Diels–Alder hydrogels with enhanced stability: First step toward controlled release of bevacizumab

Kirchhof, Susanne; Gregoritza, Manuel; Messmann, Viktoria; Hammer, Nadine; Goepferich, Achim; Brandl, Fabian

doi:10.1016/j.ejpb.2015.07.024

Cited by 40 publications

(35 citation statements)

References 34 publications

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“…Kichhoff et al have demonstrated this by creating an eight-arm PEG hydrogel and adding a hydrophobic 6-aminohexanoic acid spacer between the PEG and reactive end groups for increased stability. This resulted in reduced burst release, and prolonged degradation time, with sustained release of anti-VEGF for up to 6 weeks in vitro [88]. The hydrogel is currently being validated for biocompatibility in in vivo models of choroidal neovascularization.…”

Section: Hydrogels For Sustained Delivery Of Anti-vegfmentioning

confidence: 99%

Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases

Seah

Zhao

Lin

et al. 2020

Eye

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Anti-vascular endothelial growth factors (anti-VEGF) have become the most common treatment modality for many retinal diseases. These include neovascular age-related macular degeneration (n-AMD), proliferative diabetic retinopathy (PDR) and retinal vein occlusions (RVO). However, these drugs are administered via intravitreal injections that are associated with sight-threatening complications. The most feared of these complications is endophthalmitis, a severe infection of the eye with extremely poor visual outcomes. Patients with retinal diseases typically have to undergo multiple injections before achieving the desired therapeutic effect. Each injection incurs the risk of the sight-threatening complications. As such, there has been great interest in developing sustained delivery platforms for anti-VEGF agents to the posterior segment of the eye. In recent years, there have been various strategies that have been conceptualised. These include non-biodegradable implants, nano-formulations and hydrogels. In this review, the barriers of drug delivery to the posterior segment of the eye will be explained. The characteristics of an ideal sustained delivery platform will then be discussed. Finally, the current available strategies will be analysed with the above-mentioned characteristics in mind to determine the advantages and disadvantages of each sustained drug delivery modality. Through the above, this review attempts to provide an overview of the sustained delivery platforms in their various phases of development.These authors contributed equally: Ivan Seah Yu Jun, Zhao Xin Xin 1234567890();,:1234567890();,:

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Section: Hydrogels For Sustained Delivery Of Anti-vegfmentioning

confidence: 99%

Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases

Seah

Zhao

Lin

et al. 2020

Eye

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“…26 The complete functionalization with Boc-6-aminohexanoic acid was confirmed by a fluorescamine assay. Following this procedure, the obtained 8armPEG40k-C 6 -NH-Boc was deprotected (8armPEG40k-C 6 -NH 2 ) and subsequently functionalized with furyl (8armPEG40k-C 6 -furan) or maleimide groups (8armPEG40k-C 6 -maleimide) as described above.…”

Section: Synthesis Of Hydrophobically Modified Macromonomers (Scheme 2)mentioning

confidence: 99%

“…26 The polymer concentrations were 5% (w/V), 10% (w/V) and 15% (w/V). For the release experiments, 8armPEG40k, 8armPEG40k-C 6 and 8armPEG40k-C 12 hydrogels were loaded with bevacizumab (Avastin s ); cross-linking was carried out in 5 mM acetate buffer, pH 5.0.…”

Section: Swelling Degradation and Antibody Releasementioning

confidence: 99%

“…The in vitro release of bevacizumab was determined in phosphate buffer, pH 7.4 at 37 1C as previously described. 26 Hydrolytic stability of maleimides In order to investigate the hydrolytic stability of maleimides, 20.0 mg of 8armPEG40k-maleimide, 8armPEG40k-C 6 -maleimide or 8armPEG40k-C 12 -maleimide were dissolved in 2.0 mL of 50 mM phosphate buffer, pH 7.4. The polymer solutions were transferred into 10 mm quartz cuvettes.…”

Section: Swelling Degradation and Antibody Releasementioning

confidence: 99%

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Design of hydrogels for delayed antibody release utilizing hydrophobic association and Diels–Alder chemistry in tandem

et al. 2016

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Biodegradable hydrogels were prepared from furan-and maleimide-functionalized eight-armed poly-(ethylene glycol) with an average molecular mass of 40 000 Da (8armPEG40k-furan and 8armPEG40k-maleimide) using the Diels-Alder (DA) reaction as a cross-linking mechanism. Hydrophobic 6-aminohexanoic acid (C 6 ) and 12-aminododecanoic acid (C 12 ) spacers were introduced between the polymer backbone and the functional end-groups; the influence on the gel properties was studied. Modification with C 6 and C 12 spacers induced hydrophobic interactions between the macromonomers leading to association and increased viscosity of the polymer solutions; both effects were influenced by the spacer length. In combination with DA cross-linking, hydrophobic derivatives of 8armPEG40k-furan and 8armPEG40k-maleimide led to hydrogels with improved properties. Upon introduction of C 12 spacers, gelation of 8armPEG40k hydrogels occurred twice as fast. Interestingly, no effect was observed when only one of the two components had been modified. Our experiments suggest that the association of macromonomers by hydrophobic interactions facilitates chemical cross-linking via DA chemistry. This hypothesis is supported by calculations of the network mesh size and the Young's modulus of compression, which showed an increased cross-linking density of hydrophobically modified hydrogels. As a consequence of the increased cross-linking density, the degradation stability of C 12 -modified hydrogels increased by a factor of 4.Moreover, hydrophobic modification improved the hydrolytic resistance of maleimides; this also contributes to gel stability. The in vitro release of bevacizumab, which served as a model antibody, could be delayed for almost 60 days using modification with C 12 . Similar trends were observed for C 6 -modified 8armPEG40k hydrogels; however, the effects were considerably weaker. In summary, utilizing hydrophobic association and chemical cross-linking in tandem is a promising approach to create biodegradable hydrogels for delayed antibody release.

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“…In most of the applications in polymer science, the Diels‐Alder ‘click’ reaction has been used as a tool for conjugation of two different molecular or macromolecular constructs ,. Examples in fabrication of polymeric materials include construction of dendrimers through combination of dendrons bearing diene and dienophile groups at their focal points,, synthesis of diblock or graft copolymers,, or various network structures ,. In most instances, the coupled utilization of retro Diels‐Alder reaction is not present, other than in fabrication of self‐healable materials.…”

Section: The Diels‐alder Reaction Based Protection‐deprotection Sequencementioning

confidence: 99%

The Taming of the Maleimide: Fabrication of Maleimide‐Containing ‘Clickable’ Polymeric Materials

Sanyal

2017

The Chemical Record

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Functional polymers are widely employed in various areas of biomedical sciences. In order to tailor them for desired applications, facile and efficient functionalization of these polymeric materials under mild and benign conditions is important. Polymers containing reactive maleimide groups can be employed for such applications since they provide an excellent handle for conjugation of thiol- and diene-containing molecules and biomolecules. Until recently, fabrication of maleimide containing polymeric materials has been challenging due to the interference from the highly reactive double bond. A Diels-Alder/retro Diels-Alder reaction sequence based strategy to transiently mask the maleimide group provides access to such polymeric materials. In this personal account, we summarize contributions from our group towards the fabrication and functionalization of maleimide-containing polymeric materials over the past decade.

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Diels–Alder hydrogels with enhanced stability: First step toward controlled release of bevacizumab

Cited by 40 publications

References 34 publications

Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases

Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases

Design of hydrogels for delayed antibody release utilizing hydrophobic association and Diels–Alder chemistry in tandem

The Taming of the Maleimide: Fabrication of Maleimide‐Containing ‘Clickable’ Polymeric Materials

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