Development of a PEG Derivative Containing Hydrolytically Degradable Hemiacetals

Reid, Branden; Tzeng, Stephany Y.; Warren, Andrew C.; Kozielski, Kristen L.; Elisseeff, Jennifer H.

doi:10.1021/ma1020648

Cited by 33 publications

(42 citation statements)

References 23 publications

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“…Another interesting approach was reported by Elisseeff and coworkers, where the Fenton reaction of hydrogen peroxide and ferric chloride at a neutral pH was utilized to partially degrade PEG to introduce hemiacetals randomly into its backbone, which is then hydrolyzable into aldehydes and alcohols under acidic conditions [51]. …”

Section: Degradable Synthetic Peg Alternativesmentioning

confidence: 99%

Protein–polymer conjugation — moving beyond PEGylation

Chilkoti

2015

Current Opinion in Chemical Biology

156

120

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In this review, we summarize —from a materials science perspective— the current state of the field of polymer conjugates of peptide and protein drugs, with a focus on polymers that have been developed as alternatives to the current gold standard, poly(ethylene glycol) (PEG). PEGylation, or the covalent conjugation of PEG to biological therapeutics to improve their therapeutic efficacy by increasing their circulation half-lives and stability, has been the gold standard in the pharmaceutical industry for several decades. After years of research and development, the limitations of PEG, specifically its non-degradability and immunogenicity have become increasingly apparent. While PEG is still currently the best polymer available with the longest clinical track record, extensive research is underway to develop alternative materials in an effort to address these limitations of PEG. Many of these alternative materials have shown promise, though most of them are still in an early stage of development and their in vivo distribution, mechanism of degradation, route of elimination and immunogenicity have not been investigated to a similar extent as for PEG. Thus, further in-depth in vivo testing is essential to validate whether any of the alternative materials discussed in this review qualify as a replacement for PEG.

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Section: Degradable Synthetic Peg Alternativesmentioning

confidence: 99%

Protein–polymer conjugation — moving beyond PEGylation

Chilkoti

2015

Current Opinion in Chemical Biology

156

120

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“…[8–13] Similarly, PEG-based hydrogel devices with a breadth of in vivo lifetimes have been developed by modifying endgroup chemistries and/or by using co-polymerizations to adjust degradation profiles. [1, 10, 14–17]…”

Section: Introductionmentioning

confidence: 99%

Determination of thein vivodegradation mechanism of PEGDA hydrogels

Browning

Cereceres

Luong

et al. 2014

J. Biomed. Mater. Res.

160

172

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Poly(ethylene glycol) (PEG) hydrogels are one of the most extensively utilized biomaterials systems due to their established biocompatibility and highly tunable properties. It is widely acknowledged that traditional acrylate-derivatized PEG (PEGDA) hydrogels are susceptible to slow degradation in vivo and are therefore unsuitable for long-term implantable applications. However, there is speculation whether the observed degradation is due to hydrolysis of endgroup acrylate esters or oxidation of the ether backbone both of which are possible in the foreign body response to implanted devices. PEG diacrylamide (PEGDAA) is a polyether-based hydrogel system with similar properties to PEGDA but with amide linkages in place of the acrylate esters. This provides a hydrolytically-stable control that can be used to isolate the relative contributions of hydrolysis and oxidation to the in vivo degradation of PEGDA. Here we show that PEGDAA hydrogels remained stable over 12 weeks of subcutaneous implantation in a rat model while PEGDA hydrogels underwent significant degradation as indicated by both increased swelling ratio and decreased modulus. As PEGDA and PEGDAA have similar susceptibility to oxidation, these results demonstrate for the first time that the primary in vivo degradation mechanism of PEGDA is hydrolysis of the endgroup acrylate ester. Additionally, the maintenance of PEGDAA hydrogel properties in vivo indicates their suitability for long-term implants. These studies serve to elucidate key information about a widely used biomaterial system to allow for better implantable device design and to provide a biostable replacement option for PEGDA in applications that require long-term stability.

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“…However, PEG is not biodegradable and only those with low molecular weights (MW < 5000) can be metabolized by the human body [114]. As a result, several functional groups are introduced into PEG molecules to provide degradability and also more utility [115,116]. Several PEG-based materials have been tested in therapeutic angiogenesis: VEGF and the integrin-binding domain RGD has been linked to a PEG gel.…”

Section: Controlled Delivery Of Angiogenic Factorsmentioning

confidence: 99%

Therapeutic Angiogenesis: Controlled Delivery of Angiogenic Factors

Chu

Wang

2012

Therapeutic Delivery

126

132

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Therapeutic angiogenesis aims at treating ischemic diseases by generating new blood vessels from existing vasculature. It relies on delivery of exogenous factors to stimulate neovasculature formation. Current strategies using genes, proteins and cells have demonstrated efficacy in animal models. However, clinical translation of any of the three approaches has proved to be challenging for various reasons. Administration of angiogenic factors is generally considered safe, according to accumulated trials, and offers off-the-shelf availability. However, many hurdles must be overcome before therapeutic angiogenesis can become a true human therapy. This article will highlight protein-based therapeutic angiogenesis, concisely review recent progress and examine critical challenges. We will discuss growth factors that have been widely utilized in promoting angiogenesis and compare their targets and functions. Lastly, since bolus injection of free proteins usually result in poor outcomes, we will focus on controlled release of proteins.Blood vessels that carry oxygen, nutrients, cells and signals are critical in both developmental and adult physiology. Without sufficient blood supply, tissues and organs cannot maintain regular activities. On the other hand, induction of neovasculature provides a potential strategy to treat many ischemic illnesses, especially cardiovascular diseases (CVDs) including coronary and peripheral arterial diseases. The morbidity, mortality and cost of CVDs are highlighted by the latest statistics from the American Heart Association [1]: an estimated 82,600,000 American adults (≥20 years old) have one or more types of CVDs; CVDs caused 813,804 of all 2,243,712 deaths (33.6%) or one of every 2.9 deaths in 2007, and coronary heart disease caused approximately one of every six deaths. The direct and indirect cost of CVD was estimated to be US$286 billion in 2007. The amount is higher than the $228 billion spent on cancer and benign neoplasms. As a potential therapy to revascularize ischemic tissues, including ischemic heart, therapeutic angiogenesis has drawn much attention in the last 20 years.Neovasculature can be obtained by three approaches based on different mechanisms: promoting expression of angiogenic genes, supplying potent angiogenic factors and delivering progenitor or stem cells. No matter which approach is used, angiogenic activity has to be precisely controlled in order to achieve stable vascularization. For cell delivery, the

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Development of a PEG Derivative Containing Hydrolytically Degradable Hemiacetals

Cited by 33 publications

References 23 publications

Protein–polymer conjugation — moving beyond PEGylation

Protein–polymer conjugation — moving beyond PEGylation

Determination of thein vivodegradation mechanism of PEGDA hydrogels

Therapeutic Angiogenesis: Controlled Delivery of Angiogenic Factors

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