Michael addition reactions in macromolecular design for emerging technologies

Mather, Brian D.; Viswanathan, K.V.; Miller, Kevin M.; Long, Timothy Edward

doi:10.1016/j.progpolymsci.2006.03.001

Cited by 990 publications

(687 citation statements)

References 174 publications

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“…Therefore, the reaction conditions should be selected carefully to avoid degradation of reaction precursors. Because maleimide possesses two carbonyl groups conjugated to the double bond, presenting a highly electronegative property and more susceptible to reaction with nucleophiles [37], it is proved to be an appropriate reactive group in Michael addition under mild conditions [34,38]. We report herein a mild and simplified route to synthesize the copolymer DEX-b-PCL, in which the precursors maleimide-terminated PCL and amino-terminated dextran were synthesized previously, followed by an end to end coupling via aza-Michael addition reaction.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and self-assembly behavior of amphiphilic diblock copolymer dextran-block-poly(ε-caprolactone) (DEX-b-PCL) in aqueous media

Zhang¹,

Dou²,

Jin³

2010

Express Polym. Lett.

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Abstract. An amphiphilic diblock copolymer, dextran-block-poly(ε-caprolactone) (DEX-b-PCL), with a series of welldefined chain lengths of each block was prepared by conjugating a dextran chain with a PCL block via aza-Michael addition reaction under mild conditions. For the dextran block, samples with relatively uniform molecular weight, 3.5 and 6.0 kDa, were used, and the PCL blocks were prepared via ring-opening polymerization at defined ratios of ε-caprolactone to initiator in order to give copolymers with mass fraction of dextran (fDEX) ranging from 0.16 to 0.45. When these copolymers were allowed to self-assemble in aqueous solution, the morphology of assembled aggregates varied as a function of fDEX when characterized by transmission electron microscope (TEM), fluorescence microscope (FM) and dynamic laser scattering (DLS). As fDEX decreases gradually from 0.45 to 0.16, the morphology of the copolymer assembly changes from spherical micelles to worm-like micelles and eventually to polymersomes, together with an increase in particle sizes.

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Section: Introductionmentioning

confidence: 99%

Synthesis and self-assembly behavior of amphiphilic diblock copolymer dextran-block-poly(ε-caprolactone) (DEX-b-PCL) in aqueous media

Zhang¹,

Dou²,

Jin³

2010

Express Polym. Lett.

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“…In the present work, the tethering of molecules and gel polymerization reactions both use Cu-free [3 + 2] dipolar cycloaddition chemistry that is orthogonal to biological functional groups and can be performed in aqueous media; this expands the reach of the technology to molecules sensitive to harsh conditions (e.g., peptides and proteins) and should also avoid undesirable irreversible attachment of the drug to the gel (28). Other bioorthogonal coupling reactions, such as Michael addition of thiols (29) or tetrazine cycloadditions with dienophiles (30), should provide similar benefits. Also, because drugs are tethered to components of the hydrogel before cross-linking, it should be possible, but not necessary, to perform the polymerization in situ by mixing of filtersterilized components shortly before injection (30).…”

Section: Discussionmentioning

confidence: 99%

Hydrogel drug delivery system with predictable and tunable drug release and degradation rates

Ashley

Henise

Reid

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

320

288

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Many drugs and drug candidates are suboptimal because of short duration of action. For example, peptides and proteins often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to circulating carriers, such as PEG, that retard kidney filtration and hence increase plasma half-life of the attached drug. We recently reported an approach to half-life extension that uses sets of self-cleaving linkers to attach drugs to macromolecular carriers. The linkers undergo β-eliminative cleavage to release the native drug with predictable half-lives ranging from a few hours to over 1 y; however, half-life extension becomes limited by the renal elimination rate of the circulating carrier. An approach to overcoming this constraint is to use noncirculating, biodegradable s.c. implants as drug carriers that are stable throughout the duration of drug release. Here, we use β-eliminative linkers to both tether drugs to and cross-link PEG hydrogels, and demonstrate tunable drug release and hydrogel erosion rates over a very wide range. By using one β-eliminative linker to tether a drug to the hydrogel, and another β-eliminative linker with a longer half-life to control polymer degradation, the system can be coordinated to release the drug before the gel undergoes complete erosion. The practical utility is illustrated by a PEG hydrogel-exenatide conjugate that should allow once-a-month administration, and results indicate that the technology may serve as a generic platform for tunable ultralong half-life extension of potent therapeutics.click chemistry | regenerative medicine | tetra-PEG C onjugation of drugs to macromolecular carriers is a proven strategy for improving pharmacokinetics. In one approach, the drug is covalently attached to a long-lived circulating macromolecule-such as PEG-through a linker that is slowly cleaved to release the native drug (1, 2). We have recently reported such conjugation linkers that self-cleave by a nonenzymatic β-elimination reaction in a highly predictable manner, and with half-lives of cleavage spanning from hours to over a year (3). In this approach, a macromolecular carrier is attached to a linker that is attached to a drug or prodrug via a carbamate group (1; Scheme 1); the β-carbon has an acidic carbon-hydrogen bond (C-H) and also contains an electron-withdrawing "modulator" (Mod) that controls the pK a of that C-H. Upon hydroxide ion-catalyzed proton removal to give 2, a rapid β-elimination occurs to cleave the linkercarbamate bond and release the free drug or prodrug and a substituted alkene 3. The rate of drug release is proportional to the acidity of the proton, and that is controlled by the chemical nature of the modulator; thus, the rate of drug release is controlled by the modulator. It was shown that both in vitro and in vivo cleavages were linearly correlated with electron-withdrawing effects of the modulators and, unlike ester bonds commonly used in releasable linkers (2), the β-elimination reaction was not catalyzed by general bases or ser...

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“…All bis-retinoids appear to form from the same tautomer (N-retinylidene-phosphatidylenamine), probably arising from a [1,6] H-shift of NR-PE/NR-GPE (Liu et al, 2000;Mata et al, 2000;Wu et al, 2009;Sparrow et al, 2010a). Via a Michael-type addition reaction (Michael, 1887;Mather et al, 2006), the C 20 of NR-PE/NR-GPE would tie with C 13 of a second molecule of all-trans-retinal. After a Mannich reaction to close the ring (Mannich and Krösche, 1912), the elimination of amine group in PE/GPE yields ATR dimer, along with an electronic rearrangement in the six-membered ring (Fishkin et al, 2005).…”

Section: Bis-retinoids With a Cyclohexadiene Ringmentioning

confidence: 99%

Structures and biogenetic analysis of lipofuscin bis-retinoids

Yao

2013

J. Zhejiang Univ. Sci. B

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Age-related macular degeneration (AMD) is still an incurable blinding eye disease because of complex pathogenic mechanisms and unusual diseased regions. With the use of chemical biology tools, great progress has been achieved in improving the understanding of AMD pathogenesis. The severity of AMD is, at least in part, linked to the non-degradable lipofuscin bis-retinoids in retinal pigment epithelial (RPE). This material is thought to result from the lifelong accumulation of lysosomal residual bodies containing the end products derived from the daily phagocytosis of rod outer segments by RPE cells. Here, we present previously recognized bis-retinoids with focus on structures and biosynthetic pathways. In addition to a brief discussion on the mutual conversion relationships of bis-retinoids, future perspectives and the medical relevance of such studies on these lipofuscin constituents are also highlighted.

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Michael addition reactions in macromolecular design for emerging technologies

Cited by 990 publications

References 174 publications

Synthesis and self-assembly behavior of amphiphilic diblock copolymer dextran-block-poly(ε-caprolactone) (DEX-b-PCL) in aqueous media

Synthesis and self-assembly behavior of amphiphilic diblock copolymer dextran-block-poly(ε-caprolactone) (DEX-b-PCL) in aqueous media

Hydrogel drug delivery system with predictable and tunable drug release and degradation rates

Structures and biogenetic analysis of lipofuscin bis-retinoids

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