Enzymatic Biodegradation of Hydrogels for Protein Delivery Targeted to the Small Intestine

Knipe, Jennifer M.; Chen, Frances S.; Peppas, Nicholas A.

doi:10.1021/bm501871a

Cited by 77 publications

(56 citation statements)

References 63 publications

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“…Typical chemical methods used to achieve cross-linking of peptide−polymer hybrids include thiol−norbornene click reactions 15 with oligopeptide-pendant cysteines or carbodiimide-mediated coupling of pendant lysines or aspartic acids to the corresponding polymeric carboxylic acids or amines. 14 Peptide linkers have been designed for tunable degradation by a number of native enzymes, including matrix metalloproteinase, 15 trypsin, 14 and elastase. 16 …”

Section: Classes Of Analyte-sensitive Materialsmentioning

confidence: 99%

Analyte-Responsive Hydrogels: Intelligent Materials for Biosensing and Drug Delivery

2017

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CONSPECTUS: Nature has mastered the art of molecular recognition. For example, using synergistic non-covalent interactions, proteins can distinguish between molecules and bind a partner with incredible affinity and specificity. Scientists have developed, and continue to develop, techniques to investigate and better understand molecular recognition. As a consequence, analyte-responsive hydrogels that mimic these recognitive processes have emerged as a class of intelligent materials. These materials are unique not only in the type of analyte to which they respond but also in how molecular recognition is achieved and how the hydrogel responds to the analyte. Traditional intelligent hydrogels can respond to environmental cues such as pH, temperature, and ionic strength. The functional monomers used to make these hydrogels can be varied to achieve responsive behavior. For analyte-responsive hydrogels, molecular recognition can also be achieved by incorporating biomolecules with inherent molecular recognition properties (e.g., nucleic acids, peptides, enzymes, etc.) into the polymer network. Furthermore, in addition to typical swelling/syneresis responses, these materials exhibit unique responsive behaviors, such as gel assembly or disassembly, upon interaction with the target analyte. With the diverse tools available for molecular recognition and the ability to generate unique responsive behaviors, analyte-responsive hydrogels have found great utility in a wide range of applications. In this Account, we discuss strategies for making four different classes of analyte-responsive hydrogels, specifically, nonimprinted, molecularly imprinted, biomolecule-containing, and enzymatically responsive hydrogels. Then we explore how these materials have been incorporated into sensors and drug delivery systems, highlighting examples that demonstrate the versatility of these materials. For example, in addition to the molecular recognition properties of analyte-responsive hydrogels, the physicochemical changes that are induced upon analyte binding can be exploited to generate a detectable signal for sensing applications. As research in this area has grown, a number of creative approaches for improving the selectivity and sensitivity (i.e., detection limit) of these sensors have emerged. For applications in drug delivery systems, therapeutic release can be triggered by competitive molecular interactions or physicochemical changes in the network. Additionally, including degradable units within the network can enable sustained and responsive therapeutic release. Several exciting examples exploiting the analyte-responsive behavior of hydrogels for the treatment of cancer, diabetes, and irritable bowel syndrome are discussed in detail. We expect that creative and combinatorial approaches used in the design of analyte-responsive hydrogels will continue to yield materials with great potential in the fields of sensing and drug delivery.

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Section: Classes Of Analyte-sensitive Materialsmentioning

confidence: 99%

Analyte-Responsive Hydrogels: Intelligent Materials for Biosensing and Drug Delivery

2017

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“…9, 10 As microparticles swell, the dispersions become more optically transparent, and the refractive index of the swollen microparticle dispersion approaches that of the solvent. Therefore, the swelling of microparticle dispersions reduces the turbidity.…”

Section: Resultsmentioning

confidence: 99%

Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX

Horava

Peppas

2016

Ann Biomed Eng

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The oral administration of hematological factor IX can offer a convenient prophylactic treatment for hemophilia B patients. pH-Responsive hydrogels based on poly(methacrylic acid)-grafted-poly(ethylene glycol) (P(MAA-g-EG)) have been engineered as delivery vehicles for factor IX. In oral delivery, such hydrogel carriers protected factor IX from the gastric environment and released it under intestinal conditions as demonstrated by evaluation of the loading and release of factor IX. Tailoring of the hydrogel networks improved the loading of factor IX within the microcarriers, which is critical for minimizing protein degradation. Optimizing the loading conditions by increasing the incubation time and using a reduced ionic strength buffer further improved the delivery potential of the microcarriers. The presence of the microcarriers significantly enhanced the oral absorption of factor IX in vitro. As shown in this work, P(MAA-g-EG) microcarriers are promising candidates for the oral delivery of factor IX.

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“…Enzymatically degradable hydrogels using peptide crosslinks were prepared as described by Knipe et al[34] Uncrosslinked P(MAA-co-NVP) polymer was prepared by UV-initiated free radical polymerization. Methacrylic acid (Sigma-Aldrich) and N-vinylpyrrolidone (Sigma-Aldrich) were added to a 50:50 w/w mixture of water and ethanol at a molar ratio of 1:1 MAA:NVP and 30 wt% monomer to total solution weight.…”

Section: Methodsmentioning

confidence: 99%

pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery

Koetting

Guido

Gupta

et al. 2016

Journal of Controlled Release

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Two potential platform technologies for the oral delivery of protein therapeutics were synthesized and tested. pH-Responsive poly(itaconic acid-co-N-vinyl-2-pyrrolidone) (P(IA-co-NVP)) hydrogel microparticles were tested in vitro with model proteins salmon calcitonin, urokinase, and rituximab to determine the effects of particle size, protein size, and crosslinking density on oral delivery capability. Particle size showed no significant effect on overall delivery potential but did improve percent release of encapsulated protein over the micro-scale particle size range studied. Protein size was shown to have a significant impact on the delivery capability of the P(IA-co-NVP) hydrogel. We show that when using P(IA-co-NVP) hydrogel microparticles with 3 mol% tetra(ethylene glycol) dimethacrylate crosslinker, a small polypeptide (salmon calcitonin) loads and releases up to 45 μg/mg hydrogel while the mid-sized protein urokinase and large monoclonal antibody rituximab load and release only 19 and 24 μg/mg hydrogel, respectively. We further demonstrate that crosslinking density offers a simple method for tuning hydrogel properties to variously sized proteins. Using 5 mol% TEGDMA crosslinker offers optimal performance for the small peptide, salmon calcitonin, whereas lower crosslinking density of 1 mol% offers optimal performance for the much larger protein rituximab. Finally, an enzymatically-degradable hydrogels of P(MAA-co-NVP) crosslinked with the peptide sequence MMRRRKK were synthesized and tested in simulated gastric and intestinal conditions. These hydrogels offer ideal loading and release behavior, showing no degradative release of encapsulated salmon calcitonin in gastric conditions while yielding rapid and complete release of encapsulated protein within 1 h in intestinal conditions.

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Enzymatic Biodegradation of Hydrogels for Protein Delivery Targeted to the Small Intestine

Cited by 77 publications

References 63 publications

Analyte-Responsive Hydrogels: Intelligent Materials for Biosensing and Drug Delivery

Analyte-Responsive Hydrogels: Intelligent Materials for Biosensing and Drug Delivery

Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX

pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery

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