B. Sumerlin,et al.  Triply-responsive boronic acid block copolymers: solution self-assembly induced by changes in temperature, pH, or sugar concentration. , 2009, Chemical communications.

[55]  D. Shabat,et al.  Self-immolative comb-polymers: multiple-release of side-reporters by a single stimulus event. , 2008, Chemistry.

[56]  T. Okano,et al.  Totally Synthetic Polymer Gels Responding to External Glucose Concentration: Their Preparation and Application to On−Off Regulation of Insulin Release , 1998 .

[57]  F Leonard,et al.  Biodegradable poly(lactic acid) polymers. , 1971, Journal of biomedical materials research.

[58]  H. W. Scheeren,et al.  "Cascade-release dendrimers" liberate all end groups upon a single triggering event in the dendritic core. , 2003, Angewandte Chemie.