Precise Control and Prediction of Hydrogel Degradation Behavior

Li, Xiang; Tsutsui, Yusuke; Matsunaga, Takuro; Shibayama, Mitsuhiro; Chung, Ung‐il; Sakai, Takamasa

doi:10.1021/ma2004234

Cited by 71 publications

(76 citation statements)

References 16 publications

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“…The extensive work of Sakai and collaborators on Tetra-PEG gels 1a,b includes methods to predictably control the time of reverse gelation, 4 but does not model the mass degradation time course. None of the previous models provide methods to estimate subpopulations of degradation fragments relevant to analyzing drug delivery in semipermeable compartments.…”

Section: ■ Resultsmentioning

confidence: 99%

Analytical and Simulation-Based Models for Drug Release and Gel-Degradation in a Tetra-PEG Hydrogel Drug-Delivery System

et al. 2015

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We have recently reported drug-releasing, degradable Tetra-PEG hydrogels as a new drug delivery system. The gels contain two self-cleaving β-eliminative linkers: one that covalently tethers the drug to the gel and releases it at a predictable rate, and another with slower cleavage that is installed in each cross-link of the polymer to control gel degradation. By balancing the two cleavage rates, the system can be designed to discharge most or all of the drug before the gel undergoes significant degradation. If polymer degradation is too rapid, undesirable gel-fragments covalently bound to the drug are released; if too slow, the gel remains in the body as an inert substance for prolonged periods. Here, we describe an analytical theory as well as a Monte Carlo simulation of concurrent drug release from and degradation of Tetra-PEG polymers. Considerations are made for an ideal network as well as networks containing missing bonds and double link defects. The analytical and simulation approaches are in perfect agreement with each other and with experimental data in the regime of interest. Using these models, we are able to (a) compute the time courses of drug release and gel degradation as well as the amount of fragment-drug conjugate present at any time and (b) estimate the rate constants of drug release and gel degradation necessary to control each of the above. We can also account for the size-dependent elimination of gel fragments from a localized semipermeable compartment and hence estimate fragment mass vs time curves in such in vivo compartments. The models described allow design of an optimal Tetra-PEG drug delivery vehicle for a particular use

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Section: ■ Resultsmentioning

confidence: 99%

Analytical and Simulation-Based Models for Drug Release and Gel-Degradation in a Tetra-PEG Hydrogel Drug-Delivery System

et al. 2015

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“…Using similar β-elimination linkers as polymer cross-links, the hydrogels were also tuned to degrade at predictable times over a wide range of ∼1-100 d. As shown with Tetra-PEG gels containing ester cross-links, replacing a fraction of the cleavable linkers by stable ones should incrementally decrease the degradation rate of each gel up to at least threefold (26); in this manner, using the reported β-eliminative linkers (3), one could produce hydrogels with finely tunable degradation rates spanning ∼1 d to well over a year. Thus, by using one β-eliminative linker to tether a drug to the hydrogel, and another with a longer half-life to control polymer degradation, the cleavage rates can be optimally coordinated to release the drug before the gel undergoes complete degradation.…”

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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“…This Q value was stable at least for 3 days unless otherwise external stimuli are given, suggesting that the crosslinks formed are practically permanent as a "temporary" scaffolding material. In stark contrast, under conditions stimulated by collagenase, Gel‐M gradually swelled over time, absorbing water, and eventually resulted in macroscopic disappearance with Q values in the range of 2 < Q < 3 (Figure B), which is, to a great extent, lower than that observed in simple PEG‐based hydrogels (i.e., Q > 8) . The physical association of RCPhC1 molecules might have affected the degradation behavior although further studies are necessary to clarify the causes.…”

mentioning

confidence: 94%

Extemporaneous Preparation of Injectable and Enzymatically Degradable 3D Cell Culture Matrices from an Animal‐Component‐Free Recombinant Protein Based on Human Collagen Type I

Kamata

Ashikari‐Hada²,

Mori

et al. 2019

Macromol. Rapid Commun.

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Injectable hydrogels are considered important to realize safe and effective minimally invasive therapy. Although animal‐derived natural polymers are well studied, they typically lack injectability and fail to eliminate the potential risks of immunogenic reactions or unknown pathogen contamination. Despite extensive research activities to explore ideal injectable hydrogels, such state‐of‐the‐art technology remains inaccessible to non‐specialists. In this article, the design of a new injectable hydrogel platform that can be extemporaneously prepared from commercially available animal‐component‐free materials is described. The hydrogels can be prepared simply by mixing mutually reactive aqueous solutions without necessitating specialized knowledge or equipment. Their solidification time can be adjusted by choosing proper buffer conditions from immediate to an extended period of time, that is, few or several tens of minutes depending on the concentration of polymeric components, which not only provides injectability, but enables 3D encapsulation of cells. Mesenchymal stromal/stem cells can be encapsulated and cultured in the hydrogels at least for 2 weeks by traditional cell culture techniques, and retrieved by collagenase digestion with cell viability of approximately 80%. This hydrogel platform accelerates future cell‐related research activities.

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Precise Control and Prediction of Hydrogel Degradation Behavior

Cited by 71 publications

References 16 publications

Analytical and Simulation-Based Models for Drug Release and Gel-Degradation in a Tetra-PEG Hydrogel Drug-Delivery System

Analytical and Simulation-Based Models for Drug Release and Gel-Degradation in a Tetra-PEG Hydrogel Drug-Delivery System

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

Extemporaneous Preparation of Injectable and Enzymatically Degradable 3D Cell Culture Matrices from an Animal‐Component‐Free Recombinant Protein Based on Human Collagen Type I

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